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  • 1.
    Artur de la Villarmois, Emilce
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Gabach, Laura A
    Bianconi, Santiago
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Poretti, Maria Belen
    Occhieppo, Victoria
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Carlini, Valeria P
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Pérez, Mariela Fernanda
    Pharmacological NOS-1 Inhibition Within the Hippocampus Prevented Expression of Cocaine Sensitization: Correlation with Reduced Synaptic Transmission.2019In: Molecular Neurobiology, ISSN 0893-7648, E-ISSN 1559-1182Article in journal (Refereed)
    Abstract [en]

    Behavioral sensitization to psychostimulants hyperlocomotor effect is a useful model of addiction and craving. Particularly, cocaine sensitization in rats enhanced synaptic plasticity within the hippocampus, an important brain region for the associative learning processes underlying drug addiction. Nitric oxide (NO) is a neurotransmitter involved in both, hippocampal synaptic plasticity and cocaine sensitization. It has been previously demonstrated a key role of NOS-1/NO/sGC/cGMP signaling pathway in the development of cocaine sensitization and in the associated enhancement of hippocampal synaptic plasticity. The aim of the present investigation was to determine whether NOS-1 inhibition after development of cocaine sensitization was able to reverse it, and to characterize the involvement of the hippocampus in this phenomenon. Male Wistar rats were administered only with cocaine (15 mg/kg/day i.p.) for 5 days. Then, animals received 7-nitroindazole (NOS-1 inhibitor) either systemically for the next 5 days or a single intra-hippocampal administration. Development of sensitization and its expression after withdrawal were tested, as well as threshold for long-term potentiation in hippocampus, NOS-1, and CREB protein levels and gene expression. The results showed that NOS-1 protein levels and gene expression were increased only in sensitized animals as well as CREB gene expression. NOS-1 inhibition after sensitization reversed behavioral expression and the highest level of hippocampal synaptic plasticity. In conclusion, NO signaling within the hippocampus is critical for the development and expression of cocaine sensitization. Therefore, NOS-1 inhibition or NO signaling pathways interferences during short-term withdrawal after repeated cocaine administration may represent plausible pharmacological targets to prevent or reduce susceptibility to relapse.

  • 2.
    Bazov, Igor
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Sarkisyan, Daniil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Kononenko, Olga
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Watanabe, Hiroyuki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Yakovleva, Tatiana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hansson, Anita C
    Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Inst Psychopharmacol, D-68159 Mannheim, Germany.
    Sommer, Wolfgang H
    Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Inst Psychopharmacol, D-68159 Mannheim, Germany.
    Spanagel, Rainer
    Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Inst Psychopharmacol, D-68159 Mannheim, Germany.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Dynorphin and κ-Opioid Receptor Dysregulation in the Dopaminergic Reward System of Human Alcoholics.2018In: Molecular Neurobiology, ISSN 0893-7648, E-ISSN 1559-1182, Vol. 55, no 8, p. 7049-7061Article in journal (Refereed)
    Abstract [en]

    Molecular changes induced by excessive alcohol consumption may underlie formation of dysphoric state during acute and protracted alcohol withdrawal which leads to craving and relapse. A main molecular addiction hypothesis is that the upregulation of the dynorphin (DYN)/κ-opioid receptor (KOR) system in the nucleus accumbens (NAc) of alcohol-dependent individuals causes the imbalance in activity of D1- and D2 dopamine receptor (DR) expressing neural circuits that results in dysphoria. We here analyzed post-mortem NAc samples of human alcoholics to assess changes in prodynorphin (PDYN) and KOR (OPRK1) gene expression and co-expression (transcriptionally coordinated) patterns. To address alterations in D1- and D2-receptor circuits, we studied the regulatory interactions between these pathways and the DYN/KOR system. No significant differences in PDYN and OPRK1 gene expression levels between alcoholics and controls were evident. However, PDYN and OPRK1 showed transcriptionally coordinated pattern that was significantly different between alcoholics and controls. A downregulation of DRD1 but not DRD2 expression was seen in alcoholics. Expression of DRD1 and DRD2 strongly correlated with that of PDYN and OPRK1 suggesting high levels of transcriptional coordination between these gene clusters. The differences in expression and co-expression patterns were not due to the decline in neuronal proportion in alcoholic brain and thereby represent transcriptional phenomena. Dysregulation of DYN/KOR system and dopamine signaling through both alterations in co-expression patterns of opioid genes and decreased DRD1 gene expression may contribute to imbalance in the activity of D1- and D2-containing pathways which may lead to the negative affective state in human alcoholics.

  • 3.
    Borroto-Escuela, Dasiel O.
    et al.
    Karolinska Inst, Dept Neurosci, Biomed, Stockholm, Sweden; Univ Urbino, Dept Biomol Sci, Sect Physiol, Campus Sci Enrico Mattei, Urbino, Italy; Grp Bohio Estudio, Observ Cubano Neurociencias, Yaguajay, Cuba.
    Narváez, Manuel
    Univ Malaga, Inst Invest Biomed Malaga, Fac Med, Malaga, Spain.
    Romero Fernández, Wilber
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pinton, Luca
    Karolinska Inst, Dept Neurosci, Biomed, Stockholm, Sweden.
    Wydra, Karolina
    Polish Acad Sci, Inst Pharmacol, Dept Drug Addict Pharmacol, Krakow, Poland.
    Filip, Malgorzata
    Polish Acad Sci, Inst Pharmacol, Dept Drug Addict Pharmacol, Krakow, Poland.
    Beggiato, Sarah
    Univ Ferrara, Dept Life Sci & Biotechnol SVEB, Ferrara, Italy.
    Tanganelli, Sergio
    Univ Ferrara, Dept Life Sci & Biotechnol SVEB, Ferrara, Italy.
    Ferraro, Luca
    Univ Ferrara, Dept Life Sci & Biotechnol SVEB, Ferrara, Italy.
    Fuxe, Kjell
    Karolinska Inst, Dept Neurosci, Biomed, Stockholm, Sweden.
    Acute Cocaine Enhances Dopamine D2R Recognition and Signaling and Counteracts D2R Internalization in Sigma1R-D2R Heteroreceptor Complexes2019In: Molecular Neurobiology, ISSN 0893-7648, E-ISSN 1559-1182, Vol. 56, no 10, p. 7045-7055Article in journal (Refereed)
    Abstract [en]

    The current study was performed to establish the actions of nanomolar concentrations of cocaine, not blocking the dopamine transporter, on dopamine D2 receptor (D2R)-sigma 1 receptor (delta 1R) heteroreceptor complexes and the D2R protomer recognition, signaling and internalization in cellular models. We report the existence of D2R-delta 1R heteroreceptor complexes in subcortical limbic areas as well as the dorsal striatum, with different distribution patterns using the in situ proximity ligation assay. Also, through BRET, these heteromers were demonstrated in HEK293 cells. Furthermore, saturation binding assay demonstrated that in membrane preparations of HEK293 cells coexpressing D2R and delta 1R, cocaine (1 nM) significantly increased the D2R B-max values over cells singly expressing D2R. CREB reporter luc-gene assay indicated that coexpressed delta 1R significantly reduced the potency of the D2R-like agonist quinpirole to inhibit via D2R activation the forskolin induced increase of the CREB signal. In contrast, the addition of 100 nM cocaine was found to markedly increase the quinpirole potency to inhibit the forskolin-induced increase of the CREB signal in the D2R-delta 1R cells. These events were associated with a marked reduction of cocaine-induced internalization of D2R protomers in D2R-delta 1R heteromer-containing cells vs D2R singly expressing cells as studied by means of confocal analysis of D2R-delta 1R trafficking and internalization. Overall, the formation of D2R-delta 1R heteromers enhanced the ability of cocaine to increase the D2R protomer function associated with a marked reduction of its internalization. The existence of D2R-delta 1R heteromers opens up a new understanding of the acute actions of cocaine.

  • 4.
    Borroto-Escuela, Dasiel O.
    et al.
    Univ Urbino, Dept Biomol Sci, Sect Physiol, Campus Sci Enrico Mattei,Via Ca le Suore 2, I-61029 Urbino, Italy;Grp Bohio Estudio, Observ Cubano Neurociencias, Zayas 50, Yaguajay 62100, Cuba;Karolinska Inst, Dept Neurosci, Retzius Vag 8, S-17177 Stockholm, Sweden.
    Wydra, Karolina
    Polish Acad Sci, Inst Pharmacol, Dept Drug Addict Pharmacol, 12 Smetna St, PL-31343 Krakow, Poland.
    Li, Xiang
    Jilin Univ, Coll Life Sci, Qianjin St 2699, Changchun 130012, Jilin, Peoples R China;Karolinska Inst, Dept Neurosci, Retzius Vag 8, S-17177 Stockholm, Sweden.
    Rodriguez, David
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab. Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, SE-10691 Stockholm, Sweden.
    Carlsson, Jens
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab. Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, SE-10691 Stockholm, Sweden.
    Jastrzebska, Joanna
    Polish Acad Sci, Inst Pharmacol, Dept Drug Addict Pharmacol, 12 Smetna St, PL-31343 Krakow, Poland.
    Filip, Malgorzata
    Polish Acad Sci, Inst Pharmacol, Dept Drug Addict Pharmacol, 12 Smetna St, PL-31343 Krakow, Poland.
    Fuxe, Kjell
    Karolinska Inst, Dept Neurosci, Retzius Vag 8, S-17177 Stockholm, Sweden.
    Disruption of A2AR-D2R Heteroreceptor Complexes After A2AR Transmembrane 5 Peptide Administration Enhances Cocaine Self-Administration in Rats2018In: Molecular Neurobiology, ISSN 0893-7648, E-ISSN 1559-1182, Vol. 55, no 8, p. 7038-7048Article in journal (Refereed)
    Abstract [en]

    Antagonistic allosteric A2AR-D2R receptor-receptor interactions in heteroreceptor complexes counteract cocaine self-administration and cocaine seeking in rats as seen in biochemical and behavioral experiments. It was shown that the human A2AR transmembrane five (TM5) was part of the interface of the human A2AR-D2R receptor heteromer. In the current paper, the rat A2AR synthetic TM5 (synthTM5) peptide disrupts the A2AR-D2R heteroreceptor complex in HEK293 cells as shown by the bioluminescence resonance energy transfer method. Rat A2AR synthTM5 peptide, microinjected into the nucleus accumbens, produced a complete counteraction of the inhibitory effects of the A2AR agonist CGS21680 on cocaine self-administration. It was linked to a disappearance of the accumbal A2AR-D2R heteroreceptor complexes and the A2AR agonist induced inhibition of D2R recognition using proximity ligation assay and biochemical binding techniques. However, possible effects of the A2AR synthTM5 peptide on accumbal A2AR-D3R and A2AR-D4R heteroreceptor complexes remain to be excluded. Evidence is provided that accumbal A2AR-D2R-like heteroreceptor complexes with their antagonistic receptor-receptor interactions can be major targets for treatment of cocaine use disorder.

  • 5.
    Feng, Lianyuan
    et al.
    Bethune Int Peace Hosp, Dept Neurol, Zhongshan Rd West, Shijiazhuang, Hebei, Peoples R China..
    Sharma, Aruna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Niu, Feng
    CSPC NBP Pharmaceut Med, Zhongshan Rd West, Shijiazhuang, Hebei, Peoples R China..
    Huang, Yin
    CSPC NBP Pharmaceut Med, Zhongshan Rd West, Shijiazhuang, Hebei, Peoples R China..
    Vicente Lafuente, Jose
    Univ Basque Country UPV EHU, Dept Neurosci, LaNCE, Leioa, Bizkaia, Spain.;BioCruces Hlth Res Inst, Nanoneurosurg Grp, Baracaldo 48903, Bizkaia, Spain.;Univ Autonoma Chile, Fac Hlth Sci, Santiago, Chile..
    Muresanu, Dafin Fior
    RoNeuro Inst Neurol Res & Diagnost, 37 Mircea Eliade St, Cluj Napoca 400364, Romania.;Univ Med & Pharm, Dept Clin Neurosci, Cluj Napoca, Romania..
    Ozkizilcik, Asya
    Univ Arkansas, Dept Biomed Engn, Fayetteville, AR 72701 USA..
    Tian, Z. Ryan
    Univ Arkansas, Dept Chem & Biochem, J William Fulbright Coll Arts & Sci, Fayetteville, AR 72701 USA..
    Sharma, Hari Shanker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala Univ, Univ Hosp, Int Expt CNS Injury & Repair IECNSIR, Frodingsgatan 12,Bldg 28, SE-75421 Uppsala, Sweden..
    TiO2-Nanowired Delivery of DL-3-n-butylphthalide (DL-NBP) Attenuates Blood-Brain Barrier Disruption, Brain Edema Formation, and Neuronal Damages Following Concussive Head Injury2018In: Molecular Neurobiology, ISSN 0893-7648, E-ISSN 1559-1182, Vol. 55, no 1, p. 350-358Article in journal (Refereed)
    Abstract [en]

    DL-3-n-butylphthalide (DL-NBP) is one of the constituents of Chinese celery extract that is used to treat stroke, dementia, and ischemic diseases. However, its role in traumatic brain injury is less well known. In this investigation, neuroprotective effects of DL-NBP in concussive head injury (CHI) on brain pathology were explored in a rat model. CHI was inflicted in anesthetized rats by dropping a weight of 114.6 g from a height of 20 cm through a guide tube on the exposed right parietal bone inducing an impact of 0.224 N and allowed them to survive 4 to 24 h after the primary insult. DL-NBP was administered (40 or 60 mg/kg, i.p.) 2 and 4 h after injury in 8-h survival group and 8 and 12 h after trauma in 24-h survival group. In addition, TiO2-nanowired delivery of DL-NBP (20 or 40 mg/kg, i.p.) in 8 and 24 h CHI rats was also examined. Untreated CHI showed a progressive increase in blood-brain barrier (BBB) breakdown to Evans blue albumin (EBA) and radioiodine (I[131]-), edema formation, and neuronal injuries. The magnitude and intensity of these pathological changes were most marked in the left hemisphere. Treatment with DL-NBP significantly reduced brain pathology in CHI following 8 to 12 h at 40-mg dose. However, 60-mg dose is needed to thwart brain pathology at 24 h following CHI. On the other hand, TiO2-DL-NBP was effective in reducing brain damage up to 8 or 12 h using a 20-mg dose and only 40-mg dose was needed for neuroprotection in CHI at 24 h. These observations are the first to suggest that (i) DL-NBP is quite effective in reducing brain pathology and (ii) nanodelivery of DL-NBP has far more superior effects in CHI, not reported earlier.

  • 6.
    Muresanu, Dafin F.
    et al.
    RoNeuro Inst Neurol Res & Diagnost, Cluj Napoca, Romania.;Univ Med & Pharm Iuliu Haticganu, Dept Clin Neurosci, Cluj Napoca, Romania..
    Sharma, Aruna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Lafuente, Jose V.
    Univ Basque Country, Dept Neurosci, LaNCE, Bilbao, Spain.;Univ Autonoma Chile, Fac Hlth Sci, Santiago, Chile..
    Patnaik, Ranjana
    Banaras Hindu Univ, Sch Biomed Engn, Indian Inst Technol, Dept Biomat, Varanasi 221005, Uttar Pradesh, India..
    Tian, Z. Ryan
    Univ Arkansas, Dept Chem & Biochem, Fayetteville, AR 72701 USA..
    Nyberg, Fred
    Uppsala Univ, Biomed Ctr, Dept Pharmaceut Biosci Biol Res Drug Dependence, Uppsala, Sweden..
    Sharma, Hari S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Univ Basque Country, Dept Neurosci, LaNCE, Bilbao, Spain..
    Nanowired Delivery of Growth Hormone Attenuates Pathophysiology of Spinal Cord Injury and Enhances Insulin-Like Growth Factor-1 Concentration in the Plasma and the Spinal Cord2015In: Molecular Neurobiology, ISSN 0893-7648, E-ISSN 1559-1182, Vol. 52, no 2, p. 837-845Article in journal (Refereed)
    Abstract [en]

    Previous studies from our laboratory showed that topical application of growth hormone (GH) induced neuroprotection 5 h after spinal cord injury (SCI) in a rat model. Since nanodelivery of drugs exerts superior neuroprotective effects, a possibility exists that nanodelivery of GH will induce long-term neuroprotection after a focal SCI. SCI induces GH deficiency that is coupled with insulin-like growth factor-1 (IGF-1) reduction in the plasma. Thus, an exogenous supplement of GH in SCI may enhance the IGF-1 levels in the cord and induce neuroprotection. In the present investigation, we delivered TiO2-nanowired growth hormone (NWGH) after a longitudinal incision of the right dorsal horn at the T10-11 segments in anesthetized rats and compared the results with normal GH therapy on IGF-1 and GH contents in the plasma and in the cord in relation to blood-spinal cord barrier (BSCB) disruption, edema formation, and neuronal injuries. Our results showed a progressive decline in IGF-1 and GH contents in the plasma and the T9 and T12 segments of the cord 12 and 24 h after SCI. Marked increase in the BSCB breakdown, as revealed by extravasation of Evans blue and radioiodine, was seen at these time points after SCI in association with edema and neuronal injuries. Administration of NWGH markedly enhanced the IGF-1 levels and GH contents in plasma and cord after SCI, whereas normal GH was unable to enhance IGF-1 or GH levels 12 or 24 h after SCI. Interestingly, NWGH was also able to reduce BSCB disruption, edema formation, and neuronal injuries after trauma. On the other hand, normal GH was ineffective on these parameters at all time points examined. Taken together, our results are the first to demonstrate that NWGH is quite effective in enhancing IGF-1 and GH levels in the cord and plasma that may be crucial in reducing pathophysiology of SCI.

  • 7.
    Nylander, Ingrid
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Todkar, Aniruddha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Granholm, Linnea
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Vrettou, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuro-psycho-pharmacology.
    Bendre, Megha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuro-psycho-pharmacology.
    Boon, Wout
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Andershed, Henrik
    Tuvblad, Catherine
    Nilsson, Kent W
    Centre for Clinical Research, Västerås Central Hospital, Västerås, Sweden.
    Comasco, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuro-psycho-pharmacology.
    Evidence for a Link Between Fkbp5/FKBP5, Early Life Social Relations and Alcohol Drinking in Young Adult Rats and Humans2017In: Molecular Neurobiology, ISSN 0893-7648, E-ISSN 1559-1182, Vol. 54, no 8, p. 6225-6234Article in journal (Refereed)
    Abstract [en]

    Alcohol misuse has been linked to dysregulation of stress, emotion, and reward brain circuitries. A candidate key mediator of this association is the FK506-binding protein (FKBP5), a negative regulator of the glucocorticoid receptor. The aim of the present study was to further understand the Fkbp5/FKBP5-related genetic underpinnings underlying the relationship between early life social relations and alcohol drinking. The effect of maternal separation and voluntary alcohol drinking on Fkbp5 expression was investigated in the brain of young adult rats, whereas the interaction effect of the functional FKBP5 single nucleotide polymorphism rs1360780 genotype and parent-child relationship on problematic drinking was examined in young adult humans. In rats, Fkbp5 expression in the nucleus accumbens and ventral tegmental area, core regions of the reward system, was affected in a region-dependent manner and in opposite direction by maternal separation and alcohol drinking. Fkbp5 expression in the cingulate cortex was affected by the combined effect of maternal separation and alcohol drinking. In humans, the TT genotype, in the presence of a poor relationship between the child and parents, was associated with problematic drinking behavior. The present findings suggest that Fkbp5 expression in mesocorticolimbic dopaminergic regions associates with early life stress-mediated sensitivity to alcohol drinking and that FKBP5 genotype interacts with parent-child relationship to influence alcohol drinking. These findings are the first to point to a role of FKBP5 in propensity to alcohol misuse and call for studies of the underlying molecular mechanisms to identify potential drug targets.

  • 8.
    Ozkizilcik, Asya
    et al.
    Univ Arkansas, Dept Biomed Engn, Fayetteville, AR 72701 USA..
    Sharma, Aruna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala Univ, Univ Hosp, Int Expt CNS Injury & Repair IECNSIR, Frodingsgatan 12,Bldg 28, SE-75421 Uppsala, Sweden..
    Muresanu, Dafin F.
    Univ Med & Pharm, Dept Clin Neurosci, Cluj Napoca, Romania.;RoNeuro Inst Neurol Res & Diagnost, 37 Mircea Eliade St, Cluj Napoca 400364, Romania..
    Lafuente, Jose V.
    Univ Basque Country UPV EHU, Dept Neurosci, LaNCE, Leioa, Biscay, Spain.;BioCruces Hlth Res Inst, Nanoneurosurg Grp, Baracaldo 48903, Biscay, Spain.;Univ Autonoma Chile, Fac Hlth Sci, Santiago, Chile..
    Tian, Z. Ryan
    Univ Arkansas, Chem & Biochem, Fayetteville, AR 72701 USA..
    Patnaik, Ranjana
    Banaras Hindu Univ, Indian Inst Technol, Sch Biomed Engn, Dept Biomat, Varanasi, Uttar Pradesh, India..
    Mössler, Herbert
    RoNeuro Inst Neurol Res & Diagnost, 37 Mircea Eliade St, Cluj Napoca 400364, Romania.;EVER Neuro Pharma, Oberburgau, Austria..
    Sharma, Hari Shanker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala Univ, Univ Hosp, Int Expt CNS Injury & Repair IECNSIR, Frodingsgatan 12,Bldg 28, SE-75421 Uppsala, Sweden.;Univ Basque Country UPV EHU, Dept Neurosci, LaNCE, Leioa, Biscay, Spain..
    Timed Release of Cerebrolysin Using Drug-Loaded Titanate Nanospheres Reduces Brain Pathology and Improves Behavioral Functions in Parkinson's Disease2018In: Molecular Neurobiology, ISSN 0893-7648, E-ISSN 1559-1182, Vol. 55, no 1, p. 359-369Article in journal (Refereed)
    Abstract [en]

    Previous studies from our laboratory show that intraperitoneal injections of 1-metyl-4-phenyl-1,2,3,6-tetrahydropyridin (MPTP, 20 mg/kg) daily within 2-h intervals for 5 days in mice induce Parkinson's disease (PD)-like symptoms on the 8th day. A significant decrease in dopamine (DA) and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) along with a marked decrease in the number of tyrosine hydroxylase (TH)-positive cells in the substantia nigra pars compacta (SNpc) and striatum (STr) confirms the validity of this model for studying PD. Since cerebrolysin (CBL) is a well-balanced composition of several neurotrophic factors and active peptide fragments, in the present investigation we examined the timed release of CBL using titanate nanospheres (TiNS) in treating PD in our mouse model. Our observations show that TiNS-CBL (in a dose of 3 ml/kg, i.v.) given after 2 days of MPTP administration for 5 days resulted in a marked increase in TH-positive cells in the SNpc and STr as compared to normal CBL. Also, TiNS-CBL resulted in significantly higher levels of DA, DOPAC, and HVA in SNpc and STr on the 8th day as compared to normal CBL therapy. TiNS-CBL also thwarted increased alpha-synuclein levels in the brain and in the cerebrospinal fluid (CSF) as well as neuronal nitric oxide synthase (nNOS) in the in PD brain as compared to untreated group. Behavioral function was also significantly improved in MPTP-treated animals that received TiNS-CBL. These observations are the first to demonstrate that timed release of TiNS-CBL has far more superior neuroprotective effects in PD than normal CBL.

  • 9.
    Patnaik, Ranjana
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Banaras Hindu Univ, Indian Inst Technol, Dept Biomat, Sch Biomed Engn, Varanasi, Uttar Pradesh, India..
    Sharma, Aruna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala Univ, Univ Hosp, IECNSIR, Frodingsgatan 12,Bldg 28, SE-75421 Uppsala, Sweden..
    Skaper, Stephen D.
    Univ Padua, Dept Pharmaceut & Pharmacol Sci, Largo E Meneghetti 2, I-35131 Padua, Italy..
    Muresanu, Dafin F.
    RoNeuro Inst Neurol Res & Diagnost, 37 Mircea Eliade St, Cluj Napoca 400364, Romania.;Univ Med & Pharm, Dept Clin Neurosci, Cluj Napoca, Romania..
    Vicente Lafuente, Jose
    Univ Basque Country UPV EHU, Dept Neurosci, LaNCE, Leioa, Bizkaia, Spain.;BioCruces Hlth Res Inst, Nanoneurosurg Grp, Baracaldo 48903, Bizkaia, Spain.;Univ Autonoma Chile, Fac Hlth Sci, Santiago, Chile..
    Castellani, Rudy J.
    Univ Maryland, Dept Pathol, Baltimore, MD 21201 USA..
    Nozari, Ala
    Harvard Univ, Massachusetts Gen Hosp, Anesthesiol, Boston, MA USA..
    Sharma, Hari S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala Univ, Univ Hosp, IECNSIR, Frodingsgatan 12,Bldg 28, SE-75421 Uppsala, Sweden.;Univ Basque Country UPV EHU, Dept Neurosci, LaNCE, Leioa, Bizkaia, Spain..
    Histamine H3 Inverse Agonist BF 2649 or Antagonist with Partial H4 Agonist Activity Clobenpropit Reduces Amyloid Beta Peptide-Induced Brain Pathology in Alzheimer's Disease2018In: Molecular Neurobiology, ISSN 0893-7648, E-ISSN 1559-1182, Vol. 55, no 1, p. 312-321Article in journal (Refereed)
    Abstract [en]

    Alzheimer's disease (AD) is one of the leading causes for disability and death affecting millions of people worldwide. Thus, novel therapeutic strategies are needed to reduce brain pathology associated with AD. In view of increasing awareness regarding involvement of histaminergic pathways in AD, we explored the role of one H3 receptor inverse agonist BF 2649 and one selective H3 receptor antagonist with partial H4 agonist activity in amyloid beta peptide (A beta P) infusion-induced brain pathology in a rat model. AD-like pathology was produced by administering A beta P (1-40) intracerebroventricular (i.c.v.) in the left lateral ventricle (250 ng/10 mu l, once daily) for 4 weeks. Control rats received saline. In separate group of rats, either BF 2649 (1 mg/kg, i.p.) or clobenpropit (1 mg/kg, i.p.) was administered once daily for 1 week after 3weeks of A beta P administration. After 30 days, blood-brain barrier (BBB) breakdown, edema formation, neuronal, glial injuries, and A beta P deposits were examined in the brain. A significant reduction in A beta P deposits along with marked reduction in neuronal or glial reactions was seen in the drug-treated group. The BBB breakdown to Evans blue albumin and radioiodine in the cortex, hippocampus, hypothalamus, and cerebellum was also significantly reduced in these drug-treated groups. Clobenpropit showed superior effects than the BF2649 in reducing brain pathology in AD. Taken together, our observations are the first to show that blockade of H3 and stimulation of H4 receptors are beneficial for the treatment of AD pathology, not reported earlier.

  • 10.
    Requejo, C.
    et al.
    Univ Basque Country UPV EHU, Dept Neurosci, LaNCE, Leioa, Vizcaya, Spain..
    Ruiz-Ortega, J. A.
    Univ Basque Country UPV EHU, Dept Pharmacol, Leioa, Vizcaya, Spain..
    Cepeda, H.
    Univ Basque Country UPV EHU, Dept Neurosci, LaNCE, Leioa, Vizcaya, Spain..
    Sharma, A.
    Uppsala Univ, Int Expt CNS Injury & Repair, Uppsala, Sweden..
    Sharma, H.S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Univ Basque Country UPV EHU, Dept Neurosci, LaNCE, Leioa, Vizcaya, Spain.;Uppsala Univ, Int Expt CNS Injury & Repair, Uppsala, Sweden..
    Ozkizilcik, A.
    Univ Arkansas, Dept Biomed Engn, Fayetteville, AR 72701 USA..
    Tian, R.
    Univ Arkansas, Dept Biomed Engn, Fayetteville, AR 72701 USA.;Univ Arkansas, Dept Chem & Biochem, Fayetteville, AR 72701 USA..
    Moessler, H.
    Ever Neuro Pharma, Drug Discovery & Develop, Oberburgau, Austria..
    Ugedo, L.
    Univ Basque Country UPV EHU, Dept Pharmacol, Leioa, Vizcaya, Spain..
    Lafuente, J. V.
    Univ Basque Country UPV EHU, Dept Neurosci, LaNCE, Leioa, Vizcaya, Spain.;BioCruces Hlth Res Inst, Nanoneurosurg Grp, Baracaldo 48903, Vizcaya, Spain.;Univ Autonoma Chile, Fac Hlth Sci, Santiago, Chile..
    Nanodelivery of Cerebrolysin and Rearing in Enriched Environment Induce Neuroprotective Effects in a Preclinical Rat Model of Parkinson's Disease2018In: Molecular Neurobiology, ISSN 0893-7648, E-ISSN 1559-1182, Vol. 55, no 1, p. 286-299Article in journal (Refereed)
    Abstract [en]

    Rearing in enriched environment (EE) improves the recuperation in animal models of Parkinson's disease (PD). Administration of TiO2-nanowired cerebrolysin (CBL) could represent an additional strategy to protect or repair the nigrostriatal system. This study aims to explore morphofunctional and biochemical changes in a preclinical stage of PD testing the synergistic efficiency of combining both strategies, housing in EE, and nanodelivery of CBL. Sprague-Dawley male rats receiving intrastriatally 6-hydroxydopamine after a short evolution time were segregated into CBL group (rats receiving nanowired CBL), EE group (rats housed in EE), CBL + EE group (rats housed in EE and receiving nanowired CBL), and control group (rats without additional treatment). Prodromic stage and treatment effects were characterized by the presence of motor symptoms (amphetamine-induced rotational behavior test). Tyrosine hydroxylase (TH) immunohistochemistry and Western blot (p-Akt/Akt and p-ERK/ERK 1/2 as survival markers and caspase-3 as apoptotic marker) were performed in striatum and SN. A decrease in motor symptoms was shown by rats receiving CBL. EE monitoring cages revealed that rats from CBL + EE group showed more significant number of laps in the wheel than EE group. In SN, CBL + EE group also presented the highest neuronal density. Moreover, p-Akt/Akt and p-ERK/ERK 1/2 ratio was significant higher and caspase-3 expression was lower in CBL + EE group. In conclusion, the combination of CBL and EE provided evidence of neuoprotective-neurorestorative mechanisms by which this combined strategy promoted morphofunctional improvement by activation of survival pathways after dopamine depletion in a preclinical model of PD.

  • 11.
    Ruozi, Barbara
    et al.
    Univ Modena & Reggio Emilia, Dept Life Sci, Lab Pharmaceut Technol, I-41125 Modena, Italy..
    Belletti, Daniela
    Univ Modena & Reggio Emilia, Dept Life Sci, Lab Pharmaceut Technol, I-41125 Modena, Italy..
    Sharma, Hari Shanker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Sharma, Aruna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Muresanu, Dafin F.
    Univ Med & Pharm, Univ Hosp, Dept Clin Neurosci, Cluj Napoca, Romania..
    Moessler, Herbert
    Ever Neuro Pharma, Oberburgau, Austria..
    Forni, Flavio
    Univ Modena & Reggio Emilia, Dept Life Sci, Lab Pharmaceut Technol, I-41125 Modena, Italy..
    Vandelli, Maria Angela
    Univ Modena & Reggio Emilia, Dept Life Sci, Lab Pharmaceut Technol, I-41125 Modena, Italy..
    Tosi, Giovanni
    Univ Modena & Reggio Emilia, Dept Life Sci, Lab Pharmaceut Technol, I-41125 Modena, Italy..
    PLGA Nanoparticles Loaded Cerebrolysin: Studies on Their Preparation and Investigation of the Effect of Storage and Serum Stability with Reference to Traumatic Brain Injury2015In: Molecular Neurobiology, ISSN 0893-7648, E-ISSN 1559-1182, Vol. 52, no 2, p. 899-912Article in journal (Refereed)
    Abstract [en]

    Cerebrolysin is a peptide mixture able to ameliorate symptomatology and delay progression of neurological disorders such as Alzheimer's disease and dementia. The administration of this drug in humans presents several criticisms due to its short half-life, poor stability, and high doses needed to achieve the effect. This paper investigates the potential of polylactic-co-glycolide (PLGA) nanoparticles (NPs) as sustained release systems for iv administration of cerebrolysin in normal and brain injured rats. NPs were prepared by water-in-oil-in-water (w/o/w) double emulsion technique and characterized by light scattering for mean size and zeta potential and by scanning electron microscopy (SEM) for surface morphology. The NPs produced by double sonication under cooling at 60 W for 45 s, 12 mL of 1 % w:v of PVA, and 1:0.6 w:w drug/PLGA ratio (C-NPs4) displayed an adequate loading of drug (24 +/- 1 mg/100 mg of NPs), zeta potential value (-13 mV), and average diameters (ranged from 250 to 330 nm) suitable to iv administration. SEM images suggested that cerebrolysin was molecularly dispersed into matricial systems and partially adhered to the NP surface. A biphasic release with an initial burst effect followed by sustained release over 24 h was observed. Long-term stability both at room and at low temperature of freeze-dried NPs was investigated. To gain deeper insight into NP stability after in vivo administration, the stability of the best NP formulation was also tested in serum. These PLGA NPs loaded with cerebrolysin were able to reduce brain pathology following traumatic brain injury. However, the size, the polydispersivity, and the surface properties of sample were significantly affected by the incubation time and the serum concentration.

  • 12.
    Schiöth, Helgi B.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Craft, Suzanne
    Brooks, Samantha J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Frey, William H., II
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Brain Insulin Signaling and Alzheimer's Disease: Current Evidence and Future Directions2012In: Molecular Neurobiology, ISSN 0893-7648, E-ISSN 1559-1182, Vol. 46, no 1, p. 4-10Article in journal (Refereed)
    Abstract [en]

    Insulin receptors in the brain are found in high densities in the hippocampus, a region that is fundamentally involved in the acquisition, consolidation, and recollection of new information. Using the intranasal method, which effectively bypasses the blood-brain barrier to deliver and target insulin directly from the nose to the brain, a series of experiments involving healthy humans has shown that increased central nervous system (CNS) insulin action enhances learning and memory processes associated with the hippocampus. Since Alzheimer's disease (AD) is linked to CNS insulin resistance, decreased expression of insulin and insulin receptor genes and attenuated permeation of blood-borne insulin across the blood-brain barrier, impaired brain insulin signaling could partially account for the cognitive deficits associated with this disease. Considering that insulin mitigates hippocampal synapse vulnerability to amyloid beta and inhibits the phosphorylation of tau, pharmacological strategies bolstering brain insulin signaling, such as intranasal insulin, could have significant therapeutic potential to deter AD pathogenesis.

  • 13.
    Sharma, Aruna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Muresanu, Dafin F.
    Univ Med & Pharm, Univ Hosp, Dept Clin Neurosci, Cluj Napoca, Romania..
    Lafuente, Jose V.
    Univ Basque Country, Dept Neurosci, Bilbao, Spain..
    Patnaik, Ranjana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Banaras Hindu Univ, Indian Inst Technol, Dept Biomat, Sch Biomed Engn, Varanasi 221005, Uttar Pradesh, India..
    Tian, Z. Ryan
    Univ Arkansas, Dept Chem & Biochem, Fayetteville, AR 72701 USA..
    Buzoianu, Anca D.
    Univ Med & Pharm, Fac Med, Dept Pharmacol, Cluj Napoca, Romania..
    Sharma, Hari Shanker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Sleep Deprivation-Induced Blood-Brain Barrier Breakdown and Brain Dysfunction are Exacerbated by Size-Related Exposure to Ag and Cu Nanoparticles. Neuroprotective Effects of a 5-HT3 Receptor Antagonist Ondansetron2015In: Molecular Neurobiology, ISSN 0893-7648, E-ISSN 1559-1182, Vol. 52, no 2, p. 867-881Article in journal (Refereed)
    Abstract [en]

    Military personnel are often subjected to sleep deprivation (SD) during combat operations. Since SD is a severe stress and alters neurochemical metabolism in the brain, a possibility exists that acute or long-term SD will influence blood-brain barrier (BBB) function and brain pathology. This hypothesis was examined in young adult rats (age 12 to 14 weeks) using an inverted flowerpot model. Rats were placed over an inverted flowerpot platform (6.5 cm diameter) in a water pool where the water levels are just 3 cm below the surface. In this model, animals can go to sleep for brief periods but cannot achieve deep sleep as they would fall into water and thus experience sleep interruption. These animals showed leakage of Evans blue in the cerebellum, hippocampus, caudate nucleus, parietal, temporal, occipital, cingulate cerebral cortices, and brain stem. The ventricular walls of the lateral and fourth ventricles were also stained blue, indicating disruption of the BBB and the blood-cerebrospinal fluid barrier (BCSFB). Breakdown of the BBB or the BCSFB fluid barrier was progressive in nature from 12 to 48 h but no apparent differences in BBB leakage were seen between 48 and 72 h of SD. Interestingly, rats treated with metal nanoparticles, e.g., Cu or Ag, showed profound exacerbation of BBB disruption by 1.5- to 4-fold, depending on the duration of SD. Measurement of plasma and brain serotonin showed a close correlation between BBB disruption and the amine level. Repeated treatment with the serotonin 5-HT3 receptor antagonist ondansetron (1 mg/kg, s.c.) 4 and 8 h after SD markedly reduced BBB disruption and brain pathology after 12 to 24 h SD but not following 48 or 72 h after SD. However, TiO2-nanowired ondansetron (1 mg/kg, s.c) in an identical manner induced neuroprotection in rats following 48 or 72 h SD. However, plasma and serotonin levels were not affected by ondansetron treatment. Taken together, our observations are the first to show that (i) SD could induce BBB disruption and brain pathology, (ii) nanoparticles exacerbate SD-induced brain damage, and (iii) serotonin 5-HT3 receptor antagonist ondansetron is neuroprotective in SD that is further potentiated byTiO2-nanowired delivery, not reported earlier.

  • 14.
    Sharma, Aruna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Muresanu, Dafin F.
    Patnaik, Ranjana
    Sharma, Hari S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Size- and Age-Dependent Neurotoxicity of Engineered Metal Nanoparticles in Rats2013In: Molecular Neurobiology, ISSN 0893-7648, E-ISSN 1559-1182, Vol. 48, no 2, p. 386-396Article in journal (Refereed)
    Abstract [en]

    Earlier we showed that chronic administration of engineered nanoparticles (NPs) from metals, e.g., Cu, Ag, or Al (50-60 nm, 50 mg/kg, i.p. daily for 1 week) alter blood-brain barrier (BBB) disruption and induce brain pathology in adult rats (age 18 to 22 weeks). However, effects of size-dependent neurotoxicity of NPs in vivo are still largely unknown. In present investigation, we examined the effects of different size ranges of the above-engineered NPs on brain pathology in rats. Furthermore, the fact that age is also an important factor in brain pathology was also investigated in our rat model. Our results showed that small-sized NPs induced the most pronounced BBB breakdown (EBA +480 to 680 %; radioiodine +850 to 1025 %), brain edema formation (+4 to 6 %) and neuronal injuries (+30 to 40 %), glial fibrillary acidic protein upregulation (+40 to 56 % increase), and myelin vesiculation (+30 to 35 % damage) in young animals as compared to controls. Interestingly, the oldest animals (30 to 35 weeks of age) also showed massive brain pathology as compared to young adults (18 to 20 weeks old). The Ag and Cu exhibited greater brain damage compared with Al NPs in all age groups regardless of their size. This suggests that apart from the size, the composition of NPs is also important in neurotoxicity. The very young and elderly age groups exhibited greater neurotoxicity to NPs suggests that children and elderly are more vulnerable to NPs-induced brain damage. The NPs-induced brain damage correlated well with the upregulation of neuronal nitric oxide synthase activity in the brain indicating that NPs-induced neurotoxicity may be mediated via increased production of nitric oxide, not reported earlier.

  • 15.
    Sharma, Aruna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala Univ, Int Expt CNS Injury & Repair, Univ Hosp, Frodingsgatan 12,Bldg 28, SE-75421 Uppsala, Sweden.;Univ Basque Country UPV EHU, Dept Neurosci, LaNCE, Leioa, Bizkaia, Spain..
    Muresanu, Dafin F.
    RoNeuro Inst Neurol Res & Diagnost, 37 Mircea Eliade St, Cluj Napoca 400364, Romania.;Univ Med & Pharm, Dept Clin Neurosci, Cluj Napoca, Romania..
    Vicente Lafuente, Jose
    Univ Basque Country UPV EHU, Dept Neurosci, LaNCE, Leioa, Bizkaia, Spain.;BioCruces Hlth Res Inst, Nanoneurosurg Grp, Baracaldo 48903, Bizkaia, Spain.;Univ Autonoma Chile, Fac Hlth Sci, Santiago, Chile..
    Sjöquist, Per-Ove
    Karolinska Univ Hosp, Karolinska Inst, Div Cardiol, Dept Med, Stockholm, Sweden..
    Patnaik, Ranjana
    Banaras Hindu Univ, Sch Biomed Engn, Dept Biomat, Indian Inst Technol, Varanasi, Uttar Pradesh, India..
    Tian, Z. Ryan
    Univ Arkansas, Dept Chem & Biochem, Fayetteville, AR 72701 USA..
    Ozkizilcik, Asya
    Univ Arkansas, Dept Biomed Engn, Fayetteville, AR 72701 USA..
    Sharma, Hari S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala Univ, Int Expt CNS Injury & Repair, Univ Hosp, Frodingsgatan 12,Bldg 28, SE-75421 Uppsala, Sweden.;Univ Basque Country UPV EHU, Dept Neurosci, LaNCE, Leioa, Bizkaia, Spain..
    Cold Environment Exacerbates Brain Pathology and Oxidative Stress Following Traumatic Brain Injuries: Potential Therapeutic Effects of Nanowired Antioxidant Compound H-290/512018In: Molecular Neurobiology, ISSN 0893-7648, E-ISSN 1559-1182, Vol. 55, no 1, p. 276-285Article in journal (Refereed)
    Abstract [en]

    The possibility that traumatic brain injury (TBI) occurring in a cold environment exacerbates brain pathology and oxidative stress was examined in our rat model. TBI was inflicted by making a longitudinal incision into the right parietal cerebral cortex (2 mm deep and 4 mm long) in cold-acclimatized rats (5 degrees C for 3 h daily for 5 weeks) or animals at room temperature under Equithesin anesthesia. TBI in cold-exposed rats exhibited pronounced increase in brain lucigenin (LCG), luminol (LUM), and malondialdehyde (MDA) and marked pronounced decrease in glutathione (GTH) as compared to identical TBI at room temperature. The magnitude and intensity of BBB breakdown to radioiodine and Evans blue albumin, edema formation, and neuronal injuries were also exacerbated in cold-exposed rats after injury as compared to room temperature. Nanowired delivery of H-290/51 (50 mg/kg) 6 and 8 h after injury in cold-exposed group significantly thwarted brain pathology and oxidative stress whereas normal delivery of H-290/51 was neuroprotective after TBI at room temperature only. These observations are the first to demonstrate that (i) cold aggravates the pathophysiology of TBI possibly due to an enhanced production of oxidative stress, (ii) and in such conditions, nanodelivery of antioxidant compound has superior neuroprotective effects, not reported earlier.

  • 16.
    Sharma, Hari S.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Muresanu, Dafin F.
    Patnaik, Ranjana
    Sharma, Aruna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Exacerbation of Brain Pathology After Partial Restraint in Hypertensive Rats Following SiO2 Nanoparticles Exposure at High Ambient Temperature2013In: Molecular Neurobiology, ISSN 0893-7648, E-ISSN 1559-1182, Vol. 48, no 2, p. 368-379Article, review/survey (Refereed)
    Abstract [en]

    This investigation examines the possibility that exposure to silica dust of hypertensive individuals may exacerbate brain pathology and sensory motor dysfunction at high environmental temperature. Hypertension was produced in rats (200-250 g) by two-kidney one clip (2K1C) method, and in these animals, SiO2 nanoparticles (NPs; 50 to 60 nm) were administered at 50 mg/kg, i.p. daily for 1 week. On the 8th day, these rats were subjected to partial restraint in a Perspex box for 4 h either at room temperature (21 A degrees C) or at 33 A degrees C in a biological oxygen demand incubator (wind velocity, 2.6 cm/s; relative humidity, 65 to 67 %). In these animals, behavioral functions, blood-brain barrier (BBB) permeability to Evans blue albumin (EBA) and radioiodine (([131]-)Iodine), brain water content and neuronal injuries were determined. Hypertensive rats subjected to 4 h restraint at room temperature did not exhibit BBB dysfunction, brain edema, neural injury, or alterations in rotarod or inclined plane angle performances. However, when these hypertensive rats were subjected to restraint at 33 A degrees C, breakdown of the cortical BBB (EBA, +38 %; radioiodine, +56 %), brain water (+0.88 %), neuronal damages (+18 %), and behavioral impairment were exacerbated. Interestingly, SiO2 exposure to these rats further exacerbated BBB breakdown (EBA, 280 %; radioiodine, 350 %), brain edema (4 %), and neural injury (30 %) after identical restraint depending on the ambient temperature. SiO2 treatment also induced brain pathology and alteration in behavioral functions in normotensive rats after restraint at high temperature. These observations clearly show that hypertension significantly enhances restraint-induced brain pathology, and behavioral anomalies particularly at high ambient temperature and SiO2 intoxication further exacerbated these brain pathologies and cognitive dysfunctions.

  • 17.
    Sharma, Hari Shanker
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Kiyatkin, Eugene A.
    NIDA, Vivo Electrophysiol Unit, Behav Neurosci Branch, IRP,NIH, Baltimore, MD USA..
    Patnaik, Ranjana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Lafuente, Jose Vicente
    Univ Basque Country, Dept Neurosci, Bilbao, Spain..
    Muresanu, Dafin F.
    Univ Med & Pharm, Univ Hosp, Dept Clin Neurosci, Cluj Napoca, Romania..
    Sjoquist, Per-Ove
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Div Cardiol, Stockholm, Sweden..
    Sharma, Aruna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Exacerbation of Methamphetamine Neurotoxicity in Cold and Hot Environments: Neuroprotective Effects of an Antioxidant Compound H-290/512015In: Molecular Neurobiology, ISSN 0893-7648, E-ISSN 1559-1182, Vol. 52, no 2, p. 1023-1033Article in journal (Refereed)
    Abstract [en]

    In this study, we examined the influence of cold and hot environments on methamphetamine (METH) neurotoxicity in both drug-naive rats and animals previously exposed to different types of nanoparticles (NPs). Since METH induces oxidative stress, we also examined how a potential chain-breaking antioxidant H-290/51 (Astra-Zeneca, Molndal, Sweden) affects METH-induced neurotoxicity. Exposure of drug-naive rats to METH (9 mg/kg, s.c.) at 4, 21, or 34 A degrees C for 3 h resulted in breakdown of the blood-brain barrier (BBB), brain edema, and neuronal injuries, which all differed in severity depending upon ambient temperatures. The changes were moderate at 21 A degrees C, 120-180 % larger at 34 A degrees C, and almost absent at 4 A degrees C. In rats chronically treated with NPs (SiO2, Cu, or Ag; 50-60 nm, 50 mg/kg, i.p. for 7 days), METH-induced brain alterations showed a two- to fourfold increase at 21 A degrees C, a four- to sixfold increase at 34 A degrees C, and three- to fourfold increase at 4 A degrees C. SiO2 exposure showed the most pronounced METH-induced brain pathology at all temperatures followed by Ag and Cu NPs. Pretreatment with a potent antioxidant compound H-290/51 (50 mg/kg, p.o., 30 min before METH) significantly reduced brain pathology in naive animals exposed to METH at 21 and 34 A degrees C. In NPs-treated animals, however, attenuation of METH-induced brain pathology occurred only after repeated exposure of H-290/51 (-30 min, 0 min, and +30 min). These observations are the first to show that NPs exacerbate METH-induced brain pathology in both cold and hot environments and demonstrate that timely intervention with antioxidant H-290/51 could have neuroprotective effects.

  • 18.
    Sharma, Hari Shanker
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Muresanu, Dafin F.
    Univ Med & Pharm Cluj Napoca, Univ Hosp, Dept Clin Neurosci, Cluj Napoca, Romania.;RoNeuro Inst Neurol Res & Diagnost, Cluj Napoca 400364, Romania..
    Lafuente, Jose V.
    Univ Basque Country, Dept Neurosci, LaNCE, Bilbao, Spain.;Univ Autonoma Chile, Fac Hlth Sci, Santiago, Chile..
    Sjoquist, Per-Ove
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Div Cardiol, Stockholm, Sweden..
    Patnaik, Ranjana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Banaras Hindu Univ, Indian Inst Technol, Sch Biomed Engn, Dept Biomat, Varanasi 221005, Uttar Pradesh, India..
    Sharma, Aruna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Nanoparticles Exacerbate Both Ubiquitin and Heat Shock Protein Expressions in Spinal Cord Injury: Neuroprotective Effects of the Proteasome Inhibitor Carfilzomib and the Antioxidant Compound H-290/512015In: Molecular Neurobiology, ISSN 0893-7648, E-ISSN 1559-1182, Vol. 52, no 2, p. 882-898Article in journal (Refereed)
    Abstract [en]

    Increased levels of ubiquitin and heat shock protein (HSP) 72 kD are often seen in spinal cord injury (SCI). However, their roles in cell injury or survival are not well known. Thus, we have investigated the possible relationship between ubiquitin and HSP expressions in relation to cell injury in healthy animals, or following nanoparticle (NP) intoxication in SCI animals. A focal SCI was inflicted on the T10-11 segments over the right dorsal horn; animals were allowed to survive from 5 to 8 h after trauma. Separate groups of rats were exposed to SiO2, Ag, or Cu NPs for 7 days and subjected to SCI on the eighth day. A marked increase in ubiquitin or HSP immunoreactive cells occurred in the T9 to T12 segments 5 h after the injury, which further extended to the T4 and L5 after 8 h of survival. At this time, a marked increase in blood-spinal cord barrier (BSCB) permeability to Evans blue and radioiodine, accompanied by an intense edema formation, was observed. Changes were further exacerbated in NP-treated traumatized rats. The most marked expressions of ubiquitin and HSP in SCI were seen in rats treated with SiO2, followed by Ag, and Cu NPs. Treatment with H-290/51 (50 mg/kg p.o., 30 to 60 min after injury) or carfilzomib (1 mg/kg, i.v., 30 to 60 min after trauma) significantly reduced the ubiquitin or HSP expressions, as well as the BSCB breakdown, the edema formation, and the cell injury in the cord both 5 and 8 h after the injury, in normal animals. However, a double dose of H-290/51 (100 mg/kg) or carfilzomib (2 mg/kg) is needed to reduce cord pathology or ubiquitin and HSP expressions in traumatized animals treated with NPs. H-290/51 showed superior beneficial effects in reducing cord pathology in SCI than carfilzomib. These observations are the first to demonstrate that (i) NP-treated traumatized animals induce a widespread BSCB leakage, edema formation, and cord pathology as well as an overexpression of ubiquitin and HSP, (ii) high doses of antioxidant compounds or proteasome inhibitors are required for neuroprotection in the NP-exposed traumatized group, and (iii) ubiquitin and HSP expressions play a key role in neuronal injury in SCI, not reported earlier.

  • 19.
    Sharma, Hari Shanker
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala Univ, IECNSIR, Univ Hosp, Frodingsgatan 12,Bldg 28, SE-75421 Uppsala, Sweden.;Univ Med & Pharm, Dept Clin Neurosci, Cluj Napoca, Romania.;Univ Basque Country, Dept Neurosci, Bilbao, Spain..
    Muresanu, Dafin Fior
    Univ Med & Pharm, Dept Clin Neurosci, Cluj Napoca, Romania.;RoNeuro Inst Neurol Res & Diagnost, 37 Mircea Eliade St, Cluj Napoca 400364, Romania..
    Vicente Lafuente, Jose
    Univ Basque Country, Dept Neurosci, Bilbao, Spain.;BioCruces Hlth Res Inst, Nanoneurosurg Grp, Baracaldo 48903, Bizkaia, Spain.;Univ Autonoma Chile, Fac Hlth Sci, Santiago, Chile..
    Patnaik, Ranjana
    Banaras Hindu Univ, Dept Biomat, Sch Biomed Engn, Indian Inst Technol, Varanasi, Uttar Pradesh, India..
    Tian, Z. Ryan
    Univ Arkansas, Dept Chem & Biochem, Fayetteville, AR 72701 USA..
    Ozkizilcik, Asya
    Univ Arkansas, Dept Biomed Engn, Fayetteville, AR 72701 USA..
    Castellani, Rudy J.
    Univ Maryland, Dept Pathol, Baltimore, MD 21201 USA..
    Mossler, Herbert
    RoNeuro Inst Neurol Res & Diagnost, 37 Mircea Eliade St, Cluj Napoca 400364, Romania..
    Sharma, Aruna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala Univ, IECNSIR, Univ Hosp, Frodingsgatan 12,Bldg 28, SE-75421 Uppsala, Sweden.;RoNeuro Inst Neurol Res & Diagnost, 37 Mircea Eliade St, Cluj Napoca 400364, Romania.;Univ Basque Country, Dept Neurosci, Bilbao, Spain..
    Co-Administration of TiO2 Nanowired Mesenchymal Stem Cells with Cerebrolysin Potentiates Neprilysin Level and Reduces Brain Pathology in Alzheimer's Disease2018In: Molecular Neurobiology, ISSN 0893-7648, E-ISSN 1559-1182, Vol. 55, no 1, p. 300-311Article in journal (Refereed)
    Abstract [en]

    Neprilysin (NPL), the rate-limiting enzyme for amyloid beta peptide (A beta P), appears to play a crucial role in the pathogenesis of Alzheimer's disease (AD). Since mesenchymal stem cells (MSCs) and/or cerebrolysin (CBL, a combination of neurotrophic factors and active peptide fragments) have neuroprotective effects in various CNS disorders, we examined nanowired delivery of MSCs and CBL on NPL content and brain pathology in AD using a rat model. AD-like symptoms were produced by intraventricular (i.c.v.) administration of A beta P (1-40) in the left lateral ventricle (250 ng/10 mu l, once daily) for 4 weeks. After 30 days, the rats were examined for NPL and A beta P concentrations in the brain and related pathology. Co-administration of TiO2-nanowired MSCs (10(6) cells) with 2.5 ml/kg CBL (i.v.) once daily for 1 week after 2 weeks of A beta P infusion significantly increased the NPL in the hippocampus (400 pg/g) from the untreated control group (120 pg/g; control 420 +/- 8 pg/g brain) along with a significant decrease in the A beta P deposition (45 pg/g from untreated control 75 pg/g; saline control 40 +/- 4 pg/g). Interestingly, these changes were much less evident when the MSCs or CBL treatment was given alone. Neuronal damages, gliosis, and myelin vesiculation were also markedly reduced by the combined treatment of TiO2, MSCs, and CBL in AD. These observations are the first to show that co-administration of TiO2-nanowired CBL and MSCs has superior neuroprotective effects in AD probably due to increasing the brain NPL level effectively, not reported earlier.

  • 20.
    Sharma, Hari Shanker
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Patnaik, Ranjana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Sharma, Aruna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Vicente Lafuente, Jose
    Univ Basque Country, Dept Neurosci, Bilbao, Spain..
    Miclescu, Adriana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala Univ, Dept Surg Sci Anesthesiol & Intens Care Med, Lab Cerebrovasc Res, S-75185 Uppsala, Sweden..
    Wiklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Cardiac Arrest Alters Regional Ubiquitin Levels in Association with the Blood-Brain Barrier Breakdown and Neuronal Damages in the Porcine Brain2015In: Molecular Neurobiology, ISSN 0893-7648, E-ISSN 1559-1182, Vol. 52, no 2, p. 1043-1053Article in journal (Refereed)
    Abstract [en]

    The possibility that ubiquitin expression is altered in cardiac arrest-associated neuropathology was examined in a porcine model using immunohistochemical and biochemical methods. Our observations show that cardiac arrest induces progressive increase in ubiquitin expression in the cortex and hippocampus in a selective and specific manner as compared to corresponding control brains using enzyme-linked immunoassay technique (enzyme-linked immunosorbent assay (ELISA)). Furthermore, immunohistochemical studies showed ubiquitin expression in the neurons exhibiting immunoreaction in the cytoplasm and karyoplasm of distorted or damaged cells. Separate Nissl and ubiquitin staining showed damaged and distorted neurons and in the same cortical region ubiquitin expression indicating that ubiquitin expression after cardiac arrest represents dying neurons. The finding that methylene blue treatment markedly induced neuroprotection following identical cardiac arrest and reduced ubiquitin expression strengthens this view. Taken together, our observations are the first to show that cardiac arrest enhanced ubiquitin expression in the brain that is related to the magnitude of neuronal injury and the finding that methylene blue reduced ubiquitin expression points to its role in cell damage, not reported earlier.

  • 21.
    Sobol, Maria
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Klar, Joakim
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Laan, Loora
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Shahsavani, Mansoureh
    Karolinska Inst Solna, Dept Neurosci, Stockholm, Sweden.
    Schuster, Jens
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Annerén, Göran
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Konzer, Anne
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mi, Jia
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala Univ, Dept Chem BMC Analyt Chem, Box 599, SE-75124 Uppsala, Sweden.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nordlund, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hoeber, Jan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Huss, Mikael
    Stockholm Univ, Natl Bioinformat Infrastruct Sweden, Sci Life Lab, Dept Biochem & Biophys, Solna, Sweden.
    Falk, Anna
    Karolinska Inst Solna, Dept Neurosci, Stockholm, Sweden.
    Dahl, Niklas
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Transcriptome and Proteome Profiling of Neural Induced Pluripotent Stem Cells from Individuals with Down Syndrome Disclose Dynamic Dysregulations of Key Pathways and Cellular Functions2019In: Molecular Neurobiology, ISSN 0893-7648, E-ISSN 1559-1182, Vol. 56, no 10, p. 7113-7127Article in journal (Refereed)
    Abstract [en]

    Down syndrome (DS) or trisomy 21 (T21) is a leading genetic cause of intellectual disability. To gain insights into dynamics of molecular perturbations during neurogenesis in DS, we established a model using induced pluripotent stem cells (iPSC) with transcriptome profiles comparable to that of normal fetal brain development. When applied on iPSCs with T21, transcriptome and proteome signatures at two stages of differentiation revealed strong temporal dynamics of dysregulated genes, proteins and pathways belonging to 11 major functional clusters. DNA replication, synaptic maturation and neuroactive clusters were disturbed at the early differentiation time point accompanied by a skewed transition from the neural progenitor cell stage and reduced cellular growth. With differentiation, growth factor and extracellular matrix, oxidative phosphorylation and glycolysis emerged as major perturbed clusters. Furthermore, we identified a marked dysregulation of a set of genes encoded by chromosome 21 including an early upregulation of the hub gene APP, supporting its role for disturbed neurogenesis, and the transcription factors OLIG1, OLIG2 and RUNX1, consistent with deficient myelination and neuronal differentiation. Taken together, our findings highlight novel sequential and differentiation-dependent dynamics of disturbed functions, pathways and elements in T21 neurogenesis, providing further insights into developmental abnormalities of the DS brain.

  • 22.
    Vicente Lafuente, Jose
    et al.
    Univ Basque Country UPV EHU, Dept Neurosci, LaNCE, Leioa, Biscay, Spain.;BioCruces Hlth Res Inst, Nanoneurosurg Grp, Baracaldo 48903, Biscay, Spain.;Univ Autonoma Chile, Fac Hlth Sci, Santiago, Chile..
    Sharma, Aruna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Univ Basque Country UPV EHU, Dept Neurosci, LaNCE, Leioa, Biscay, Spain.; Uppsala Univ, Univ Hosp, Int Expt CNS Injury & Repair IECNSIR, Frodingsgatan 12,Bldg 28, SE-75421 Uppsala, Sweden..
    Muresanu, Dafin F.
    RoNeuro Inst Neurol Res & Diagnost, 37 Mircea Eliade St, Cluj Napoca, Romania.;Univ Med & Pharm, Dept Clin Neurosci, Cluj Napoca, Romania..
    Ozkizilcik, Asya
    Univ Arkansas, Dept Biomed Engn, Fayetteville, AR 72701 USA..
    Tian, Z. Ryan
    Univ Arkansas, Dept Chem & Biochem, J William Fulbright Coll Arts & Sci, Fayetteville, AR 72701 USA..
    Patnaik, Ranjana
    Banaras Hindu Univ, Indian Inst Technol, Dept Biomat, Sch Biomed Engn, Varanasi, Uttar Pradesh, India..
    Sharma, Hari S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Univ Basque Country UPV EHU, Dept Neurosci, LaNCE, Leioa, Biscay, Spain.; Uppsala Univ, Univ Hosp, Int Expt CNS Injury & Repair IECNSIR, Frodingsgatan 12,Bldg 28, SE-75421 Uppsala, Sweden..
    Repeated Forced Swim Exacerbates Methamphetamine-Induced Neurotoxicity: Neuroprotective Effects of Nanowired Delivery of 5-HT3-Receptor Antagonist Ondansetron2018In: Molecular Neurobiology, ISSN 0893-7648, E-ISSN 1559-1182, Vol. 55, no 1, p. 322-334Article in journal (Refereed)
    Abstract [en]

    The possibility that stress associated with chronic forced swim (FS) may exacerbate methamphetamine (METH) neurotoxicity was examined in a rat model. Rats were subjected to FS in a pool (30 degrees C) for 15 min daily for 8 days. Control rats were kept at room temperature. METH was administered (9 mg/kg, s.c.) in both control and FS rats and allowed to survive 4 h after the drug injection. METH in FS rats exacerbated BBB breakdown to Evans blue albumin (EBA) by 150 to 220% and ([131])-Iodine by 250 to 380% as compared to naive rats after METH. The METH-induced BBB leakage was most pronounced in the cerebral cortex followed by the hippocampus, cerebellum, thalamus, and hypothalamus in both FS and naive rats. The regional BBB changes were associated with a reduction in the local cerebral blood flow (CBF). Brain edema was also higher by 2 to 4% in FS rats after METH than in naive animals. Neuronal and glial cell injuries were aggravated by threefold to fivefold after METH in FS than the control group. Pretreatment with ondansetron (1 mg/kg, i.p.) 30 min before METH injection in naive rats reduced the brain pathology and improved the CBF. However, TiO2-nanowired delivery of ondansetron (1 mg/kg, i.p.) was needed to reduce METH-induced brain damage, BBB leakage, reduction in CBF, and edema formation in FS. Taken together, these observations are the first to show that METH exacerbates BBB breakdown leading to neurotoxicity in FS animals. This effect of METH-induced BBB breakdown and brain pathology in naive and FS rats is attenuated by ondansetron treatment indicating an involvement of 5-HT3 receptors, not reported earlier.

  • 23.
    Wiklund, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Patnaik, Ranjana
    National Institute of Technology, School of Biomedical Engineering, Banaras Hindu University, Varanasi, India.
    Sharma, Aruna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Miclescu, Adriana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Sharma, Hari Shanker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Cerebral Tissue Oxidative Ischemia-Reperfusion Injury in Connection with Experimental Cardiac Arrest and Cardiopulmonary Resuscitation: Effect of Mild Hypothermia and Methylene Blue2018In: Molecular Neurobiology, ISSN 0893-7648, E-ISSN 1559-1182, Vol. 55, no 1, p. 115-121Article in journal (Refereed)
    Abstract [en]

    The present investigation is an expansion of previous studies which all share a basic experimental protocol of a porcine-induced cardiac arrest (CA) of 12 min followed by 8 min of cardiopulmonary resuscitation (CPR), different experimental treatments (immediate as well as postponed induced mild hypothermia and administration of much or less cool intravenous fluids), and a follow-up period of 3 h after which the animals were sacrificed. Another group of animals was studied according to the same protocol after 12-min CA and Bstandard CPR.^ After death (within 1 min), the brains were harvested and frozen in liquid nitrogen awaiting analysis. Control brains of animals were collected in the same way after short periods of untreated CA (0 min, 5 min, and 15–30 min). Previous studies concerning chiefly neuropathological changes were now expanded with analyses of different tissue indicators (glutathione, luminol, leucigenin, malonialdehyde, and myeloperoxidase) of cerebral oxidative injury. The results indicate that a great part of oxidative injury occurs within the first 5 min after CA. Immediate cooling by administration of much intravenous fluid results in less cerebral oxidative injury compared to less intravenous fluid administration. A 30-min postponement of induction of hypothermia results in a cerebral oxidative injury comparable to that of Bstandard CPR^ or the oxidative injury found after 5 min of untreated CA. Intravenous administration of methylene blue (MB) during and immediately after CPR in combination with postponed cooling resulted in no statistical difference in any of the indicators of oxidative injury, except myeloperoxidase, and glutathione, when this treatment was compared with the negative controls, i.e., animals subjected to anesthesia alone.

1 - 23 of 23
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