Spermidine prevents high glucose‐induced senescence in HT‐22 cells by upregulation of CB1 receptor

Abstract

Hyperglycaemia-induced neurotoxicity involved in the pathogenesis of diabetic encephalopathy and neuronal senescence is one of the worst effects of hyperglyceamic neurotoxicity. Cannabinoid receptor type 1 (CB1) has neuroprotective function in a series of neuropathy. Spermidine (Spd) has anti-aging function in many tissues. However, the role of Spd in hyperglyceamia-induced neuronal senescence remains unexplored. Therefore, we used high glucose (HG)-treated HT-22 cell as vitro model to investigate whether Spd protects neurons against hyperglyceamia-induced senescence and the mediatory role of CB1 receptor. The HT-22 cells were cultured in HG condition in the presence of different dose of Spd. Then, the viability of cells was measured by Cell Counting Kit-8 (CCK-8) assay. The senescence of cells was detected by Senescence-associated β-galactosidase (SA-β-Gal) staining. The expressions of p16 , p21 and CB1 receptor were measured by western blot. We found that Spd inhibited HG-induced neurotoxicity (the loss of cell viability) and senescence (the increase of SA-β-Gal positive cells, the upregulation of p16 and p21 ) in HT-22 cells. Also, Spd prevented HG-induced downregulation of CB1 receptor in HT-22 cells. Furthermore, we demonstrated that AM251 (a specific inhibitor of the CB1 receptor) reversed the protective effects of Spd on HG-induced neurotoxicity and senescence. These results indicated that Spd prevents HG-induced neurotoxicity and senescence via the upregulation of CB1 receptor. Our findings provide a promising future of Spd-based preventions and therapies for diabetic encephalopathy.

Hydrogen Sulfide Inhibits High Glucose-Induced Neuronal Senescence by Improving Autophagic Flux via Up-regulation of SIRT1

“…Due to their higher metabolic demands, HT22 cells require higher levels of glucose in normal growth media (25 mM glucose; Ward and Ergul, 2016). We have previously confirmed that treatment of HT22 cells with HG (150 mM) for 48 h, the cell viability was decreased to 70% compared with the control group (Zhu et al, 2018). In order to eliminate the effect of HG concentration on alteration of osmolarity, we have previously found that equal concentration of mannitol (150 mM) had no significant effect on the cell viability compared with the control group (Zhu et al, 2018).…”

“…Accumulating evidence demonstrates that long-term hyperglycemia causes neurotoxicity (Liu et al, 2014; Bahniwal et al, 2017; Li Y. et al, 2017; Renaud et al, 2018). It is well established that neuronal senescence plays a crucial role in the neurotoxicity of hyperglycemia (Sinadinos et al, 2014; Song et al, 2016; Zhu et al, 2018). Therefore, strategies to preserve neuronal cells by increasing the defenses of hyperglycemia-induced neuronal senescence are emerging as promising therapeutic approaches to prevent hyperglycemia-induced neurotoxicity.…”

Dietary and Gut Microbiota Polyamines in Obesity- and Age-Related Diseases

“…Likewise, in animal models, supplementation with polyamines could have a beneficial effect on several age-related disorders including memory decline, neuroinflammation, and cardiovascular disease (107, 180–182). Several in vitro studies have shown that the administration of spermidine in cell lines of neuronal origin inhibits the process of cellular senescence (183, 184). It has been proposed that the mechanism by which polyamines produces these beneficial anti-aging effects could be through the activation of autophagy (34, 101), either through the inhibition of the activity of the acetyltransferase EP300, which is involved in the modulation of autophagic flux (185–187), or the stabilization of pro-autophagic factors such as MAP1S (179).…”

Advancements in therapeutic drugs targeting of senescence

“… 174 Hyperglycaemia (HG)-induced neurotoxicity leads to the pathogenesis of diabetic encephalopathy and neuronal senescence, while spermidine can prevent HG-induced neurotoxicity and senescence. 81 In a kidney ischemia/reperfusion injury model, spermidine supplementation can markedly attenuate increases in plasma creatinine concentrations and tubular injury, inhibit oxidative stress, and suppress tissue necrosis. 175 The healthy aging effect of spermidine may be related to the enhancement of autophagy.…”