Enhanced neurogenesis is involved in neuroprotection provided by rottlerin against trimethyltin-induced delayed apoptotic neuronal damage

초록

Aims: We here investigated the effect of lateand post-ictal treatment with rottlerin, a polyphenol compound isolated from Mallotus philippinensis, on delayed apoptotic neuronal death induced by trimethyltin (TMT) in mice. Main methods: Male C57BL/6N mice received a single injection of TMT (2.4 mg/kg, i.p.), and mice were treated with rottlerin after a peak time (i.e., 2 d post-TMT) of convulsive behaviors and apoptotic cell death (5.0 mg/kg, i.p. at 3 and 4 d after TMT injection). Object location test and tail suspension test were performed at 5 d after TMT injection. In addition, changes in the expression of apoptotic and neurogenic markers in the dentate gyrus were examined. Key findings: Lateand post-ictal treatment with rottlerin suppressed delayed neuronal apoptosis in the dentate gyrus, and attenuated memory impairments (as evaluated by object location test) and depression-like behaviors (as evaluated by tail suspension test) at 5 days after TMT injection in mice. In addition, rottlerin enhanced the expression of Sox2 and DCX, and facilitated p-ERK expression in BrdU-incorporated cells in the dentate gyrus of TMT-treated mice. Rottlerin also increased p-Akt expression, and attenuated the increase in the ratio of proapoptotic factors/anti-apoptotic factors, and consequent cytosolic cytochrome c release and caspase-3 cleavage. Rottlerin-mediated action was significantly reversed by SL327, an ERK inhibitor. Significance: Our results suggest that lateand post-ictal treatment with rottlerin attenuates TMT-induced delayed neuronal apoptosis in the dentate gyrus of mice via promotion of neurogenesis and inhibition of an ongoing apoptotic process through up-regulation of p-ERK.

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