Inhibition of Connexin43 hemichannels with Gap19 protects cerebral ischemia/reperfusion injury via the JAK2/STAT3 pathway in mice

Targeting Connexin43 provides anti-inflammatory effects after intracerebral hemorrhage injury by regulating YAP signaling

“…Our data showed that TAT-Gap19 treatment did not in uence mouse neurobehavioral function under physiological conditions (P>0.05, Figure G-J), which is consistent with our previous studies [11,12]. The mNSSs of the mice were signi cantly increased by ICH damage, while TAT-Gap19 treatment markedly reduced mNSSs (11.20 ± 1.30 vs 6.50 ± 1.29, P<0.01, Figure 2G).…”

“…However, increasing evidence has demonstrated that blockers of Cx43Hcs can regulate many intracellular signaling pathways.Yin et al showed that carbenoxolone and Gap26, blockers of Cx43Hcs, signi cantly inhibit neuroin ammation in an astrocytic ischemia model by regulating PKC,PKB and Src signaling in both the membrane and cytoplasm [24].Li et al found that the Cx43 mimetic peptides Gap26 and Gap27 promote cytoplasmic degradation of astroglial Cx43 via the PI3K/Akt pathway in neonatal rats after ischemic brain injury [38]. Our previous study also found that Gap19 exerts its anti-in ammatory effects by inhibiting the activation of the JAK2/STAT3 and TLR4 signaling pathways in astrocytes after cerebral ischemic stroke [11,12]. Consistent with these results, we believe that modulating intracellular signaling pathways may change the function of astrocytic Cx43 on the cellular plasma membrane.…”

“…However, abnormal opening of Cx43Hcs on the surface of reactive astrocytes can release small molecules into the intercellular space under pathological conditions [33].These small molecules in uence the steady state of the cell microenvironment, which induces in ammatory and cell death programs by regulating the crosstalk between reactive astrocytes and other cells in the CNS [34]. De nite evidence has shown that like Cx43 overexpression, abnormal Cx43Hc opening leads to further brain damage in different CNS diseases.Suppressing pathological Cx43 expression can reduce the formation of hemichannels and promote the production of survival genes [35,36].Inhibition of Cx43Hcs with selective blockers has been shown to provide protective effects under different pathological stresses [37].Our previous research con rmed that Cx43Hc blockers signi cantly alleviate neurological de cits and infarct volume in a rodent model of ischemic stroke [12,38].To our knowledge,there have been no reports on the characteristics of Cx43Hcs after ICH injury.In our current study, sustained overexpression of Cx43 coupled with abnormal opening of Cx43Hcs was observed in a mouse model of ICH injury (Figure 1). Delayed treatment with the selective Cx43Hc blocker TAT-Gap19 for three days after ICH injury signi cantly blocked the excessive opening of Cx43Hcs and reduced neuronal apoptosis and white matter damage.Gap19 signi cantly alleviated the hematoma volume and neurological de cits after ICH injury (Figure 2).…”

“…The Cx43 mimetic peptide Gap19 is used as a selective blocker of Cx43Hcs in the CNS under pathological conditions [20,21]. Our previous research revealed that Gap19 provides protective effects against cerebral ischemic stroke by reducing infarct volume and alleviating neurological de cits [11,12].…”

Danegaptide Enhances Astrocyte Gap Junctional Coupling and Reduces Ischemic Reperfusion Brain Injury in Mice

“…We have recently shown that pharmacological inhibition of Cx43 hemichannels, without affecting Cx43 GJ coupling, is neuroprotective in stroke [26]. Similarly, Chen et al (2019) showed neuroprotective effects by inhibiting Cx43 hemichannels in an ischemia/reperfusion mouse model [27]. However, whether increasing astrocyte Cx43 coupling in brain ischemia is neuroprotective is unknown.…”