Inhibition of the Connexin 43 Elevation May be Involved in the Neuroprotective Activity of Leptin Against Brain Ischemic Injury

Deng, Zihui; Liao, Jie; Zhang, Jinying; Chen, Liang; Song, Cuihong; Han, Ming; Wang, Lu-Huan; Hou, Xue; Zhang, Kai; Zabeau, Lennart; Tavernier, Jan; Yan, Gaoliang

doi:10.1007/s10571-014-0066-5

Cited by 31 publications

(24 citation statements)

References 25 publications

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“…Cx43 Is Increased After HI Injury While brain injury has been shown to increase Cx43 expression in brain and retina (Danesh-Meyer et al, 2012;Deng et al, 2014;Haupt et al, 2007), there is no prior study on Cx43 expression after cerebral HI injury in neonatal rats. In this study, we examined the dynamic expression of Cx43 after HI injury.…”

Section: Resultsmentioning

confidence: 99%

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Inhibition of connexin43 improves functional recovery after ischemic brain injury in neonatal rats

Zhao

Tan

et al. 2015

Glia

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Connexin43 (Cx43) is one of the most abundant gap junction proteins in the central nervous system. Abnormal opening of Cx43 hemichannels after ischemic insults causes apoptotic cell death. In this study, we found persistently increased expression of Cx43 8 h to 7 d after hypoxia/ischemia (HI) injury in neonatal rats. Pre-treatment with Gap26 and Gap27, two Cx43 mimetic peptides, significantly reduced cerebral infarct volume. Gap26 treatment at 24 h after ischemia improved functional recovery on muscle strength, motor coordination, and spatial memory abilities. Further, Gap26 inhibited Cx43 expression and reduced active astrogliosis. Gap26 interacted and co-localized with Cx43 together in brain tissues and cultured astrocytes. After oxygen glucose deprivation, Gap26 treatment reduced the total Cx43 level in cultured astrocytes; but Cx43 level in the plasma membrane was increased. Degradation of Cx43 in the cytoplasm was mainly via the ubiquitin proteasome pathway. Concurrently, phosphorylated Akt, which phosphorylates Cx43 on Serine(373) and facilitates the forward transport of Cx43 to the plasma membrane, was increased by Gap26 treatment. Microdialysis showed that increased membranous Cx43 causes glutamate release by opening Cx43 hemichannels. Extracellular glutamate concentration was significantly decreased by Gap26 treatment in vivo. Finally, we found that cleaved caspase-3, an apoptosis marker, was attenuated after HI injury by Gap26 treatment. Effects of Gap27 were analogous to those of Gap26. In summary, our findings demonstrate that modulation of Cx43 expression and astroglial function is a potential therapeutic strategy for ischemic brain injury.

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Section: Resultsmentioning

confidence: 99%

“…Previous studies have shown that ischemic injury increases Cx43 expression in brain and retina (Danesh‐Meyer et al ; Deng et al, ; Haupt et al, ). In our study, we found that OGD increased expression of Cx43 not only in the membrane but also in cytoplasm.…”

Section: Discussionmentioning

confidence: 98%

Inhibition of connexin43 improves functional recovery after ischemic brain injury in neonatal rats

Zhao

Tan

et al. 2015

Glia

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“…Although this study does not allow us to directly test this hypothesis, we note that putative protective effects of leptin have been reported, as increased leptin serum levels facilitate learning and memory performance in preclinical studies, 39 and have a neuroprotective role in ischemic brain injury. 40 Translational studies, however, are needed to fully address the possible cross-talk between ghrelin and leptin in alcohol craving and drinking.…”

Section: Discussionmentioning

confidence: 99%

Leptin levels are reduced by intravenous ghrelin administration and correlated with cue-induced alcohol craving

et al. 2015

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Increasing evidence supports the role of appetite-regulating pathways, including ghrelin and leptin, in alcoholism. This study tested the hypothesis that intravenous exogenous ghrelin administration acutely decreases endogenous serum leptin levels, and that changes in leptin levels negatively correlate with alcohol craving. This was a double-blind, placebo-controlled human laboratory study. Non-treatment-seeking, alcohol-dependent, heavy drinkers (n=45) were randomized to receive intravenous ghrelin or placebo, followed by a cue-reactivity procedure, during which participants were exposed to neutral (juice) and alcohol trial cues. There was a main effect for intravenous ghrelin administration, compared with placebo, in reducing serum leptin levels (P<0.01). Post hoc analysis showed significant differences in serum leptin levels at the alcohol trial (P<0.05) that persisted at the end of the experiment (P<0.05). By contrast, there were no significant differences in serum leptin levels at the juice trial (P=not significant (NS)). The change of serum leptin level at the alcohol trial correlated with the increase in alcohol urge (P<0.05), whereas urge to drink juice was not correlated with the leptin change at the juice trial (P=NS). These findings provide preliminary evidence of ghrelin–leptin cross-talk in alcoholic individuals and suggest that their relationship may have a role in alcohol craving.

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“…Both Cx40 and have been shown to be associated with brain pathophysiology. For example, Deng et al reported that inhibition of Cx43 by leptin contributes leptin’s neuroprotective activity against brain ischemic injury [ 6 ]. Merier and colleagues detected the differences in expression of Cx43 in response to brain injury, and they also found overexpression or deletion of Cx43 was associated with the pathophysiological outcome [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

Phosphorylation of astrocytic connexin43 by ERK1/2 impairs blood–brain barrier in acute cerebral ischemia

2017

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BackgroundConnexins are a family of transmembrane proteins that form gap junctions, which are important for diffusion of cytosolic factors such as ions and second messenger signaling molecules. Our previous study has shown that Connexin40 (Cx40), one dominant connexin expressed in brain, was involved in brain injury. In this study, Cx43, another dominant connexin in brain, was investigated. Using bilateral common carotid artery occlusion-induced ischemia rat model, we tested the expression and phosphorylation level of Cx43 as well as heteromeric Cx40/Cx43 complex formation in brain after ischemia induction. We screened total 16 kinase inhibitors to identify the kinase for Cx43 phosphorylation and confirmed the result using siRNA targeting the specific kinase. Finally, we explored the role of the identified kinase in brain damage using in vivo rat model.ResultsWe discovered that phosphorylation of Cx43 increased after ischemia. The formation of Cx40/Cx43 heteromeric complex on membrane also increased. Inhibition of ERK activity resulted in inhibition of Cx43 phosphorylation on astrocytes. In in vivo model, application of ERK inhibitor and siRNA prevented brain damage and protected blood–brain barrier integrity in rat.ConclusionOur study provides evidence that Cx43 phosphorylation by ERK is implicated in ischemia induced brain damage.

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Inhibition of the Connexin 43 Elevation May be Involved in the Neuroprotective Activity of Leptin Against Brain Ischemic Injury

Cited by 31 publications

References 25 publications

Inhibition of connexin43 improves functional recovery after ischemic brain injury in neonatal rats

Inhibition of connexin43 improves functional recovery after ischemic brain injury in neonatal rats

Leptin levels are reduced by intravenous ghrelin administration and correlated with cue-induced alcohol craving

Phosphorylation of astrocytic connexin43 by ERK1/2 impairs blood–brain barrier in acute cerebral ischemia

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