uu.seUppsala University Publications
Change search
Link to record
Permanent link

Direct link
BETA
Sharma, Aruna
Alternative names
Publications (10 of 124) Show all publications
Sharma, A., Castellani, R. J., Smith, M. A., Muresanu, D. F., Dey, P. K. & Sharma, H. S. (2019). 5-Hydroxytryptophan: A precursor of serotonin influences regional blood-brain barrier breakdown, cerebral blood flow, brain edema formation, and neuropathology. In: Sharma, HS Sharma, A (Ed.), New Therapeutic Strategies for Brain Edema and Cell Injury: (pp. 1-44). Elsevier
Open this publication in new window or tab >>5-Hydroxytryptophan: A precursor of serotonin influences regional blood-brain barrier breakdown, cerebral blood flow, brain edema formation, and neuropathology
Show others...
2019 (English)In: New Therapeutic Strategies for Brain Edema and Cell Injury / [ed] Sharma, HS Sharma, A, Elsevier, 2019, p. 1-44Chapter in book (Refereed)
Abstract [en]

5-Hydroxytryptophan (5-HTP), a precursor of serotonin, is therapeutically used for several psychiatric disorders such as anxiety and depression in the clinic. However, severe side effects, including abnormal mental functions, behavioral disturbances and intolerance are associated with this treatment. 5-HTP-induced elevation of plasma and brain serotonin levels may affect blood-brain barrier (BBB) breakdown, edema formation and regional cerebral blood flow (CBF) disturbances. Breakdown of BBB to serum proteins leads to vasogenic brain edema formation and cellular injuries. However, 5-HTP-neurotoxicity is still not well known. In this investigations 5-HTP induced elevation of endogenous plasma and brain serotonin levels and its effect on BBB breakdown, edema formation neuronal injuries was examined in a rat model. Furthermore, potential role of oxidative stress and nitric oxide (NO) was evaluated. In addition, several neurochemical agents such as p-CPA (5-HT synthesis inhibitor) indomethacin (prostaglandin synthase inhibitor), diazepam (ant stress drug), cyproheptadine, ketanserin (5-HT2 receptor antagonists) and vinblastine (inhibitor of microtubule function) were examined on 5-HT neurotoxicity. Our observations suggest that 4h after 5-HTP administrations, the endogenous serotonin levels increased by fourfold (150mg/kg) in the plasma and brain associated with profound hyperthermia (+3.86 +/- 0.24 degrees C, oxidative stress and NO upregulation. Breakdown of the BBB to Evans blue albumin (EBA) in 8 brain regions and to ([131])Iodine in 14 brain regions was observed. The CBF exhibited marked reduction in all the brain regions examined. Brain edema and cellular injuries are present in the areas associated with BBB disruption. Drug treatments reduced the BBB breakdown, edema formation NO production and brain pathology. These observations are the first to point out that 5-HTP-neurotoxicity caused by BBB breakdown, edema formation and NO production is instrumental in causing adverse mental and behavioral abnormalities, not reported earlier.

Place, publisher, year, edition, pages
Elsevier, 2019
Series
International Review of Neurobiology, ISSN 0074-7742 ; 146
National Category
Neurology Neurosciences
Identifiers
urn:nbn:se:uu:diva-401922 (URN)10.1016/bs.irn.2019.06.005 (DOI)000501592100002 ()31349924 (PubMedID)978-0-12-816754-0 (ISBN)
Funder
Swedish Research Council, 2710NIH (National Institute of Health), R01 AG028679AstraZenecaGöran Gustafsson Foundation for Research in Natural Sciences and Medicine
Available from: 2020-01-13 Created: 2020-01-13 Last updated: 2020-01-13Bibliographically approved
Sharma, H. S., Muresanu, D. F., Nozari, A., Castellani, R. J., Dey, P. K., Wiklund, L. & Sharma, A. (2019). Anesthetics influence concussive head injury induced blood-brain barrier breakdown, brain edema formation, cerebral blood flow, serotonin levels, brain pathology and functional outcome. In: Sharma, HS Sharma, A (Ed.), New Therapeutic Strategies for Brain Edema and Cell Injury: (pp. 45-81). Elsevier
Open this publication in new window or tab >>Anesthetics influence concussive head injury induced blood-brain barrier breakdown, brain edema formation, cerebral blood flow, serotonin levels, brain pathology and functional outcome
Show others...
2019 (English)In: New Therapeutic Strategies for Brain Edema and Cell Injury / [ed] Sharma, HS Sharma, A, Elsevier, 2019, p. 45-81Chapter in book (Refereed)
Abstract [en]

Several lines of evidences show that anesthetics influence neurotoxicity and neuroprotection. The possibility that different anesthetic agents potentially influence the pathophysiological and functional outcome following neurotrauma was examined in a rat model of concussive head injury (CHI). The CHI was produced by an impact of 0.224N on the right parietal bone by dropping a weight of 114.6g from a 20cm height under different anesthetic agents, e.g., inhaled ether anesthesia or intraperitoneally administered ketamine, pentobarbital, equithesin or urethane anesthesia. Five hour CHI resulted in profound volume swelling and brain edema formation in both hemispheres showing disruption of the blood-brain barrier (BBB) to Evans blue and radio-iodine. A marked decrease in the cortical CBF and a profound increase in plasma or brain serotonin levels were seen at this time. Neuronal damages were present in several parts of the brain. These pathological changes were most marked in CHI under ether anesthesia followed by ketamine (35mg/kg, i.p.), pentobarbital (50 mg/kg, i.p.), equithesin (3 mL/kg, i.p.) and urethane (1 g/kg, i.p.). The functional outcome on Rota Rod performances or grid walking tests was also most adversely affected after CHI under ether anesthesia followed by pentobarbital, equithesin and ketamine. Interestingly, the plasma and brain serotonin levels strongly correlated with the development of brain edema in head injured animals in relation to different anesthetic agents used. These observations suggest that anesthetic agents are detrimental to functional and pathological outcomes in CHI probably through influencing the circulating plasma and brain serotonin levels, not reported earlier. Whether anesthetics could also affect the efficacy of different neuroprotective agents in CNS injuries is a new subject that is currently being examined in our laboratory.

Place, publisher, year, edition, pages
Elsevier, 2019
Series
International Review of Neurobiology, ISSN 0074-7742 ; 146
National Category
Anesthesiology and Intensive Care Neurosciences
Identifiers
urn:nbn:se:uu:diva-401923 (URN)10.1016/bs.irn.2019.06.006 (DOI)000501592100003 ()31349932 (PubMedID)978-0-12-816754-0 (ISBN)
Funder
Swedish Research Council, 2710Göran Gustafsson Foundation for Research in Natural Sciences and MedicineAstraZenecaNIH (National Institute of Health), R01 AG028679
Available from: 2020-01-10 Created: 2020-01-10 Last updated: 2020-01-10Bibliographically approved
Chen, H., Tan, Q., Xie, C., Li, C., Chen, Y., Deng, Y., . . . Sharma, H. S. (2019). Application of olfactory ensheathing cells in clinical treatment of spinal cord injury: meta-analysis and prospect. JOURNAL OF NEURORESTORATOLOGY, 7(2), 70-81
Open this publication in new window or tab >>Application of olfactory ensheathing cells in clinical treatment of spinal cord injury: meta-analysis and prospect
Show others...
2019 (English)In: JOURNAL OF NEURORESTORATOLOGY, ISSN 2324-2426, Vol. 7, no 2, p. 70-81Article in journal (Refereed) Published
Abstract [en]

Background:

A number of clinical trials of olfactory ensheathing cells (OECs) for the treatment of chronic spinal cord injury (SCI) have been carried out all over the world. However, their safety and efficacy have not been basically evaluated. Moreover, there are no uniform standards laid out for the use of optimal source, transplantation method and the dosage of OECs.

Objective:

This study evaluated the source, dose, and route of transplantation of OECs for the treatment of chronic SCI.

Methods:

PubMed, Cochrane Library, EMBASE, CNKI, and Wanfang Data were searched for the clinical studies of OECs in the treatment of chronic SCI on July 2018.

Results:

A total of 30 articles on OECs transplantation for chronic SCI were selected for comprehensive evaluation of OECs sources, doses, and transplantation methods. The efficacy of OECs in the treatment of chronic SCI was evaluated using Review Manager 5.3.

Conclusion:

Fetal OECs are the primary source of cells for the treatment of chronic SCI in OECs, with standardized cell-culture and quality-control processes. Fetal OECs can significantly improve the neurological function of patients with chronic SCI. It is an ideal cell therapy for neurorestoration. However to explore more precise and minimally invasive treatment options are required in the future.

Keywords
olfactory ensheathing cell (OEC), spinal cord injury (SCI), meta-analysis
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-396558 (URN)10.26599/JNR.2019.9040008 (DOI)000489629300003 ()
Available from: 2019-11-06 Created: 2019-11-06 Last updated: 2019-11-06Bibliographically approved
Muresanu, D. F., Sharma, A., Patnaik, R., Menon, P. K., Mössler, H. & Sharma, H. S. (2019). Exacerbation of blood-brain barrier breakdown, edema formation, nitric oxide synthase upregulation and brain pathology after heat stroke in diabetic and hypertensive rats. Potential neuroprotection with cerebrolysin treatment. In: Sharma, HS Sharma, A (Ed.), New Therapeutic Strategies for Brain Edema and Cell Injury: (pp. 83-102). Elsevier
Open this publication in new window or tab >>Exacerbation of blood-brain barrier breakdown, edema formation, nitric oxide synthase upregulation and brain pathology after heat stroke in diabetic and hypertensive rats. Potential neuroprotection with cerebrolysin treatment
Show others...
2019 (English)In: New Therapeutic Strategies for Brain Edema and Cell Injury / [ed] Sharma, HS Sharma, A, Elsevier, 2019, p. 83-102Chapter in book (Refereed)
Abstract [en]

There is a growing trend of hypertension among military and civilian populations due to lifetime stressful situations. If hypertension is uncontrolled it leads to development of diabetes and serious neurological complications. Most of the World populations live in temperate zone across the World. Thus, a possibility exists that these hypertensive and diabetic people may have external heat as potential risk factors for brain damage. We have seen brain edema and brain damage following exposure to heat stress at 38 degrees C for 4h. A possibility exists that heat exposure in diabetic-hypertensive (DBHY) cases exacerbates exacerbation of brain pathology and edema formation. This hypothesis is examined in a rat model. The role of nitric oxide (NO) in exacerbation of HS-induced brain pathology was also evaluated using nitric oxide synthase (NOS) immunoreactivity. Hypertensive rats (produced by two-kidney one clip (2K1C) method) were made diabetic with streptozotocine (50 mg/kg, i.p./day for 3 days) treatment. After 6 weeks, DBHY rats show 20-30 mM/L Blood Glucose and hypertension (180-200 mmHg). Subjection of these rats to 4h HS resulted in six- to eightfold higher BBB breakdown, brain edema formation and brain pathology. At this time, neuronal or inducible NOS expression was four- to sixfold higher in DBHY rats compared to controls. Interestingly, iNOS expression was higher than nNOS in DBHY rats. Cerebrolysin in high doses (10-mL/kg, i.v. instead of 5-mL/kg) induced significant neuroprotection and downregulation of nNOS and iNOS in DBHY animals whereas normal animals need only 5-mL/kg doses for this purpose. Our observations demonstrate that co-morbidly factors exacerbate brain damage in HS through NOS expression and require double dose of cerebrolysin for neuroprotection as compared to normal rats, not reported earlier.

Place, publisher, year, edition, pages
Elsevier, 2019
Series
International Review of Neurobiology, ISSN 0074-7742 ; 146
National Category
Neurology Anesthesiology and Intensive Care
Identifiers
urn:nbn:se:uu:diva-401921 (URN)10.1016/bs.irn.2019.06.007 (DOI)000501592100004 ()31349933 (PubMedID)978-0-12-816754-0 (ISBN)
Funder
Swedish Research Council, 2710Göran Gustafsson Foundation for Research in Natural Sciences and MedicineAstraZeneca
Available from: 2020-01-10 Created: 2020-01-10 Last updated: 2020-01-10Bibliographically approved
Ozkizilcik, A., Sharma, A., Vicente Lafuente, J., Muresanu, D. F., Castellani, R. J., Nozari, A., . . . Sharma, H. S. (2019). Nanodelivery of cerebrolysin reduces pathophysiology of Parkinson's disease. In: Sharma, A Sharma, HS (Ed.), NANONEUROPROTECTION AND NANONEUROTOXICOLOGY: (pp. 201-246). ACADEMIC PRESS LTD-ELSEVIER SCIENCE LTD
Open this publication in new window or tab >>Nanodelivery of cerebrolysin reduces pathophysiology of Parkinson's disease
Show others...
2019 (English)In: NANONEUROPROTECTION AND NANONEUROTOXICOLOGY / [ed] Sharma, A Sharma, HS, ACADEMIC PRESS LTD-ELSEVIER SCIENCE LTD , 2019, p. 201-246Chapter in book (Refereed)
Abstract [en]

Parkinson's disease (PD) is affecting >10 million people worldwide for which no suitable cure has been developed so far. Roughly, about two people per thousand populations are affected with PD like symptoms especially over the age of 50. About 1% of the populations above 60 years suffer from PD-like disease. The prevalence of the disease is increasing over the years, and future projections by 2020 could be 12-14 millions people affected by the disease. Thus, exploration of suitable therapeutic measures is the need of the hour to enhance quality of the life of PD patients. PD induced brain pathology includes loss of dopaminergic neurons in the substantia niagra that could later extends to other cortical regions causing loss of voluntary motor control. Deposition of alpha-synuclein in the brain further leads to neurodegeneration. However, the exact cause of PD is still unknown. It appears that breakdown of the blood-brain barrier (BBB) and leakage of serum component into the brain could lead to neurodegeneration in PD. Thus, novel treatment strategies that are able to restore BBB breakdown and enhance neuronal plasticity and neuroregeneration in PD could be effective in future therapy. With the advancement of nanotechnology, it is worthwhile to understand the role of nanodelivery of selected agents in PD to enhance neuroprotection. In this review new role of BBB, brain edema, and neuropathology in PD is discussed. In addition, superior neuroprotection induced by nanowired delivery of a multimodal drug cerebrolysin in PD is summarized based on our own investigations.

Place, publisher, year, edition, pages
ACADEMIC PRESS LTD-ELSEVIER SCIENCE LTD, 2019
Series
Progress in Brain Research, ISSN 0079-6123 ; 245
Keywords
Parkinson's disease, Blood-brain barrier, Brain edema, Alpha-synuclein, Cerebrolysin, Nanowired delivery
National Category
Neurology Neurosciences
Identifiers
urn:nbn:se:uu:diva-401953 (URN)10.1016/bs.pbr.2019.03.014 (DOI)000500699500007 ()30961868 (PubMedID)978-0-444-64208-0 (ISBN)
Available from: 2020-01-10 Created: 2020-01-10 Last updated: 2020-01-10Bibliographically approved
Sharma, A. & Sharma, H. S. (2019). Nanoneuroprotection and Nanoneurotoxicology. In: Sharma, A Sharma, HS (Ed.), NANONEUROPROTECTION AND NANONEUROTOXICOLOGY: (pp. XIII-XVI). ACADEMIC PRESS LTD-ELSEVIER SCIENCE LTD
Open this publication in new window or tab >>Nanoneuroprotection and Nanoneurotoxicology
2019 (English)In: NANONEUROPROTECTION AND NANONEUROTOXICOLOGY / [ed] Sharma, A Sharma, HS, ACADEMIC PRESS LTD-ELSEVIER SCIENCE LTD , 2019, p. XIII-XVIChapter in book (Refereed)
Place, publisher, year, edition, pages
ACADEMIC PRESS LTD-ELSEVIER SCIENCE LTD, 2019
Series
Progress in Brain Research, ISSN 0079-6123 ; 245
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-401948 (URN)000500699500001 ()30961874 (PubMedID)978-0-444-64208-0 (ISBN)
Available from: 2020-01-10 Created: 2020-01-10 Last updated: 2020-01-10Bibliographically approved
Sharma, H. S., Muresanu, D. F., Castellani, R. J., Nozari, A., Vicente Lafuente, J., Tian, Z. R., . . . Sharma, A. (2019). Nanowired delivery of cerebrolysin with neprilysin and p-Tau antibodies induces superior neuroprotection in Alzheimer's disease. In: Sharma, A Sharma, HS (Ed.), NANONEUROPROTECTION AND NANONEUROTOXICOLOGY: (pp. 145-200). ACADEMIC PRESS LTD-ELSEVIER SCIENCE LTD
Open this publication in new window or tab >>Nanowired delivery of cerebrolysin with neprilysin and p-Tau antibodies induces superior neuroprotection in Alzheimer's disease
Show others...
2019 (English)In: NANONEUROPROTECTION AND NANONEUROTOXICOLOGY / [ed] Sharma, A Sharma, HS, ACADEMIC PRESS LTD-ELSEVIER SCIENCE LTD , 2019, p. 145-200Chapter in book (Refereed)
Abstract [en]

Alzheimer's disease (AD) is estimated to be afflicting over 55 millions of individual worldwide in 2018-19 for which no suitable clinical therapeutic measures have been developed so far. Thus, there is an urgent need to explore novel therapeutic strategies using nanodelivery of drugs and agents either alone or in combination for superior neuroprotection in AD and enhanced quality of life of the affected individuals. There are reports that AD is often associated with diminished neurotrophic factors and neprilysin together with enhancement of phosphorylated Tau (p-Tau) within the brain and in the cerebrospinal fluid (CSF). Thus, studies aiming to enhance neurotrophic factors and neprilysin together with neutralizing p-Tau within the central nervous system (CNS) may alleviate brain pathology in AD. In this review these strategies are discussed using nanotechnological approaches largely based on our own investigations in relation to current literature in the field.

Place, publisher, year, edition, pages
ACADEMIC PRESS LTD-ELSEVIER SCIENCE LTD, 2019
Series
Progress in Brain Research, ISSN 0079-6123 ; 245
Keywords
Alzheimer's disease, Neurotrophic factors, Cerebrolysin, Antibodies, Phosphorylated Tau protein, Brain pathology, Blood-brain barrier, Brain edema, Nanowired delivery
National Category
Neurology Neurosciences
Identifiers
urn:nbn:se:uu:diva-401956 (URN)10.1016/bs.pbr.2019.03.009 (DOI)000500699500006 ()30961867 (PubMedID)978-0-444-64208-0 (ISBN)
Available from: 2020-01-10 Created: 2020-01-10 Last updated: 2020-01-10Bibliographically approved
Niu, F., Sharma, A., Feng, L., Ozkizilcik, A., Muresanu, D. F., Vicente Lafuente, J., . . . Sharma, H. S. (2019). Nanowired delivery of DL-3-n-butylphthalide induces superior neuroprotection in concussive head injury. In: Sharma, A Sharma, HS (Ed.), NANONEUROPROTECTION AND NANONEUROTOXICOLOGY: (pp. 89-118). ACADEMIC PRESS LTD-ELSEVIER SCIENCE LTD
Open this publication in new window or tab >>Nanowired delivery of DL-3-n-butylphthalide induces superior neuroprotection in concussive head injury
Show others...
2019 (English)In: NANONEUROPROTECTION AND NANONEUROTOXICOLOGY / [ed] Sharma, A Sharma, HS, ACADEMIC PRESS LTD-ELSEVIER SCIENCE LTD , 2019, p. 89-118Chapter in book (Refereed)
Abstract [en]

Concussive head injury (CHI) is quite prevalent in military personnel leading to lifetime disability in more than 85% of cases. Other reasons of CHI include motor vehicle accident, fall or blunt trauma under various conditions. In United States of America (USA) alone more than 150k cases of head injury are added every year for which no suitable therapeutic strategies are still available. Thus, there is a need to expand our knowledge in treating CHI cases with novel therapeutic measures to enhance the quality of life of head injury victims. With recent advancements in nanodelivery of drugs for superior neuroprotective effects in neurological diseases, our laboratory is engaged in understanding the role of nanowired delivery of suitable drugs in treating CHI and other neurodegenerative diseases. DL-3-n-butylphthalide (NBP) is an extract of Chinese celery and is able to induce profound neuroprotection following ischemic stroke and other related neurological dysfunction. Thus, it is quite likely that synthetic NBP could have pronounced neuroprotective effects in CHI as well. We believe that nanodelivery of NBP have superior neuroprotection in CHI. In this review neuroprotective effects of nanowired delivery of NBP in CHI induced brain pathology is described. Our experimental observations show that nanowired delivery of NBP results in superior neuroprotection than the regular NBP in CHI. The probable mechanisms and functional significance of our finding in relation to military medicine is discussed based on our own investigations.

Place, publisher, year, edition, pages
ACADEMIC PRESS LTD-ELSEVIER SCIENCE LTD, 2019
Series
Progress in Brain Research, ISSN 0079-6123 ; 245
Keywords
Concussive head injury, Blood-brain barrier, Brain edema, DL-3-n-butylphthalide (NBP), TiO2 nanowired delivery, Neuroprotection
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-401955 (URN)10.1016/bs.pbr.2019.03.008 (DOI)000500699500004 ()30961873 (PubMedID)978-0-444-64208-0 (ISBN)
Available from: 2020-01-10 Created: 2020-01-10 Last updated: 2020-01-10Bibliographically approved
Sharma, A., Patnaik, R. & Sharma, H. S. (2019). Neuroprotective effects of 5-HT3 receptor antagonist ondansetron on morphine withdrawal induced brain edema formation, blood-brain barrier dysfunction, neuronal injuries, glial activation and heat shock protein upregulation in the brain. In: Sharma, HS Sharma, A (Ed.), New Therapeutic Strategies for Brain Edema and Cell Injury: (pp. 209-228). Elsevier
Open this publication in new window or tab >>Neuroprotective effects of 5-HT3 receptor antagonist ondansetron on morphine withdrawal induced brain edema formation, blood-brain barrier dysfunction, neuronal injuries, glial activation and heat shock protein upregulation in the brain
2019 (English)In: New Therapeutic Strategies for Brain Edema and Cell Injury / [ed] Sharma, HS Sharma, A, Elsevier, 2019, p. 209-228Chapter in book (Refereed)
Abstract [en]

Morphine withdrawal response is associated with brain edema formation, blood-brain barrier (BBB) disruption, activation of glial cells and heat shock protein (HSP 72kDa) responses in the CNS. Thus, exploration of suitable therapeutic measures is the need of the hour to induce neuroprotection in morphine withdrawal cases. There are reports that 5-HT3-receptor antagonists ondansetron attenuate some of the behavioral changes in morphine-withdrawal symptoms. However, brain protection in morphine withdrawal using pharmacological approaches is still not well known. In present investigation, effect of ondansetron the potent 5-HT3 receptor antagonist on brain edema formation BBB disruption, glial activation and/or HSP response following morphine withdrawal was examined. Rats received ondansetron (1mg or 2mg/kg, s.c) or saline once daily from 2 days before morphine administration (10 mg/kg, s.c. once daily for 10 days) that continued up to 2days after its withdrawal (day 13th). Cessation of morphine on day 11th results in withdrawal symptoms and BBB breakdown to proteins in the cerebral cortex, hippocampus, cerebellum, thalamus, hypothalamus, brain stem and spinal cord along with activation of glial fibrillary acidic protein (GFAP) and HSP immunoreactivity. In these animals brain edema and neurotoxicity are prominent on day 13th as compared to controls. Ondansetron treatment significantly reduced withdrawal symptoms on the day 13th in a dose dependent manner and attenuated BBB breakdown, edema formation, GFAP and HSP expression and neuronal injuries. These observations are the first to show that ondansetron is neuroprotective following morphine withdrawal indicating an important role of 5-HT3 receptors in psychostimulants abuse.

Place, publisher, year, edition, pages
Elsevier, 2019
Series
International Review of Neurobiology, ISSN 0074-7742 ; 146
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-401913 (URN)10.1016/bs.irn.2019.06.011 (DOI)000501592100008 ()31349928 (PubMedID)978-0-12-816754-0 (ISBN)
Funder
Swedish Research Council, 2710
Available from: 2020-01-13 Created: 2020-01-13 Last updated: 2020-01-13Bibliographically approved
Sharma, H. S., Feng, L., Muresanu, D. F., Castellani, R. J. & Sharma, A. (2019). Neuroprotective effects of a potent bradykinin B2 receptor antagonist HOE-140 on microvascular permeability, blood flow disturbances, edema formation, cell injury and nitric oxide synthase upregulation following trauma to the spinal cord. In: Sharma, HS Sharma, A (Ed.), New Therapeutic Strategies for Brain Edema and Cell Injury: (pp. 103-152). Elsevier
Open this publication in new window or tab >>Neuroprotective effects of a potent bradykinin B2 receptor antagonist HOE-140 on microvascular permeability, blood flow disturbances, edema formation, cell injury and nitric oxide synthase upregulation following trauma to the spinal cord
Show others...
2019 (English)In: New Therapeutic Strategies for Brain Edema and Cell Injury / [ed] Sharma, HS Sharma, A, Elsevier, 2019, p. 103-152Chapter in book (Refereed)
Abstract [en]

Bradykinin is a mediator of vasogenic brain edema formation. Recent reports suggest that bradykinin interacts with nitric oxide synthase (NOS) system in the central nervous system (CNS). However, role of bradykinin in spinal cord injury (SCI) induced alterations in the blood-spinal cord barrier (BSCB), spinal cord blood flow (SCBF), edema formation and cell changes are still not well known. Our previous reports showed that SCI induces marked upregulation of neuronal NOS (nNOS) in the cord associated with BSCB disruption, edema formation and cell injury. Thus, a possibility exists that bradykinin participates in SCI induced nNOS upregulation and cord pathology. To explore this idea a potent bradykinin B2 receptor antagonist HOE-140 was used in our rat model of SCI and cord pathology. SCI was inflicted in Equithesin anesthetized rats by making a longitudinal incision (2mm deep and 5mm long) into the right dorsal horn of the T10-11 segment. The animals were allowed to survive 5h after injury. A focal SCI significantly disrupted BSCB to Evans blue and I-[131]-sodium in the traumatized and adjacent segments. Interestingly, far remote spinal cord segments C4 and T5 segments also affected within 5 h. These spinal cord segments also exhibited pronounced reductions in the SCBF (mean-30%), increased edematous swelling and profound neuronal damages. Upregulation of nNOS expression is seen in both the dorsal and ventral horns of the spinal cord exhibiting cord pathology. At the ultrastructural level, exudation of lanthanum is seen within the endothelial cell cytoplasm and occasionally in the basal lamina. Pretreatment with low doses of HOE-140 (0. 1mg to 1mg/kg, i.v.) 30 min prior to SCI significantly enhanced the SCBF and reduced the BSCB disruption, edema formation, nNOS upregulation and cell injury. However, HOE-140 in doses ranging from 2mg to 5mg/kg, i.v. did not induce significant neuroprotection. These observations are the first to suggest that bradykinin B2 receptors play an important role in BSCB permeability, SCBF, edema formation, nNOS upregulation and cell injury following acute SCI, not reported earlier.

Place, publisher, year, edition, pages
Elsevier, 2019
Series
International Review of Neurobiology, ISSN 0074-7742 ; 146
National Category
Cell and Molecular Biology Neurology
Identifiers
urn:nbn:se:uu:diva-401917 (URN)10.1016/bs.irn.2019.06.008 (DOI)000501592100005 ()31349925 (PubMedID)978-0-12-816754-0 (ISBN)
Funder
Swedish Research Council, 2710Göran Gustafsson Foundation for Research in Natural Sciences and MedicineAstraZenecaNIH (National Institute of Health), R01 AG028679
Available from: 2020-01-13 Created: 2020-01-13 Last updated: 2020-01-13Bibliographically approved
Organisations

Search in DiVA

Show all publications