Ischemia-Induced Brain Damage Depends on Specific Gap-Junctional Coupling

Abstract

Ischemic brain injury results in neuronal loss and associated neurologic deficits. Although there is some evidence that intercellular communication via gap junctions can spread oxidative cell injury, the possible role of gap-junctional communication in ischemia-induced cell death is the object of debate. Because gap junctions directly connect the cytoplasms of coupled cells, they offer a way to propagate stress signals from cell to cell. The authors investigated the contribution of gap-junctional communication to cell death using an in vitro ischemia model, which was reproduced by submersion of organotypic hippocampal slices into glucose-free deoxygenated medium. The gap-junctional blocker carbenoxolone significantly decreased the spread of cell death, as measured by propidium iodide staining, over a 48-hour period after the ischemic episode. Carbenoxolone ameliorated the hypoxia-induced impairment of the intrinsic neuronal electrophysiologic characteristics, as measured by whole-cell patch clamp recordings. To determine whether specific connexins were involved in the spread of postischemic cell death, the authors partially reduced the synthesis of specific connexins using antisense oligodeoxynucleotides. Simultaneous knockdown of two connexins localized mostly in neurons, connexins 32 and 26, resulted in significant neuroprotection 48 hours after the hypoxic-hypoglycemic episode. Similarly, partial reduction of the predominant glial connexin 43 significantly decreased cell death. These results indicate that gap-junctional communication contributes to the propagation of hypoxic injury and that specific gap junctions could be a novel target to reduce brain damage.

Increased Apoptosis and Inflammation after Focal Brain Ischemia in Mice Lacking Connexin43 in Astrocytes

“…Some reports note that astrocytic gap junctions spread the Ca 2ϩ wave after ischemic insult causing the expansion of stroke volume, 7,8 suggesting that the astrocytic gap junctions play a deleterious role in ischemic brain damage. In contrast, several reports have shown evidence for a neuroprotective role of astrocytic gap junctions.…”

“…Astrocytic gap junctions remain open during ischemia 6 and it is assumed that the wave of spreading depression passes through astrocytic gap junction channels causing expansion of stroke volume. 7,8 On the other hand, glial cells protect neurons from hypoxic depolarization. 9 In primary neuron-glial coculture and in hippocampal slice culture, gap junctional intercellular communication (GJIC) between astrocytes decreases neuronal vulnerability to oxidative stress.…”

The Complex of Ciliary Neurotrophic Factor-Ciliary Neurotrophic Factor Receptor α Up-Regulates Connexin43 and Intercellular Coupling in Astrocytes via the Janus Tyrosine Kinase/Signal Transducer and Activator of Transcription Pathway

“…It should not go without mention that other studies support the notion that gap junctions are detrimental to cells of the CNS in the wake of injury or disease (Rawanduzy et al, 1997;Saito et al, 1997;Cotrina et al, 1998;Rami et al, 2001;Frantseva et al, 2002). The conflicting notions of gap junctions as beneficial and detrimental agents may, however, be a product of the research model used, including animal species, injury type and Cx isoform impeded.…”

Protein kinase C γ mutations in the C1B domain cause caspase-3-linked apoptosis in lens epithelial cells through gap junctions

“…The passage of apoptotic signals through open gap junctions is linked to oxidative stressinduced cell death (Naus et al, 2001;Frantseva, 2002). Inhibition of gap junctions prevents cell death (Farahani et al, 2005;de Pina-Benabou et al, 2005;Krysko et al, 2005).…”