title: Vitamin D(3) attenuates 6-hydroxydopamine-induced neurotoxicity in rats.
abstract: Previous reports have demonstrated that exogeneous administration of glial cell line-derived neurotrophic factor (GDNF) reduces ventral mesencephalic (VM) dopaminergic (DA) neuron damage induced by 6-hydroxydopamine (6-OHDA) lesioning in rats. Recent studies have shown that 1,25-dihydroxyvitamin D(3) (D3) enhances endogenous GDNF expression in vitro and in vivo. The purpose of present study was to investigate if administration of D3 in vivo and in vitro would protect against 6-OHDA-induced DA neuron injury. Adult male Sprague-Dawley rats were injected daily with D3 or with saline for 8 days and then lesioned unilaterally with 6-OHDA into the medial forebrain bundle. Locomotor activity was measured using automated activity chambers. We found that unilateral 6-OHDA lesioning reduced locomotor activity in saline-pretreated animals. Pretreatment with D3 for 8 days significantly restored locomotor activity in the lesioned animals. All animals were sacrificed for neurochemical analysis 6 weeks after lesioning. We found that 6-OHDA administration significantly reduced dopamine (DA), 3,4-dihydroxy-phenylacetic acid (DOPAC) and homovanilic acid (HVA) levels in the substantia nigra (SN) on the lesioned side in the saline-treated rats. D3 pretreatment protected against 6-OHDA-mediated depletion of DA and its metabolites in SN. Using primary cultures obtained from the VM of rat embryos, we found that 6-OHDA or H(2)O(2) alone caused significant cell death. Pretreatment with D3 (10(-10) M) protected VM neurons against 6-OHDA- or H(2)O(2)-induced cell death in vitro. Taken together, our data indicate that D3 pretreatment attenuates the hypokinesia and DA neuronal toxicity induced by 6-OHDA. Since both H(2)O(2) and 6-OHDA may injure cells via free radical and reactive oxygen species, the neuroprotection seen here may operate via a reversal of such a toxic mechanism.
authors.affiliation: Department of Physiology, National Defense Medical Center, Taipei, Taiwan.
authors.forename: J Y
authors.initials: JY
authors.lastname: Wang
authors.forename: J N
authors.initials: JN
authors.lastname: Wu
authors.forename: T L
authors.initials: TL
authors.lastname: Cherng
authors.forename: B J
authors.initials: BJ
authors.lastname: Hoffer
authors.forename: H H
authors.initials: HH
authors.lastname: Chen
authors.forename: C V
authors.initials: CV
authors.lastname: Borlongan
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002762:Cholecalciferol / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D004347:Drug Interactions / Q000502:physiology*; D051100:Glial Cell Line-Derived Neurotrophic Factor; D007150:Immunohistochemistry; D008297:Male; D008636:Mesencephalon / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009410:Nerve Degeneration / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009498:Neurotoxins / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D016627:Oxidopamine / Q000494:pharmacology*; D010300:Parkinson Disease / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D013565:Sympatholytics / Q000494:pharmacology*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology
chemical_list: C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D009498:Neurotoxins; D013565:Sympatholytics; D002762:Cholecalciferol; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine