Gap Junctions and Connexins in Microglia-Related Oxidative Stress and Neuroinflammation: Perspectives for Drug Discovery

Abstract

Microglia represent the immune system of the brain. Their role is central in two phenomena, neuroinflammation and oxidative stress, which are at the roots of different pathologies related to the central nervous system (CNS). In order to maintain the homeostasis of the brain and re-establish the equilibrium after a threatening imbalance, microglia communicate with each other and other cells within the CNS by receiving specific signals through membrane-bound receptors and then releasing neurotrophic factors into either the extracellular milieu or directly into the cytoplasm of nearby cells, such as astrocytes and neurons. These last two mechanisms rely on the activity of protein structures that enable the formation of channels in the membrane, namely, connexins and pannexins, that group and form gap junctions, hemichannels, and pannexons. These channels allow the release of gliotransmitters, such as adenosine triphosphate (ATP) and glutamate, together with calcium ion (Ca2+), that seem to play a pivotal role in inter-cellular communication. The aim of the present review is focused on the physiology of channel protein complexes and their contribution to neuroinflammatory and oxidative stress-related phenomena, which play a central role in neurodegenerative disorders. We will then discuss how pharmacological modulation of these channels can impact neuroinflammatory phenomena and hypothesize that currently available nutraceuticals, such as carnosine and N-acetylcysteine, can modulate the activity of connexins and pannexins in microglial cells and reduce oxidative stress in neurodegenerative disorders.

Perspective and Therapeutic Potential of the Noncoding RNA–Connexin Axis

“…In addition, although hemichannel-mediated diseases have not yet been proven, Caruso et al reviewed the molecular mechanisms of Cx43 hemichannel opening and their contribution to neuroinflammation and oxidative stress [ 37 ]. Activation of the inflammasome complex, NF-κB signaling pathways, and alterations in intracellular calcium levels can induce the opening of Cx43 hemichannels, thereby facilitating the release of ATP [ 37 ]. Dysregulated secretion of ATP and other gliotransmitters through Cx43 hemichannels disrupts CNS homeostasis [ 37 ].…”

“…Activation of the inflammasome complex, NF-κB signaling pathways, and alterations in intracellular calcium levels can induce the opening of Cx43 hemichannels, thereby facilitating the release of ATP [ 37 ]. Dysregulated secretion of ATP and other gliotransmitters through Cx43 hemichannels disrupts CNS homeostasis [ 37 ]. The non-canonical functions of Cx43 include participation in gene transcription, development, and scaffolding complexes, as well as facilitating glioma invasion via a channel-independent pathway [ 38 , 39 ].…”

Effect of General Anesthetic Agents on Microglia

“…Upregulation of Cx43 after ischemia is considered to promote the transport of cytotoxic molecules (such as TNFα and IL-1β), cell fragments, and dying cells to neighboring cells and tissues and even aggravates cell injury and brain inflammation by transmitting cytotoxic signals through GJs [ 83 , 84 ]. Regulation of connexin activity in microglia contributes to the reduction of oxidative stress in neurodegenerative diseases and has potential pharmacological promise to delay or halt the progression of these diseases [ 85 ]. Therefore, propofol's inhibition of Cx43 may reduce the transmission of inflammatory signals and crosstalk of microglial activation information (such as ATP and TNF-α signaling), thus protecting the brain.…”

Dibenzocyclooctadiene Lignans from Schisandra chinensis with Anti-Inflammatory Effects

“…Gap junction intercellular communication (GJIC) allows communication between cells and the exchange of small molecules through connexin-based gap junction channels [ 23 ]. Gap junction-coupled cells can be found in various organs in the body, where GJIC helps to maintain tissue homeostasis and protects the cells from harmful substances and conditions such as oxidative stress or inflammation [ 24 ]. Disruption and dysregulation of communication by inflammatory mediators or endotoxins (lipopolysaccharides-LPS) can cause inflammatory substances to spread to other cells and organs in the body and can lead to systemic inflammation [ 25 ].…”