SKF-96365 attenuates toxin-induced neuronal injury through opposite regulatory effects on Homer1a and Homer1b/c in cultured rat mesencephalic cells

•SKF-96365 protects mesencephalic cells against MPP+ induced cytotoxicity.•SKF-96365 attenuates MPP+ induced calcium overload in DA neurons.•SKF-96365-induced protection is independent on TRPC1.•SKF-96365 regulates the expression of Homer1a and Homer1b/c. Disturbances in Ca2+ homeostasis have been i...

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Published in:Neuroscience letters 2013-05, Vol.543, p.183-188
Main Authors: Zeng, Xuan, Pan, Zhi-guo, Shao, Yu, Wu, Xiao-na, Liu, Shen-xi, Li, Nan-lin, Wang, Wei-min
Format: Article
Language:English
Subjects:
1-Methyl-4-phenylpyridinium
Animals
Calcium
Calcium - metabolism
Calcium Channel Blockers - pharmacology
Carrier Proteins - physiology
Cell Death
Cells, Cultured
Embryo, Mammalian - cytology
Homer
Homer Scaffolding Proteins
Imidazoles - pharmacology
Mesencephalon - cytology
Neurons - cytology
Neurons - drug effects
Neurons - metabolism
Neuroprotective Agents - pharmacology
Parkinsons disease
Rats
Rats, Sprague-Dawley
TRPC Cation Channels - metabolism
TRPC channel
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Summary:•SKF-96365 protects mesencephalic cells against MPP+ induced cytotoxicity.•SKF-96365 attenuates MPP+ induced calcium overload in DA neurons.•SKF-96365-induced protection is independent on TRPC1.•SKF-96365 regulates the expression of Homer1a and Homer1b/c. Disturbances in Ca2+ 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 30min 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.
ISSN:0304-3940
1872-7972
DOI:10.1016/j.neulet.2013.03.030