Specific Gap Junctions Enhance the Neuronal Vulnerability to Brain Traumatic Injury

Abstract

Traumatic brain injury results in neuronal loss and associated neurological deficits. Although most research on the factors leading to trauma-induced damage focuses on synaptic or ionic mechanisms, the possible role of direct intercellular communication via gap junctions has remained unexplored. Gap junctions connect directly the cytoplasms of coupled cells; hence, they offer a way to propagate stress signals from cell to cell. We investigated the contribution of gap junctional communication (GJC) to cell death using an in vitro trauma model. The impact injury, induced by a weight dropped on the distal CA1 area of organotypic hippocampal slices, results in glutamate-dependent cell loss. The gap junctional blockers carbenoxolone and octanol decreased significantly post-traumatic cell death, measured by propidium iodide staining over a 72 hr period after the impact. Dye coupling in the pyramidal layers was enhanced immediately after the injury and decreased over the following 24 hr. To determine whether specific connexins were involved in the spread of trauma-induced cell death, we used organotypic slices from connexin43 (Cx43) knock-out mice, as well as acute knock-outs by incubation with antisense oligodeoxynucleotides. Simultaneous knockdown of two neuronal connexins resulted in significant neuroprotection. Slices from the null-mutant Cx43 mice, as well as the acute Cx43 knockdown, also showed decreased cell death after the impact. The gap junctional blockers alleviated the trauma-induced impairment of synaptic function as measured by electrophysiological field potential recordings. These results indicate that GJC enhances the cellular vulnerability to traumatic injury. Hence, specific gap junctions could be a novel target to reduce injury and secondary damage to the brain and maximize recovery from trauma.

A1Receptor and Adenosinergic Homeostatic Regulation of Sleep-Wakefulness: Effects of Antisense to the A1Receptor in the Cholinergic Basal Forebrain

“…Lately, however, it has been suggested that sense controls do not provide any additional advantage over nonsense ODNs, especially because any potentially critical sequence motifs (recurring sequences of 3-8 bases in the mRNA) that may contribute to the structure or function of the targeted mRNA are lost (Stein, 1999). In addition, sense ODNs are known to produce nonspecific effects (Helene and Toulme, 1990;Nicot and Pfaff, 1997;Kalra and Kalra, 2000), including inhibition of the targeted protein (Georgieva et al, 1995), and therefore, several recent studies (in vivo and in vitro) have not used the sense control (Turchi and Sarter, 2001;Clayton et al, 2002;Frantseva et al, 2002;Grimpe et al, 2002;Torner et al, 2002). There also appears to be agreement that demonstration of antisense-induced suppression of the desired protein without any neurotoxicity and reversal of the behavioral changes after termination of antisense administration are essential to ascertain the efficacy and specificity of antisense (Nicot and Pfaff, 1997;Stein, 1999Stein, , 2001).…”

Role of connexin43 and ATP in long-range bystander radiation damage and oncogenesis in vivo

“…Alternatively, spread of sodium or calcium ions could instantly involve large number of neurons, resulting in more uniform damage (Frantseva et al, 2002). Here no evidence was obtained for spatial/ Figure 4 Role of the spinal cord and exogenous ATP in extending radiation injury to the unexposed brain.…”

Protective effects of carbenoxolone are associated with attenuation of oxidative stress in ischemic brain injury

“…In this study, we attempted to explore whether specific gap-junction blockers affect the cellular sensitivity to ischemic injury in rats and whether such blockade diminishes the diffusion of reactive oxygen species (ROS) in vitro. Carbenoxolone (CBX) is effective in blocking gap-junction coupling [15] , interferes little with synaptic function in vivo and in vitro [16][17][18][19] , and induces minimal changes in intrinsic neuronal characteristics [20,21] .…”