title: Melatonin prevents dopaminergic cell loss induced by lentiviral vectors expressing A30P mutant alpha-synuclein.
abstract: Two hallmarks of Parkinson's disease (PD) are dopaminergic cell loss and the presence of cytoplasmic inclusions (Lewy bodies). Different point mutations in alpha-synuclein, the main constituent of Lewy bodies, have been identified in familial PD. Alpha-synuclein also constitutes one of the main components of Lewy bodies in sporadic cases of PD. Moreover, oxidant stress and generation of free radicals from both mitochondrial impairment and dopamine metabolism are considered to play critical roles in PD etiopathogenesis. Melatonin, a known potent antioxidant secreted by the pineal gland, may protect against the effect of several Parkinsonogenic compounds that are associated with progressive impairment of mitochondrial function and increased oxidative damage. However, the neuroprotective effect of melatonin has never been tested in the newly available genetic models of PD based on the viral expression of mutated alpha-synuclein. Lentiviral vectors encoding A30P mutant human alpha-synuclein (lenti-A30P) were stereotactically injected into the right substantia nigra of adult male Sprague-Dawley rats and neuroprotection was examined by administration of melatonin or vehicle from two days before nigral administration of lenti-A30P until eight weeks after injection. It was found that lenti-A30P induced a significant TH⁺ cell-loss both in the medial and lateral substantia nigra versus the contrallateral side injected with lenti-eGFP. However, melatonin administration showed a total neuroprotective effect in both regions of the substantia nigra. In conclusion, the data here show that melatonin is neuroprotective against mutant alpha-synuclein-induced injury in the substantia nigra.
authors: Department of Physiology, School of Medicine, University of La Laguna, Tenerife, Spain.
authors: J M
authors: JM
authors: Brito-Armas
authors: V
authors: V
authors: Baekelandt
authors: J R
authors: JR
authors: Castro-Hernández
authors: T
authors: T
authors: González-Hernández
authors: M
authors: M
authors: Rodríguez
authors: R
authors: R
authors: Castro
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000737:chemistry; D018076:DNA, Complementary / Q000378:metabolism; D004298:Dopamine / Q000737:chemistry; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins / Q000737:chemistry; D006801:Humans; D007150:Immunohistochemistry; D016086:Lentivirus / Q000235:genetics; D008297:Male; D008550:Melatonin / Q000737:chemistry*; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D018696:Neuroprotective Agents / Q000737:chemistry; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011954:Receptors, Dopamine / Q000737:chemistry*; D013378:Substantia Nigra / Q000378:metabolism; D051844:alpha-Synuclein / Q000235:genetics* / Q000378:metabolism
chemical_list: D000975:Antioxidants; D018076:DNA, Complementary; D018696:Neuroprotective Agents; D011954:Receptors, Dopamine; D051844:alpha-Synuclein; D049452:Green Fluorescent Proteins; D008550:Melatonin; D004298:Dopamine