Astrocytic gap junction inhibition by carbenoxolone enhances the protective effects of ischemic preconditioning following cerebral ischemia.

Abstract

BACKGROUND:

Stroke is the second leading cause of death worldwide and the most common cause of adult-acquired disability in many nations. Thus, attenuating the damage after ischemic injury and improving patient prognosis are of great importance. We have indicated that ischemic preconditioning (IP) can effectively reduce the damage of ischemia reperfusion and that inhibition of gap junctions may further reduce this damage. Although we confirmed that the function of gap junctions is closely associated with glutamate, we did not investigate the mechanism. In the present study, we aimed to clarify whether the blockade of cellular communication at gap junctions leads to significant reductions in the levels of glutamate released by astrocytes following cerebral ischemia.

METHODS:

To explore this hypothesis, we utilized the specific blocking agent carbenoxolone (CBX) to inhibit the opening and internalization of connexin 43 channels in an in vitro model of oxygen-glucose deprivation/re-oxygenation (OGD/R), following IP.

RESULTS:

OGD/R resulted in extensive astrocytic glutamate release following upregulation of hemichannel activity, thus increasing reactive oxygen species (ROS) generation and subsequent cell death. However, we observed significant increases in neuronal survival in neuron-astrocyte co-cultures that were subjected to IP prior to OGD/R. Moreover, the addition of CBX enhanced the protective effects of IP during the re-oxygenation period following OGD, by means of blocking the release of glutamate, increasing the level of the excitatory amino acid transporter 1, and downregulating glutamine expression.

CONCLUSIONS:

Our results suggest that combined use of IP and CBX represents a novel therapeutic strategy to attenuate damage from cerebral ischemia with minimal adverse side effects.

• Authors: Di Ma, Liangshu Feng, Yingying Cheng, Meiying Xin, Jiulin You, Xiang Yin, Yulei Hao, Li Cui, Jiachun Feng
• Journal: Journal of neuroinflammation (J Neuroinflammation) Vol. 15 Issue 1 Pg. 198 (Jul 05 2018) ISSN: 1742-2094 [Electronic] England
• PMID: 29976213 (Publication Type: Journal Article)

Chemical References

• Amino Acid Transport System X-AG
• CD11b Antigen
• Glial Fibrillary Acidic Protein
• Interleukin-1beta
• Neuroprotective Agents
• Reactive Oxygen Species
• Tumor Necrosis Factor-alpha
• Nitric Oxide
• Carbenoxolone
• Oxygen

Topics

• Amino Acid Transport System X-AG (genetics, metabolism)
• Animals
• Animals, Newborn
• CD11b Antigen (metabolism)
• Carbenoxolone (pharmacology)
• Cells, Cultured
• Cerebral Cortex (cytology)
• Coculture Techniques
• Embryo, Mammalian
• Gap Junctions (drug effects, metabolism)
• Gene Expression Regulation (drug effects)
• Glial Fibrillary Acidic Protein (metabolism)
• Interleukin-1beta (metabolism)
• Neuroglia (drug effects, metabolism)
• Neurons (drug effects, metabolism)
• Neuroprotective Agents (pharmacology)
• Nitric Oxide (metabolism)
• Oxygen (metabolism, pharmacology)
• Rats
• Rats, Wistar
• Reactive Oxygen Species (metabolism)
• Tumor Necrosis Factor-alpha (metabolism)