Induction of autophagy by spermidine is neuroprotective via inhibition of caspase 3-mediated Beclin 1 cleavage

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.

Spermidine reduces cancer-related mortality in humans

“…The association between high spermidine uptake and reduced mortality is independent from confounding factors including age, sex, body mass index, consumption of alcohol or aspirin, metabolic syndrome, diabetes, physical activity, and socioeconomic status, as well as conventional dietary scores distinguishing healthy from unhealthy eating. These results confirm our long-lasting suspicion that spermidine has broad health-improving effects [2][3][4][5][6][7][8][9], based on our observation that nutritional supplementation of this polyamine can extend the longevity of multiple model species, including yeast, nematodes, flies and mice [10][11][12]. Here, we explore the literature linking spermidine to reduced cancer risk.…”

Spermidine‐enhanced autophagic flux improves cardiac dysfunction following myocardial infarction by targeting the AMPK/mTOR signalling pathway

“…Recent studies have proposed that spermidine can induce autophagy in several cellular models (Yang et al, ; Zheng et al, ). Thus, to determine whether stimulation with spermidine might promote autophagic flux in Ang II‐treated NRCs, protein expression of the autophagy‐associated molecules (LC3 II and p62) was evaluated after spermidine administration.…”

Autophagy induction in the treatment of Alzheimer's disease

“…Another less studied inducer of autophagy is spermidine, whose levels decline with aging, and a possible connection between reduced endogenous spermidine levels and age-related degeneration has been suggested (Madeo, Bauer, Carmona-Gutierrez, & Kroemer, 2019). It was shown to induce neuroprotective autophagy by several mechanisms, including prevention of beclin cleavage 1 by caspase-3, which occurs under various neuronal damage conditions, including AD, as well as by enhancing expression of ATGs and by inhibiting the endogenous autophagy repressor EP300 (Madeo et al, 2019;Morselli et al, 2009;Yang et al, 2017). Spermidine also prevented Aβ aggregation in vitro and improved age-induced memory impairments in vivo (Nirzhor, Khan, & Neelotpol, 2018).…”