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  • 51.
    Karlsson, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Berg, Anna-Lena
    Lindström, Anna-Karin
    Hanrieder, Jorg
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Arnerup, Gunnel
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Lindquist, Nils Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Brittebo, Eva B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Andersson, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Neonatal Exposure to the Cyanobacterial Toxin BMAA Induces Changes in Protein Expression and Neurodegeneration in Adult Hippocampus2012In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 130, no 2, p. 391-404Article in journal (Refereed)
    Abstract [en]

    The cyanobacterial toxin -N-methylamino-l-alanine (BMAA) has been proposed to contribute to neurodegenerative disease. We have previously reported a selective uptake of BMAA in the mouse neonatal hippocampus and that exposure during the neonatal period causes learning and memory impairments in adult rats. The aim of this study was to characterize effects in the brain of 6-month-old rats treated neonatally (postnatal days 910) with the glutamatergic BMAA. Protein changes were examined using the novel technique Matrix-Assisted Laser Desorption Ionization (MALDI) imaging mass spectrometry (IMS) for direct imaging of proteins in brain cryosections, and histological changes were examined using immunohistochemistry and histopathology. The results showed long-term changes including a decreased expression of proteins involved in energy metabolism and intracellular signaling in the adult hippocampus at a dose (150mg/kg) that gave no histopathological lesions in this brain region. Developmental exposure to a higher dose (460mg/kg) also induced changes in the expression of S100, histones, calcium- and calmodulin-binding proteins, and guanine nucleotide-binding proteins. At this dose, severe lesions in the adult hippocampus including neuronal degeneration, cell loss, calcium deposits, and astrogliosis were evident. The data demonstrate subtle, sometimes dose-dependent, but permanent effects of a lower neonatal dose of BMAA in the adult hippocampus suggesting that BMAA could potentially disturb many processes during the development. The detection of BMAA in seafood stresses the importance of evaluating the magnitude of human exposure to this neurotoxin.

  • 52.
    Karlsson, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Berg, Cecilia
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Brittebo, Eva B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Lindquist, Nils Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Retention of the cyanobacterial neurotoxin beta-N-methylamino-l-alanine in melanin and neuromelanin-containing cells: a possible link between Parkinson-dementia complex and pigmentary retinopathy2009In: Pigment cell & melanoma research, ISSN 1755-1471, Vol. 22, no 1, p. 120-130Article in journal (Refereed)
    Abstract [en]

    beta-N-methylamino-l-alanine (BMAA), a neurotoxic amino acid produced by cyanobacteria, has been suggested to be involved in the etiology of a neurodegenerative disease complex which includes Parkinson-dementia complex (PDC). In PDC, neuromelanin-containing neurons in substantia nigra are degenerated. Many PDC patients also have an uncommon pigmentary retinopathy. The aim of this study was to investigate the distribution of (3)H-BMAA in mice and frogs, with emphasis on pigment-containing tissues. Using autoradiography, a distinct retention of (3)H-BMAA was observed in melanin-containing tissues such as the eye and neuromelanin-containing neurons in frog brain. Analysis of the binding of (3)H-BMAA to Sepia melanin in vitro demonstrated two apparent binding sites. In vitro-studies with synthetic melanin revealed a stronger interaction of (3)H-BMAA with melanin during synthesis than the binding to preformed melanin. Long-term exposure to BMAA may lead to bioaccumulation in melanin- and neuromelanin-containing cells causing high intracellular levels, and potentially changed melanin characteristics via incorporation of BMAA into the melanin polymer. Interaction of BMAA with melanin may be a possible link between PDC and pigmentary retinopathy.

  • 53.
    Karlsson, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Jiang, Liying
    Andersson, Marie
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Ilag, Leopold L.
    Brittebo, Eva B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Protein association of the neurotoxin and non-protein amino acid BMAA (beta-N-methylamino-L-alanine) in the liver and brain following neonatal administration in rats2014In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 226, no 1, p. 1-5Article in journal (Refereed)
    Abstract [en]

    The environmental neurotoxin beta-N-methylamino-L-alanine (BMAA) is not an amino acid that is normally found in proteins. Our previous autoradiographic study of H-3-labeled BMAA in adult mice unexpectedly revealed a tissue distribution similar to that of protein amino acids. The aim of this study was to characterize the distribution of free and protein-bound BMAA in neonatal rat tissues following a short exposure using autoradiographic imaging and ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). The autoradiographic imaging of C-14-L-BMAA demonstrated a distinct uptake of radioactivity that was retained following acid extraction in tissues with a high rate of cell turnover and/or protein synthesis. The UHPLC-MS/MS analysis conclusively demonstrated a dose-dependent increase of protein-associated BMAA in neonatal rat tissues. The level of protein-associated BMAA in the liver was more than 10 times higher than that in brain regions not fully protected by the blood-brain barrier which may be due to the higher rate of protein synthesis in the liver. In conclusion, this study demonstrated that BMAA was associated with rat proteins suggesting that BMAA may be mis-incorporated into proteins. However, protein-associated BMAA seemed to be cleared over time, as none of the samples from adult rats had any detectable free or protein-associated BMAA.

  • 54.
    Karlsson, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Jiang, Liying
    Stockholm Univ, Dept Environm Sci & Analyt Chem, SE-10691 Stockholm, Sweden..
    Ersson, Lisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Malmstrom, Tim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Ilag, Leopold L.
    Stockholm Univ, Dept Environm Sci & Analyt Chem, SE-10691 Stockholm, Sweden..
    Brittebo, Eva B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Environmental neurotoxin interaction with proteins: Dose-dependent increase of free and protein-associated BMAA (beta-N-methylamino-L-alanine) in neonatal rat brain2015In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, article id 15570Article in journal (Refereed)
    Abstract [en]

    beta-Methylamino-L-alanine (BMAA) is implicated in the aetiology of neurodegenerative disorders. Neonatal exposure to BMAA induces cognitive impairments and progressive neurodegenerative changes including intracellular fibril formation in the hippocampus of adult rats. It is unclear why the neonatal hippocampus is especially vulnerable and the critical cellular perturbations preceding BMAA-induced toxicity remains to be elucidated. The aim of this study was to compare the level of free and protein-associated BMAA in neonatal rat brain and peripheral tissues after different exposures to BMAA. Ultra-high performance liquid chromatography-tandem mass spectrometry analysis revealed that BMAA passed the neonatal blood-brain barrier and was distributed to all studied brain areas. BMAA was also associated to proteins in the brain, especially in the hippocampus. The level in the brain was, however, considerably lower compared to the liver that is not a target organ for BMAA. In contrast to the liver there was a significantly increased level of protein-association of BMAA in the hippocampus and other brain areas following repeated administration suggesting that the degradation of BMAA-associated proteins may be lower in neonatal brain than in the liver. Additional evidence is needed in support of a role for protein misincorporation in the neonatal hippocampus for long-term effects of BMAA.

  • 55.
    Karlsson, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Kultima, Kim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Wadensten, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nilsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Andrén, Per E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Brittebo, Eva B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Neurotoxin-Induced Neuropeptide Perturbations in Striatum of Neonatal Rats2013In: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 12, no 4, p. 1678-1690Article in journal (Refereed)
    Abstract [en]

    The cyanobacterial toxin β-N-methylamino-l-alanine (BMAA) is suggested to play a role in neurodegenerative disease. We have previously shown that although the selective uptake of BMAA in the rodent neonatal striatum does not cause neuronal cell death, exposure during the neonatal development leads to cognitive impairments in adult rats. The aim of the present study was to characterize the changes in the striatal neuropeptide systems of male and female rat pups treated neonatally (postnatal days 9-10) with BMAA (40-460 mg/kg). The label-free quantification of the relative levels of endogenous neuropeptides using mass spectrometry revealed that 25 peptides from 13 neuropeptide precursors were significantly changed in the rat neonatal striatum. The exposure to noncytotoxic doses of BMAA induced a dose-dependent increase of neurosecretory protein VGF-derived peptides, and changes in the relative levels of cholecystokinin, chromogranin, secretogranin, MCH, somatostatin and cortistatin-derived peptides were observed at the highest dose. In addition, the results revealed a sex-dependent increase in the relative level of peptides derived from the proenkephalin-A and protachykinin-1 precursors, including substance P and neurokinin A, in female pups. Because several of these peptides play a critical role in the development and survival of neurons, the observed neuropeptide changes might be possible mediators of BMAA-induced behavioral changes. Moreover, some neuropeptide changes suggest potential sex-related differences in susceptibility toward this neurotoxin. The present study also suggests that neuropeptide profiling might provide a sensitive characterization of the BMAA-induced noncytotoxic effects on the developing brain.

  • 56.
    Karlsson, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Lindquist, Nils Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Brittebo, Eva B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Selective Brain Uptake and Behavioral Effects of the Cyanobacterial Toxin BMAA (β-N-Methylamino-L-alanine) following Neonatal Administration to Rodents2009In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 109, no 2, p. 286-295Article in journal (Refereed)
    Abstract [en]

    Cyanobacteria are extensively distributed in terrestrial and aquatic environments all over the world. Most cyanobacteria can produce the neurotoxin ss-N-methylamino-L-alanine (BMAA), which has been detected in several water systems and could accumulate in food chains. The aim of the study was to investigate the transfer of BMAA to fetal and neonatal brains and the effects of BMAA on the development of behavioral characteristics during the brain growth spurt (BGS) in rodents Pregnant and neonatal mice were given an injection of (3)H-BMAA on gestational day 14 and postnatal day (PND) 10, respectively, and processed for tape-section autoradiography. The study revealed transplacental transfer of (3)H-BMAA and a significant uptake in fetal mouse. The radioactivity was specifically located in the hippocampus, striatum, brainstem, spinal cord and cerebellum of 10-day-old mice. The effect of repeated BMAA treatment (200 or 600 mg/kg sc) during BGS on rat behavior was also studied. BMAA treatment on PND 9-10 induced acute alterations, such as impaired locomotor ability and hyperactivity, in the behavior of neonatal rats. Furthermore, rats given the high dose of BMAA failed to habituate to the test environment when tested at juvenile age. In conclusion, the results demonstrated that BMAA was transferred to the neonatal brain and induced significant changes in the behavior of neonatal rats following administration during BGS. The observed behavioral changes suggest possible cognitive impairment. Increased information on the long-term effects of BMAA on cognitive function following fetal and neonatal exposure is required for assessment of the risk to children's health.

  • 57.
    Karlsson, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Berg, Anna-Lena
    Brittebo, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Early hippocampal cell death, and late learning and memory deficits in rats exposed to the environmental toxin BMAA (β-N-methylamino-l-alanine) during the neonatal period2011In: Behavioural Brain Research, ISSN 0166-4328, E-ISSN 1872-7549, Vol. 219, no 2, p. 310-320Article in journal (Refereed)
    Abstract [en]

    We have reported previously that exposure to the cyanobacterial neurotoxin β-N-methylamino-l-alanine (BMAA) during the neonatal period causes cognitive impairments in adult rats. The aim of this study was to investigate the long-term effects of neonatal BMAA exposure on learning and memory mechanisms and to identify early morphological changes in the neonatal brain. BMAA was injected subcutaneously in rat pups on postnatal days 9-10. BMAA (50 and 200mg/kg) caused distinct deficits in spatial learning and memory in adult animals but no morphological changes. No impairment of recognition memory was detected, suggesting that neonatal exposure to BMAA preferentially affects neuronal systems that are important for spatial tasks. Histopathological examination revealed early neuronal cell death as determined by TUNEL staining in the hippocampus 24h after a high dose (600mg/kg) of BMAA whereas no changes were observed at lower doses (50 and 200mg/kg). In addition, there was a low degree of neuronal cell death in the retrosplenial and cingulate cortices, areas that are also important for cognitive function. Taken together, these results indicate that BMAA is a developmental neurotoxin inducing long-term changes in cognitive function. The risk posed by BMAA as a potential human neurotoxin merits further consideration, particularly if the proposed biomagnifications in the food chain are confirmed.

  • 58.
    Karlsson, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Brittebo, Eva B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Long-term cognitive impairments in adult rats treated neonatally with beta-N-Methylamino-L-Alanine2009In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 112, no 1, p. 185-195Article in journal (Refereed)
    Abstract [en]

    Most cyanobacteria (blue-green algae) can produce the neurotoxin beta-N-methylamino-L-alanine (BMAA). Dietary exposure to BMAA has been suggested to be involved in the etiology of the neurodegenerative disease amyotrophic lateral sclerosis/Parkinsonism-dementia complex (ALS/PDC). Little is known about BMAA-induced neurotoxicity following neonatal administration. Our previous studies have revealed an uptake of BMAA in the hippocampus and striatum of neonatal mice. Furthermore, rats treated with BMAA during the neonatal period displayed acute but transient motoric disturbances and failed to show habituation at juvenile age suggesting impairments in learning functions. In the present study, the aim was to investigate long-term behavioral effects of BMAA administration in neonatal rats. BMAA was administered on postnatal days 9-10 (200 or 600 mg/kg; subcutaneous injection). Spatial learning and memory was investigated in adulthood using the radial arm maze test. The results revealed impaired learning but not memory in BMAA-treated animals. The observed impairments were not due to alterations in motoric capacity, general activity, or behavioral profiles, as assessed in the multivariate concentric square field (MCSF) and open field tests. An aversive stimulus in the MCSF test revealed impairments in avoidance learning and/or memory. There was no difference in basal serum corticosterone levels in BMAA-treated animals, indicating that the observed long-term effects were not secondary to an altered basal hypothalamic-pituitary-adrenal axis function. The present data demonstrated long-term learning impairments following neonatal BMAA administration. Further studies on biochemical effects in various brain regions and subsequent behavioral alterations are needed to elucidate the mechanisms of BMAA-induced developmental neurotoxicity.

  • 59.
    Klint, Helén
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Lejonklou, Margareta H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Karimullina, Elina
    University of California, Irvine, Department of Developmental and Cell Biology, Irvine, CA 92697, USA.
    Rönn, Monika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Lind, P. Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Brittebo, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Low-dose exposure to bisphenol A in combination with fructose increases expression of genes regulating angiogenesis and vascular tone in juvenile Fischer 344 rat cardiac tissue2017In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 122, no 1, p. 20-27Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Epidemiological studies report associations between exposure to the high-volume chemical and endocrine disruptor bisphenol A (BPA) and cardiovascular disorders, but there is a lack of experimental studies addressing the mechanisms of action of BPA on the cardiovascular system. In the present study, effects on markers for cardiovascular function of exposure to BPA and fructose in vivo in rat cardiac tissues, and of BPA exposure in human cardiomyocytes in vitro, were investigated.

    MATERIALS: Juvenile female Fischer 344 rats were exposed to 5, 50, and 500 μg BPA/kg bodyweight/day in their drinking water from 5 to 15 weeks of age, in combination with 5% fructose. Further, cultured human cardiomyocytes were exposed to 10 nM BPA to 1 × 10(4) nM BPA for six hours. Expression of markers for cardiovascular function and BPA target receptors was investigated using qRT-PCR.

    RESULTS: Exposure to 5 μg BPA/kg bodyweight/day plus fructose increased mRNA expression of Vegf, Vegfr2, eNos, and Ace1 in rat heart. Exposure of human cardiomyocytes to 1 × 10(4) nM BPA increased mRNA expression of eNOS and ACE1, as well as IL-8 and NFκβ known to regulate inflammatory response.

    CONCLUSIONS: . Low-dose exposure of juvenile rats to BPA and fructose induced up-regulation of expression of genes controlling angiogenesis and vascular tone in cardiac tissues. The observed effects of BPA in rat heart were in line with our present and previous studies of BPA in human endothelial cells and cardiomyocytes. These findings may aid in understanding the mechanisms of the association between BPA exposure and cardiovascular disorders reported in epidemiological studies.

  • 60. Lindh, CH
    et al.
    Jonsson, BAG
    Johannesson, G
    Zhang, XD
    Brittebo, EB
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Binding of the potent allergen hexahydrophthalic anhydride in the mucosa of the upper respiratory and alimentary tract following single inhalation exposures in guinea pigs and rats1999In: TOXICOLOGY, Vol. 134, p. 153-Article in journal (Refereed)
  • 61. Mancuso, M
    et al.
    Giovanetti, A
    Brittebo, EB
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Effects of dichlobenil on ultrastructural morphology and cell replication in the mouse olfactory mucosa1997In: TOXICOLOGIC PATHOLOGY, Vol. 25, p. 186-Article in journal (Refereed)
  • 62. Orrhage, Kerstin
    et al.
    Annas, Anita
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nord,
    Brittebo, Eva
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Rafter,
    Effects of lactic acid bacteria on the distribution of Trp-p-2 in mice.2002In: Scandinavian Journal of Gastroenterology, Vol. 37, p. 215-Article in journal (Refereed)
  • 63.
    Ostergren, A
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Fredriksson, A
    Faculty of Medicine, Department of Neuroscience.
    Brittebo, E B
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Norharman-induced motoric impairment in mice: neurodegeneration and glial activation in substantia nigra.2006In: J Neural Transm, ISSN 0300-9564, Vol. 113, no 3, p. 313-29Article in journal (Refereed)
  • 64.
    Ostergren, Anna
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Svensson, Anne-Lie
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Lindquist, Nils Gunnar
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Brittebo, Eva B
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Dopamine melanin-loaded PC12 cells: a model for studies on pigmented neurons.2005In: Pigment Cell Res, ISSN 0893-5785, Vol. 18, no 4, p. 306-14Article in journal (Refereed)
  • 65. Piras, Elena
    et al.
    Franzen, Anna
    Fernandez, Estibaliz
    Bergström, Ulrika
    Raffalli-Mathieu, Francoise
    Lang, Matti
    Brittebo, Eva
    Cell specific expression of CYP2A5 in the mouse respiratory tract: Effects of olfactory toxicants2003In: Journal of Histochemistry and Cytochemistry, ISSN 0022-1554, E-ISSN 1551-5044, Vol. 51, p. 1545-1555Article in journal (Refereed)
  • 66.
    Piras, Elena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Franzén, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Fernández, Estíbaliz
    Bergström, Ulrika
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Environmental Toxicology.
    Raffalli-Mathieu, Francoise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Lang, Matti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Brittebo, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Cell-specific Expression of CYP2A5 in the Mouse Respiratory Tract: Effects of Olfactory Toxicants2003In: Journal of Histochemistry and Cytochemistry, ISSN 0022-1554, E-ISSN 1551-5044, Vol. 51, no 11, p. 1545-1555Article in journal (Refereed)
    Abstract [en]

    We performed a detailed analysis of mouse cytochrome P450 2A5 (CYP2A5) expression by in situ hybridization (ISH) and immunohistochemistry (IHC) in the respiratory tissues of mice. The CYP2A5 mRNA and the corresponding protein co-localized at most sites and were predominantly detected in the olfactory region, with an expression in sustentacular cells, Bowman's gland, and duct cells. In the respiratory and transitional epithelium there was no or only weak expression. The nasolacrimal duct and the excretory ducts of nasal and salivary glands displayed expression, whereas no expression occurred in the acini. There was decreasing expression along the epithelial linings of the trachea and lower respiratory tract, whereas no expression occurred in the alveoli. The hepatic CYP2A5 inducers pyrazole and phenobarbital neither changed the CYP2A5 expression pattern nor damaged the olfactory mucosa. In contrast, the olfactory toxicants dichlobenil and methimazole induced characteristic changes. The damaged Bowman's glands displayed no expression, whereas the damaged epithelium expressed the enzyme. The CYP2A5 expression pattern is in accordance with previously reported localization of protein and DNA adducts and the toxicity of some CYP2A5 substrates. This suggests that CYP2A5 is an important determinant for the susceptibility of the nasal and respiratory epithelia to protoxicants and procarcinogens.

  • 67.
    Piras, Elena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Franzén, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Fernández, Estíbaliz L.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bergström, Ulrika
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organism Biology, Environmental Toxicology.
    Raffalli-Mathieu, Françoise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Lang, Matti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Brittebo, Eva B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Cell-specific expression of CYP2A5 in the mouse respiratory tract: effects of olfactory toxicants.2003In: Journal of Histochemistry and Cytochemistry, ISSN 0022-1554, E-ISSN 1551-5044, Vol. 51, no 11, p. 1545-1555Article in journal (Refereed)
    Abstract [en]

    We performed a detailed analysis of mouse cytochrome P450 2A5 (CYP2A5) expression by in situ hybridization (ISH) and immunohistochemistry (IHC) in the respiratory tissues of mice. The CYP2A5 mRNA and the corresponding protein co-localized at most sites and were predominantly detected in the olfactory region, with an expression in sustentacular cells, Bowman's gland, and duct cells. In the respiratory and transitional epithelium there was no or only weak expression. The nasolacrimal duct and the excretory ducts of nasal and salivary glands displayed expression, whereas no expression occurred in the acini. There was decreasing expression along the epithelial linings of the trachea and lower respiratory tract, whereas no expression occurred in the alveoli. The hepatic CYP2A5 inducers pyrazole and phenobarbital neither changed the CYP2A5 expression pattern nor damaged the olfactory mucosa. In contrast, the olfactory toxicants dichlobenil and methimazole induced characteristic changes. The damaged Bowman's glands displayed no expression, whereas the damaged epithelium expressed the enzyme. The CYP2A5 expression pattern is in accordance with previously reported localization of protein and DNA adducts and the toxicity of some CYP2A5 substrates. This suggests that CYP2A5 is an important determinant for the susceptibility of the nasal and respiratory epithelia to protoxicants and procarcinogens.

  • 68.
    Westin, Ulrika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Piras, Elena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Jansson, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Bergström, Ulrika
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Dahlin, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Brittebo, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Björk, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Transfer of morphine along the olfactory pathway to the central nervous system after nasal administration to rodents2005In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 24, no 5, p. 565-573Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to investigate whether morphine can be transferred along the olfactory pathway to the CNS, thereby circumventingthe blood–brain barrier, after nasal administration to rodents. Radiolabelled and unlabelled morphine were administered via the right nostrilto mice and rats. Olfactory bulbs, brain tissue and blood samples were collected. Morphine-derived radioactivity was measured using liquidscintillation (LS) and the concentrations of morphine and its metabolite morphine-3-glucuronide (M3G) were also assessed with highperformanceliquid chromatography. The location of morphine-derived radioactivity in the rat brain was visualised by autoradiography.Overall, the levels of morphine in the right olfactory bulbs (ROBs) significantly exceeded those in the left olfactory bulbs (LOBs) and braintissue samples 15, 60 and 240 min after right-sided nasal administration. Fifteen minutes after intravenous administration, there were nosignificant differences between olfactory bulbs and the other brain areas. Five minutes after nasal administration, autoradiography revealedradioactivity surrounding the ROB and reaching one of the ventricles in the brain. After 60 min, radioactivity had reached the peripheral partsof the ROB. All the techniques used in this study demonstrate that morphine was transferred along the olfactory pathway to the CNS afternasal administration to rodents.

  • 69.
    Östergren, A
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Annas, A
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Skog, K
    Lindquist, Nils Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Brittebo, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Long-term retention of neurotoxic ß-carbolines in brain neuromelanin2003In: Journal of neural transmission, ISSN 0300-9564, E-ISSN 1435-1463, Vol. 111, no 2, p. 141-157Article in journal (Refereed)
    Abstract [en]

    beta-Carbolines show structural resemblance to the neurotoxic N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and are metabolized to mitochondrial toxicants. Humans are continuously exposed to low levels of beta-carbolines through cooked food, coffee, alcoholic beverages and tobacco smoke. beta-Carbolines have previously been detected in higher levels in the pigmented substantia nigra than in the cortex of humans. The distribution of 3H-labelled harman and norharman in the brain of pigmented and albino mice and in frogs (a species having neuromelanin) was studied by tape-section and light-microscopic autoradiography. Furthermore, the binding of these beta-carbolines to dopamine-melanin and melanin granules from Sepia officinalis was examined. The results revealed a high affinity binding to melanin and a long-term retention (up to 30 days) in pigmented tissues, including neuromelanin-containing neurons of frogs after a single injection. The role of long-term exposure to food-related beta-carbolines and a retention of these compounds in pigment-containing neurons in the induction of idiopathic Parkinson's disease should be further considered.

  • 70.
    Östergren, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Annas, Anita
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Skog, Kerstin
    Lindquist, Nils Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Brittebo, Eva B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Long-term retention of β-carbolines in brain neuromelanin2004In: Journal of neural transmission, ISSN 0300-9564, E-ISSN 1435-1463, Vol. 111, no 2, p. 141-157Article in journal (Refereed)
    Abstract [en]

    beta-Carbolines show structural resemblance to the neurotoxic N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and are metabolized to mitochondrial toxicants. Humans are continuously exposed to low levels of beta-carbolines through cooked food, coffee, alcoholic beverages and tobacco smoke. beta-Carbolines have previously been detected in higher levels in the pigmented substantia nigra than in the cortex of humans. The distribution of 3H-labelled harman and norharman in the brain of pigmented and albino mice and in frogs (a species having neuromelanin) was studied by tape-section and light-microscopic autoradiography. Furthermore, the binding of these beta-carbolines to dopamine-melanin and melanin granules from Sepia officinalis was examined. The results revealed a high affinity binding to melanin and a long-term retention (up to 30 days) in pigmented tissues, including neuromelanin-containing neurons of frogs after a single injection. The role of long-term exposure to food-related beta-carbolines and a retention of these compounds in pigment-containing neurons in the induction of idiopathic Parkinson's disease should be further considered.

  • 71.
    Östergren, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Fredriksson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, Ulleråker, University Hospital.
    Brittebo, Eva B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Norharman-induced motoric impairment in mice: Neurodegeneration and glial activation in substantia nigra2006In: Journal of neural transmission, ISSN 0300-9564, E-ISSN 1435-1463, Vol. 113, no 3, p. 313-329Article in journal (Refereed)
    Abstract [en]

    The beta-carboline norharman is present in cooked food and tobacco smoke and show structural resemblance to the neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. C57BL/6 mice were injected subcutaneously with norharman (3 and 10 mg/kg) twice per day for five consecutive days. Eighteen hours after the last dose an increased expression of glial fibrillary acidic protein and fluoro-jade staining were demonstrated whereas the number of tyrosine hydroxylase positive cells were unchanged in the substantia nigra. Two weeks after the last treatment a decreased motor activity was observed whereas cognitive functions remained intact. In cultured PC12 cells norharman treatment induced mitochondrial dysfunction and increased the number of caspase-3 and TUNEL-positive cells. The results demonstrate that norharman induced apoptosis in cultured cells as well as early neurodegeneration, glial activation and sustained motor deficits in mice and suggest that exposure to norharman may contribute to idiopathic Parkinson's disease.

  • 72.
    Östergren, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Lindquist, Nils Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Brittebo, Eva B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Differential effects of dopamine melanin on norharman-induced toxicity in PC12 cells2007In: Journal of neural transmission, ISSN 0300-9564, E-ISSN 1435-1463, Vol. 114, no 7, p. 909-918Article in journal (Refereed)
    Abstract [en]

    The food contaminant norharman structurally resembles MPTP a compound that selectively damages pigmented brain areas. Both compounds are sequestered and retained in melanin-containing neurons. The aim of the study was to examine whether intracellular melanin can modulate the toxicity of norharman in melanin-loaded PC12 cells. Dopamine melanin protected against norharman-induced upregulation of grp78, activation of caspase 3 and necrosis at low concentrations (5 and 50 µM). In contrast, at a high conentration (500 µM) there was a significantly increased expression of grp78, hsp90 and caspase and a disassociation of melanin aggregates and dispersal of melanin granules to swollen neurite terminals. In human populations, a long-term low-level exposure to toxicants with a high affinity to melanin will probably result in accumulation in melanin-containing neurons in vivo. Our data suggest that accumulation of a neurotoxicant in melanin-loaded cells may lead to increased cell stress, apoptotic signaling and disassociation of melanin aggregates.

  • 73.
    Östergren, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Svensson, Anne-Lie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Lindquist, Nils Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Brittebo, Eva B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Dopamine melanin-loaded PC12 cells: A model for studies on pigmented neurons of substantia nigra2005In: Pigment Cell Research, ISSN 1755-1471, E-ISSN 1755-148X, Vol. 18, no 4, p. 306-314Article in journal (Refereed)
    Abstract [en]

    The most conspicuous feature in idiopathic parkinsonism is the degeneration of pigmented neurons in the substantia nigra. A major problem for the study of the significance of neuromelanin for the development of parkinsonism is that common experimental animals lack neuromelanin in substantia nigra. The aim of this study was to develop an in vitro model that could be used to study the role of neuromelanin in chemically induced toxicity in dopaminergic cells. Cultured neuron-like PC12 cells were exposed to synthetic dopamine melanin (0-1.0 mg/ml) for 48 h, resulting in uptake of dopamine melanin particles into the cells. The intracellular distribution of dopamine melanin granules was similar to that found in neuromelanin-containing neurons. Dopamine melanin, up to 0.5 mg/ml, had negligible effects on ultrastructure, induction of the endoplasmic reticulum-stress protein glucose regulating protein 78, activation of caspase-3 and cell viability. The decreased cell viability in response to the cytotoxic peptide amyloid-beta25-35 was similar in melanin-loaded cells and in control cells without melanin. The results of the studies suggest that melanin-loaded PC12 cells can serve as an in vitro model for studies on the role of neuromelanin for the toxicity of chemicals, in particular neurotoxicants with melanin affinity, in pigmented neurons.

12 51 - 73 of 73
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