Connexin 43 stabilizes astrocytes in a stroke-like milieu to facilitate neuronal recovery

Abstract

Aim: Connexin 43 (Cx43) is a member of connexin family mainly expressed in astrocytes, which forms gap junctions and hemichannels and maintains the normal shape and function of astrocytes. In this study we investigated the role of Cx43 in astrocytes in facilitating neuronal recovery during ischemic stroke. Methods: Primary culture of astrocytes or a mixed culture of astrocytes and cortical neurons was subjected to oxygen glucose deprivation and reperfusion (OGD/R). The expression of Cx43 and Ephrin-A4 in astrocytes was detected using immunocytochemical staining and Western blot assays. Intercellular Ca 2+ concentration was determined with Fluo-4 AM fluorescent staining. Middle cerebral artery occlusion (MCAO) model rats were used for in vivo studies. Results: OGD/R treatment of cultured astrocytes caused a decrement of Cx43 expression and translocation of Cx43 from cell membrane to cytoplasm, accompanied by cell retraction. Furthermore, OGD/R increased intracellular Ca 2+ concentration, activated CaMKII/CREB pathways and upregulated expression of Ephrin-A4 in the astrocytes. All these changes in OGD/R-treated astrocytes were alleviated by overexpression of Cx43. In the cortical neurons cultured with astrocytes, OGD/R inhibited the neurite growth, whereas overexpression of Cx43 or knockdown of Ephrin-A4 in astrocytes restored the neurite growth. In MCAO model rats, neuronal recovery was found to be correlated with the recuperation of Cx43 and Ephrin-A4 in astrocytes. Conclusion: Cx43 can stabilize astrocytes and facilitate the resistance to the deleterious effects of a stroke-like milieu and promote neuronal recovery.

Roles of astrocytic connexin-43, hemichannels, and gap junctions in oxygen-glucose deprivation/reperfusion injury induced neuroinflammation and the possible regulatory mechanisms of salvianolic acid B and carbenoxolone

“…In contrast, a “good Samaritan” role is supported by studies showing that Cx43 gene knockout is associated with larger stroke lesions, amplified apoptosis, and inflammation [ 91 , 92 ]. Furthermore, post-injury gap junction channel inhibition correlates with glutamate cytotoxicity and neuronal injury aggravation [ 93 , 94 ]. Our findings seem to support the “good Samaritan” hypothesis, but there may be a balance between the “bystander” and “good Samaritan” hypotheses.…”

Immunofluorescence characterization of spinal cord dorsal horn microglia and astrocytes in horses

“…Despite its high sensitivity, astrocyte labeling with GFAP antibody is usually accompanied by the detection of another specific marker, called Connexin 43 (Cx-43) ( Ochalski et al, 1996 ), which is an important component of astrocyte gap junctions ( Rouach et al, 2002 ). Cx-43 maintains the normal shape and function of astrocytes, which is important for their integrity and stability ( Wu, Yu & Feng, 2015 ). After peripheral or central nervous damage, Cx-43 expression markedly increases, and its deletion in astrocytes can reduce acute astrogliosis, and can produce analgesia in different pain models ( Gao & Ji, 2010 ; Huang et al, 2012 ).…”

Connexin43 Containing Gap Junction Channels Facilitate HIV Bystander Toxicity: Implications in NeuroHIV

“…Cx43 knockout animals have been shown to exhibit impaired neuronal plasticity ( Han et al, 2014 ), altered glutamatergic synaptic activity ( Chever et al, 2014 ), and neurodevelopmental defects ( Wiencken-Barger et al, 2007 ). However, limiting GJ-mediated communication during stroke ( Wu et al, 2015 ), ischemia ( Contreras et al, 2004 ), and oxidative stress ( Blanc et al, 1998 ) has been documented to reduce neuronal apoptosis. Moreover, certain GJ blockers have been shown to exhibit neuroprotective as well as cardioprotective effects, and hence partially blocking gap-junctional communication could be favorable in certain pathological events ( Herve and Sarrouilhe, 2005 ; Schulz et al, 2015 ).…”