Abstract
Hyperglycemia-induced neuronal apoptosis is one of the important reasons for diabetic neuropathy. Long-time exposure to high glucose accelerates many aberrant glucose metabolic pathways and eventually leads to neuronal injury. However, the underlying mechanisms of metabolic alterations remain unknown. TP53-inducible glycolysis and apoptosis regulator (TIGAR) is an endogenous inhibitor of glycolysis and increases the flux of pentose phosphate pathway (PPP) by regulating glucose 6-phosphate dehydrogenase (G6PD). TIGAR is highly expressed in neurons, but its role in hyperglycemia-induced neuronal injury is still unclear. In this study, we observed that TIGAR and G6PD are decreased in the hippocampus of streptozotocin (STZ)-induced diabetic mice. Correspondingly, in cultured primary neurons and Neuro-2a cell line, stimulation with high glucose induced significant neuronal apoptosis and down-regulation of TIGAR expression. Overexpression of TIGAR reduced the number of TUNEL-positive neurons and prevented the activation of Caspase-3 in cultured neurons. Furthermore, enhancing the expression of TIGAR rescued high glucose-induced autophagy impairment and the decrease of G6PD. Nitric oxide synthase 1 (NOS1), a negative regulator of autophagy, is also inhibited by overexpression of TIGAR. Inhibition of autophagy abolished the protective effect of TIGAR in neuronal apoptosis in Neuro-2a. Importantly, overexpression of TIGAR in the hippocampus ameliorated STZ-induced cognitive impairment in mice. Therefore, our data demonstrated that TIGAR may have an anti-apoptosis effect via up-regulation of autophagy in diabetic neuropathy.
Highlights
Diabetes mellitus (DM) is a systemic metabolic, disease and more than 60% patients are subjected to diabetic neuropathy, leading to severe neuronal injury and cognitive impairments (Vincent and Feldman, 2004; Sullivan et al, 2007; Vincent et al, 2011)
By immunofluorescent staining and western blotting for TP53-inducible glycolysis and apoptosis regulator (TIGAR), we observed that TIGAR was significantly decreased in the hippocampus of STZ-treated mice (Figures 1A–E)
We focus on the significance of TIGAR on neuronal glucose metabolism and provide several new insights into the effect of TIGAR on hyperglycemia-induced neuronal apoptosis
Summary
Diabetes mellitus (DM) is a systemic metabolic, disease and more than 60% patients are subjected to diabetic neuropathy, leading to severe neuronal injury and cognitive impairments (Vincent and Feldman, 2004; Sullivan et al, 2007; Vincent et al, 2011). Chronic hyperglycemia is the most prevalent characteristic of diabetes patients. TIGAR Prevents Hyperglycemia-Induced Apoptosis energy-demanding organ, consuming excessive amounts of glucose leads to an overloaded process. Many aberrant glucose metabolic pathways may be activated or up-regulated under chronic hyperglycemia (Luo et al, 2016). The activity of glucose 6-phosphate dehydrogenase (G6PD), a rate-limiting enzyme in the pentose phosphate pathway (PPP), is decreased after stimulation with high glucose (Okouchi et al, 2005; Sun et al, 2019). PPP has been regarded as a main metabolic pathway to regenerate glutathione at the expense of NADPH and protect neurons from oxidative stress (Herrero-Mendez et al, 2009). Understanding how to transform aberrant glucose metabolic pathways into antioxidant metabolic pathways may provide new therapeutic strategies for the treatment of diabetic neuropathy
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