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5-Hydroxytryptophan: A precursor of serotonin influences regional blood-brain barrier breakdown, cerebral blood flow, brain edema formation, and neuropathology
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
Univ Maryland, Dept Pathol, Baltimore, MD 21201 USA.
Case Western Reserve Univ, Dept Pathol, Cleveland, OH 44106 USA.
Univ Med & Pharm, Dept Clin Neurosci, Cluj Napoca, Romania;RoNeuro Inst Neurol Res & Diagnost, Cluj Napoca, Romania.
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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. p. 1-44
Series
International Review of Neurobiology, ISSN 0074-7742 ; 146
National Category
Neurology Neurosciences
Identifiers
URN: urn:nbn:se:uu:diva-401922DOI: 10.1016/bs.irn.2019.06.005ISI: 000501592100002PubMedID: 31349924ISBN: 978-0-12-816754-0 (print)OAI: oai:DiVA.org:uu-401922DiVA, id: diva2:1385115
Funder
Swedish Research Council, 2710NIH (National Institute of Health), R01 AG028679AstraZenecaGöran Gustafsson Foundation for Research in Natural Sciences and MedicineAvailable from: 2020-01-13 Created: 2020-01-13 Last updated: 2020-01-13Bibliographically approved

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Sharma, ArunaSharma, Hari Shanker

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