TIGAR Attenuates High Glucose-Induced Neuronal Apoptosis via an Autophagy Pathway

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.

The Effect of TIGAR Knockdown on Apoptotic and Epithelial‐Mesenchymal Markers Expression in Doxorubicin‐Resistant Non‐Small Cell Lung Cancer A549 Cell Lines

“…Enhanced expression of TIGAR can ameliorate autophagy impairment and the decrease in G6PD in the neurons exposed to high glucose. [22] Thus, the role of TIGAR in adaptive cellular response in cancer cells is tightly related to the reprogramming glucose metabolism. However, whether TIGAR could regulate chemo-resistance of cancer cells by alteration of metabolic pathways remains unclear.…”

“…Presented results are conformed with recently reported data that TIGAR can contribute to anti-apoptotic effect through autophagy flux initiation. [22] Growing evidence demonstrates that besides tumor microenvironment, [48] the various cellular mechanisms including up regulated drug efflux [49] and EMT-related signaling pathways [50] are involved in the acquiring drug resistance. [51] The epithelial-mesenchymal transition plays an important role not only in embryonic development and tissue damage repair but also in the processes of invasion and metastasis by triggering the primary cancer epithelial cells into invasive, metastatic mesenchymal cancer cells with enhanced mobility.…”

Collateral Glucose-Utlizing Pathwaya in Diabetic Polyneuropathy

“…In new onset DPN within one year, the single nucleotide polymorphism (SNP) rs7648309 in transketolase was significantly correlated with an elevated total symptom score, and the rs62255988 SNP was correlated with delayed thermal threshold [ 8 ]. In an experimental DPN model, activation of glucose 6-phosphate dehydrogenase facilitated flux into the pentose phosphate pathway, resulting in inhibition of neuronal death due to hyperglycemia [ 9 ]. Thus, activation of the pentose phosphate pathway could ameliorate DPN.…”

“…The incidence of metabolic syndrome modifies the pathology of DPN in type 2 diabetes [ 6 , 7 ]. Hyperglycemia can activate multiple collateral glucose-utilizing pathways, such as the polyol pathway, protein kinase C (PKC) pathway, advanced glycation end-products (AGEs) formation, hexosamine biosynthetic pathway, pentose phosphate pathway, and anaerobic glycolytic pathway [ 1 , 5 , 8 , 9 , 10 ]. These mechanisms are assumed to individually or synergistically trigger the onset and progression of DPN.…”

Distal Symmetric Polyneuropathy Pain in Diabetes Mellitus

“…Pathophysiological studies report loss of nerve fibers, axonal degeneration, and demyelination associated with oxidative stress. The latter is induced by chronic hyperglycemia that causes mitochondrial damage and thus neural apoptosis (11,12).…”