title: SKF-96365 attenuates toxin-induced neuronal injury through opposite regulatory effects on Homer1a and Homer1b/c in cultured rat mesencephalic cells.
abstract: Disturbances in Ca(2+) homeostasis have been implicated in a variety of neuro-pathological conditions including Parkinson's disease (PD). In the present study, we investigated the potential protective effect of SKF-96365, an originally identified blocker of receptor-mediated calcium entry, on MPP(+) induced neuronal injury in cultured rat mesencephalic cells. We found that pretreatment with SKF-96365 30 min before injury significantly reduced nuclear damage, decreased LDH release and inhibited apoptotic neuronal death. The results of calcium image also showed that SKF-96365 inhibited the increase of intracellular calcium induced by MPP(+), which was not dependent on the expression and function of TRPC1. In addition, SKF-96365 increased the expression of Homer1a, but decreased the expression of Homer1b/c in the presence or absence of MPP(+). Furthermore, overexpression of Homer1a by using recombinant lentivirus and knockdown of Homer1b/c by short interfering RNA (siRNA) further enhanced protective effects of SKF-96365 against MPP(+) injury. Taken together, these data suggest that SKF-96365 protects cultured rat mesencephalic cells against MPP(+) induced cytotoxicity, and this protection may be at least in part dependent on attenuating intracellular calcium overload, opposite regulatory effects on Homer1a and Homer1b/c expressions.
authors.affiliation: Department of Neurosurgery, Guangzhou General Hospital of Guangzhou Military Command, Guangzhou 510010, China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Zeng
authors.forename: Zhi-Guo
authors.initials: ZG
authors.lastname: Pan
authors.forename: Yu
authors.initials: Y
authors.lastname: Shao
authors.forename: Xiao-Na
authors.initials: XN
authors.lastname: Wu
authors.forename: Shen-Xi
authors.initials: SX
authors.lastname: Liu
authors.forename: Nan-Lin
authors.initials: NL
authors.lastname: Li
authors.forename: Wei-Min
authors.initials: WM
authors.lastname: Wang
mesh_terms: D015655:1-Methyl-4-phenylpyridinium; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002352:Carrier Proteins / Q000502:physiology*; D016923:Cell Death; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology; D000072233:Homer Scaffolding Proteins; D007093:Imidazoles / Q000494:pharmacology*; D008636:Mesencephalon / Q000166:cytology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D050052:TRPC Cation Channels / Q000378:metabolism
chemical_list: D002121:Calcium Channel Blockers; D002352:Carrier Proteins; D000072233:Homer Scaffolding Proteins; D007093:Imidazoles; D018696:Neuroprotective Agents; D050052:TRPC Cation Channels; C096351:transient receptor potential cation channel, subfamily C, member 1; C063159:1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole; D015655:1-Methyl-4-phenylpyridinium; D002118:Calcium