A Key Role for Connexin Hemichannels in Spreading Ischemic Brain Injury

Abstract

Brain damage resulting from cerebral ischemia remains a significant problem at all stages of life. In adults, ischemic stroke is the third leading cause of death and the leading cause of disability in the developed world. In term newborns, moderate to severe brain damage after hypoxia-ischemia (HI) occurs in 1-3 per 1000 live births. One of the most striking features of HI injury is that after initial recovery of cellular oxidative metabolism, there is a delayed, 'secondary' mitochondrial failure that spreads over time from the most severely damaged areas outwards, into previously undamaged regions. This secondary failure is accompanied by transient seizure activity and cytotoxic edema. The specific mechanisms of this spread are poorly understood, but it is at least partly associated with spreading waves of depression that can trigger cell death in neighboring uninjured tissues. The waves are propagated through cell-cell communication via gap junction channels (the so called "bystander effect"). It has recently been proposed that unopposed connexin hemichannels (connexons) also play a significant role by mediating release of paracrine molecules that in turn propagate cell death messages by releasing intracellular mediators such as ATP, NAD(+), or glutamate or by abnormally prolonged opening to allow cell edema. There is increasing evidence that connexin hemichannels contribute to injury after many neural insults and that it is possible to significantly reduce the spread of damage after injury by suppressing the induction or activity of the connexin proteins that form hemichannels.

Chronic Cerebral Hypoperfusion Induced Synaptic Proteome Changes in the rat Cerebral Cortex

“…Among them, GJA1, SLCA2 and Leukocyte surface antigen CD47 (CD47) showed decreased, while APOE, MAP2K1, TF and PEA-15 showed increased expression in CCH rats. Interestingly, downregulation or absence of GJA1 reduced neuronal loss, capillary fragmentation, astrocytosis and microglia activation (Davidson et al, 2013), while reactive astrogliosis increases GJA1 expression (Masaki et al, 2013, Wallach et al, 2014. Moreover, brain microgliosis and astrogliosis are also affected in APOE transgenic mice (Bales et al, 1999) and the absence of APOE dramatically reduced amyloid deposition and the resulting astrogliosis and microgliosis (Ophir et al, 2003).…”

Oxidative Stress in Hypoxic-Ischemic Encephalopathy: Molecular Mechanisms and Therapeutic Strategies

“…Previous research has revealed that unopposed connexons also play an important role. They mediate the release of paracrine molecules, which in turn transmit cell death messages by the secretion of intracellular mediators (such as ATP, Nicotinamide adenine dinucleotide (NAD + ), and glutamate), which ultimately leads to cell edema [103,104]. …”

Can heart function lost to disease be regenerated by therapeutic targeting of cardiac scar tissue?

“…Decreased electrical coupling during acute MI has been correlated with dephosphorylation and reorganization of Cx43, as well as translocation from the cell surface to intracellular pools [60,61]. While the reduction in Cx43 is likely a protective mechanism (GJs are implicated in the spread of injury signals in skin [62], neural tissues [63], and heart [64]), Cx43 lateralization interrupts normal electrical conduction patterns in the heart, and may contribute to arrhythmias [10–13]. …”