IDF21-0041 Hyperglycemia aggravates apoptosis and neuroinflammation at the intermediate stage after post-traumatic brain injury

Abstract

Background: Traumatic brain injury (TBI) is a highly lethal event with a poor prognosis. Recovering residual neuronal function in the intermediate stage of TBI is important for treatment; however, neuroinflammation and neuronal apoptosis impede residual neuronal repair processes. Hyperglycemia influences inflammatory processes and neuronal survival. Aim: We explored the effects of high glucose on neuroinflammation and neuronal death during the intermediate phase of TBI. Method: Rat models of type 2 diabetes mellitus and/or TBI were developed and behaviorally assessed. The histopathological changes were detected by Hematoxylin and eosin staining. Proinflammatory and anti-inflammatory in serum and hippocampal tissue were tested. And neural apoptosis was observed by Tunel staining and the expression of cleaved caspase-3 (CC-3) protein and Bax/Bcl-2 ratio were recorded. In in vitro assays, levels of inflammatory factors and apoptosis associated proteins were measured after MEK5 activation. Immunofluorescence colocalization of neuron-specific nuclear protein and p-MEK5 was analyzed by immunofluorescence cytochemistry. Results: Neurological function and cognitive abilities were impaired in TBI rats and worsened by type 2 diabetes mellitus. Histopathological staining and analyses of serum and hippocampal mRNA and protein levels indicated that neuroinflammation and apoptosis were induced in TBI rats and exacerbated by hyperglycemia. Hyperglycemia inhibited hippocampal MEK5 phosphorylation in TBI rats. In vitro assays were used to assess inflammatory factor expression, apoptotic protein levels and neuronal survival after MEK5 activation in TBI- and/or high-glucose-treated neurons. MEK5/extracellular signal-regulated kinase 5 (ERK5) pathway activation reduced the inflammation, cleaved caspase-3 expression, Bax/Bcl-2 ratio and apoptosis of TBI neurons, even under high-glucose conditions. Discussion: Our results indicated that HG exacerbated hippocampal injury and exaggerated the neurological deficits and learning/memory problems after TBI. We observed that HG aggravated neuroinflammation partly by inhibiting the MEK5/ERK5 signaling pathway. In addition to activating inflammation, HG has been reported to reduce neuronal survival by upregulating CC-3 and disrupting the balance between Bax and Bcl-2. The pro-apoptotic effects of HG have frequently been observed in individuals exposed to prolonged hyperglycemia. ERK5 was found to inhibit endoplasmic reticulum stress and apoptosis in pancreatic β-cells, thereby ameliorating the tissue damage caused by hyperglycemia. In the present study, activation of MEK5/ERK5 may reduced TBI cauded neuronal apoptosis. In conclusion, HG exacerbated hippocampal injury after TBI, largely by disrupting the homeostasis of pro- and anti-inflammatory cytokines and inducing hippocampal neuronal apoptosis. The MEK5/ERK5 pathway participated in both of these processes. These experimental findings emphasize the importance of good glycemic control for the functional recovery of residual neurons in TBI patients.