Effects of mild induced hypothermia on hippocampal connexin 43 and glutamate transporter 1 expression following traumatic brain injury in rats

Abstract

Traumatic brain injury (TBI) is a common cause of worldwide disability and mortality. Currently, the incidence and prevalence of TBI is markedly increasing and an effective therapy is lacking. Therapeutic hypothermia (32‑35˚C) has been reported to reduce intracranial pressure and induce putative neuroprotective effects. However, the underlying molecular mechanisms remain to be elucidated. The aim of the present study was to investigate the effects of mild induced hypothermia (MIH) on the expression of connexin 43 (Cx43) and glutamate transporter 1 (GLT‑1) in the hippocampus following TBI in rats. A rat model of TBI was created using a modified weight‑drop device, followed by 4 h of hypothermia (33˚C) or normothermia (37˚C). A wet‑dry weight method was used to assess brain edema and spatial learning ability was evaluated using a Morris water maze. The levels of Cx43 and GLT‑1 were detected by immunohistochemical and western blot analysis, respectively. The results demonstrated that MIH treatment improved TBI‑induced brain edema and neurological function deficits. In addition, therapeutic MIH significantly downregulated Cx43 expression and upregulated the levels of GLT‑1 in the hippocampus post‑TBI. These findings suggested that treatment with MIH may provide a novel neuroprotective therapeutic strategy for TBI through reversing the increase in Cx43 protein and the decrease in GLT‑1.

Traumatic Brain Injury: Mechanisms of Glial Response

“…Studies in postmortem human brain tissue derived from TBI patients have demonstrated decreased expression of EAAT1 and 2 in astrocytes and microglia (Ikematsu et al, 2002;van Landeghem et al, 2006;Beschorner et al, 2007), which could contribute to impaired glutamate buffering. Mouse models of TBI have corroborated these observations (Rao et al, 1998;Li et al, 2015), and it could be reverted by treatment with ceftriaxone, an antibiotic that upregulates GLT-1 (Goodrich et al, 2013). In this regard, the increase expression in GLT-1 by ceftriaxone reduce post-traumatic seizures and gliosis (Goodrich et al, 2013).…”

The contribution of the meningeal immune interface to neuroinflammation in traumatic brain injury

“…Astrogliosis is categorized by increased GFAP + and vimentin across TBI models, yet away from the glial scar, the morphological significance of this gliosis is temporally and spatially dynamic [ 14 ]. They contribute to brain edema after injury [ 150 – 152 ], and contain decreased expression of GLT-1, GLAST and EAAT1/2, evidencing their role in TBI-induced glutamate dysregulation [ 153 – 156 ]. They also contribute directly to immune responses through DAMP/TLRs signaling as well as proinflammatory cytokine and chronic complement production after TBI [ 157 – 160 ].…”

Therapeutic hypothermia and targeted temperature management in traumatic brain injury: Clinical challenges for successful translation

“…To address this issue, experimental and clinical investigations have clarified an extensive list of injury processes that are sensitive to brain temperature variations during or following injury (Atkins et al, 2007; Chatzipanteli et al, 1999; Chatzipanteli et al, 2000; Polderman, 2009; Suzuki et al, 2003; Vitarbo et al, 2004). Previous review articles have thoroughly discussed these temperature sensitive processes that include excitotoxicity, free radical generation, programmed cell death and neuroinflammation (Dietrich, 1992; Dietrich et al, 2009; Dietrich and Bramlett, 2010; Han et al, 2015; Li et al, 2015; Lotocki et al, 2011; Truettner et al, 2005; Yenari and Han, 2012; Yenari and Han, 2013). In one early study using in vivo microdialysis, Globus and colleagues for example reported that extracellular levels of glutamate and indicators of free radical formation were dramatically reduced with hypothermia compared to normothermia (Globus et al, 1995).…”