Abstract
Spermidine, a natural polyamine presented widely in mammalian cells, has been implicated to extend the lifespan of several model organisms by inducing autophagy. However, the effect of spermidine against neuronal damage has not yet been fully determined. In this study, neuronal cell injury was induced by treating PC12 cells and cortical neurons with 1 μM staurosporine (STS). We found that STS-induced cell injury could be efficiently attenuated by pretreatment with 1 mM spermidine. Spermidine inhibited the caspase 3 activation induced by STS. Moreover, STS incubation resulted in autophagic degradation failure, which could be attenuated by the pretreatment of spermidine. Knocking down the expression of Beclin 1 efficiently suppressed autophagosome and autolysosome accumulation, and abolished the protective effects of spermidine against STS-induced neurotoxicity. Increased Beclin 1 cleavage and partial nuclear translocation of Beclin 1 fragment was detected in STS-treated cells, which could be blocked by spermidine, pan-caspase inhibitor or caspase 3-specific inhibitor. The nuclear translocation of Beclin 1 fragment universally occurs in damaged neurons. Beclin 1 mutation at the sites of 146 and 149 prevented the intracellular re-distribution of Beclin 1 induced by STS. In addition, intraperitoneal injection of spermidine ameliorated ischemia/reperfusion-induced neuronal injury in the hippocampus and cortex of rats, possibly via blocking caspase 3 activation and consequent Beclin 1 cleavage. Our findings suggest that caspase 3-mediated Beclin 1 cleavage occurs in acute neuronal cell injury both in vitro and in vivo. The neuroprotective effect of spermidine may be related to inhibition of the caspase 3-mediated Beclin 1 cleavage and restoration of the Beclin 1-dependent autophagy.
Highlights
Spermidine, a naturally formed polyamine in mammalian living cells, has crucial roles in various cellular processes under pathophysiological conditions.[1]
We investigated the involvement of caspase 3-mediated Beclin 1 cleavage during neuronal cell injury using cultured neuronal cells and rodents brain samples
Our results showed that Beclin 1 cleavage followed by partial nuclear translocation of N-terminal fragments occurred universally in damaged neuronal cells
Summary
Spermidine, a naturally formed polyamine in mammalian living cells, has crucial roles in various cellular processes under pathophysiological conditions.[1] Recent studies highlight its ability in extending lifespan of many model organisms, including yeast, nematodes, flies and mice.[2,3] Importantly, the longevity-promoting activity of spermidine is known to be associated with its capacity in enhancing autophagy.[2,4] Exogenous supply of spermidine ameliorates the ageinduced memory impairment in fruit flies by eliciting autophagic activity.[5] the underlying mechanism of neuroprotection yielded by spermidine against acute or chronic neuronal injury remains largely unknown. Our findings indicate that spermidine may represent a promising natural compound for the treatment of neurological diseases
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