High glucose exacerbates neuroinflammation and apoptosis at the intermediate stage after post-traumatic brain injury

Abstract

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. Considering that hyperglycemia influences inflammatory processes and neuronal survival, we examined the effects of high glucose on neuroinflammation and neuronal death during the intermediate phase of TBI. Rat models of type 2 diabetes mellitus and/or TBI were developed and behaviorally assessed. 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 mitogen-activated protein kinase kinase 5 (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-glucosetreated 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 highglucose conditions. Thus, high glucose exacerbated neuroinflammation and apoptosis in the intermediate stage post-TBI by inhibiting the MEK5/ERK5 pathway.

Hyperglycemia Aggravates Blood–Brain Barrier Disruption Following Diffuse Axonal Injury by Increasing the Levels of Inflammatory Mediators through the PPARγ/Caveolin-1/TLR4 Pathway

“…Hyperglycemia (both peak glucose and persistent hyperglycemia) in TBI patients is associated with injury severity and clinical outcomes [7,23,24] . Previous studies have shown that primary trauma evokes a cascade of changes that result in secondary axonal injury [25] .…”

“…Moreover, brain injury itself stimulates systemic in ammation, leading to increased permeability of the BBB, which is exacerbated by secondary brain injury. High glucose has been demonstrated to exacerbate neuroin ammation and apoptosis in the intermediate stage post-TBI by inhibiting the MEK5/ERK5 pathway [24] . In this study, the levels of in ammatory mediators, including TNF-α, IL-1β, and IL-6, were increased after DAI and OGD.…”

GLP-1(7–36) protected against oxidative damage and neuronal apoptosis in the hippocampal CA region after traumatic brain injury by regulating ERK5/CREB

“…Primary hippocampal neurons were cultivated as previously described [ 30 ]. Hippocampal neurons were isolated from hippocampal tissues extracted from 17-day-old SD rat embryos ( n = 54).…”

Hyperglycemia disrupted the integrity of the blood‐brain barrier following diffuse axonal injury through the sEH/NF‐κB pathway

“…Hyperglycemia has been regarded as one of the most used biomarkers with respect to the prognosis of various disorders, including TBI, cerebral ischemia/reperfusion, and subarachnoid hemorrhage. 22,23 Our previous study has found that hyperglycemia aggravates BBB disruption following DAI by increasing the levels of inflammatory mediators. 9 However, the role of hyperglycemia in neuronal and BBB damage after DAI needs further research.…”