Blockade of Gap Junction Hemichannel Suppresses Disease Progression in Mouse Models of Amyotrophic Lateral Sclerosis and Alzheimer's Disease

Abstract

BackgroundGlutamate released by activated microglia induces excitotoxic neuronal death, which likely contributes to non-cell autonomous neuronal death in neurodegenerative diseases, including amyotrophic lateral sclerosis and Alzheimer's disease. Although both blockade of glutamate receptors and inhibition of microglial activation are the therapeutic candidates for these neurodegenerative diseases, glutamate receptor blockers also perturbed physiological and essential glutamate signals, and inhibitors of microglial activation suppressed both neurotoxic/neuroprotective roles of microglia and hardly affected disease progression. We previously demonstrated that activated microglia release a large amount of glutamate specifically through gap junction hemichannel. Hence, blockade of gap junction hemichannel may be potentially beneficial in treatment of neurodegenerative diseases.Methods and FindingsIn this study, we generated a novel blood-brain barrier permeable gap junction hemichannel blocker based on glycyrrhetinic acid. We found that pharmacologic blockade of gap junction hemichannel inhibited excessive glutamate release from activated microglia in vitro and in vivo without producing notable toxicity. Blocking gap junction hemichannel significantly suppressed neuronal loss of the spinal cord and extended survival in transgenic mice carrying human superoxide dismutase 1 with G93A or G37R mutation as an amyotrophic lateral sclerosis mouse model. Moreover, blockade of gap junction hemichannel also significantly improved memory impairments without altering amyloid β deposition in double transgenic mice expressing human amyloid precursor protein with K595N and M596L mutations and presenilin 1 with A264E mutation as an Alzheimer's disease mouse model.ConclusionsOur results suggest that gap junction hemichannel blockers may represent a new therapeutic strategy to target neurotoxic microglia specifically and prevent microglia-mediated neuronal death in various neurodegenerative diseases.

New Insights on Astroglial Connexins as a Therapeutic Target for Alzheimer's Disease

“…Activated HCs have been involved in the release of gliotransmitters such as ATP and glutamate as well as chemokines that have deleterious consequences on neurons as reported in murine models of AD [18][19][20], experimental allergic encephalomyelitis [21], amyotrophic lateral sclerosis [20,22] and neuropathic pain [23,24]. In our study, it has also been demonstrated that activated HCs can allow Ca 2+ influx, contributing to a maintenance of high [Ca 2+ ]i.…”

Conditioned Medium from the Stem Cells of Human Exfoliated Deciduous Teeth Ameliorates Experimental Autoimmune Encephalomyelitis

“…Furthermore, we evaluated axonal injury by SMI31 immunostaining. Previously, we reported that bead-like swelling along axons (axonal beading) is a good pathological marker of axonal injury resulting from axonal transport impairment (27)(28)(29). The reduction in axonal beading is associated with recovery from EAE (30).…”

Contribution of Pannexin 1 and Connexin 43 Hemichannels to Extracellular Calcium–Dependent Transport Dynamics in Human Blood-Brain Barrier Endothelial Cells

“…ATP and glutamate significantly inhibited SR-101 and PI uptake. In contrast, an in vivo BBB-permeable analog of GA INI-0602, which has been reported to inhibit Cx32-mediated glutamate release from microglial cells (Takeuchi et al, 2011), increased SR-101 and PI uptake. Addition of 1.4 mM CaCl 2 in the Ca 21 -free ECF buffer significantly reduced the enhanced uptake of SR-101 and PI.…”