Blockade of Gap Junction Hemichannel Protects Secondary Spinal Cord Injury from Activated Microglia-Mediated Glutamate Exitoneurotoxicity

Abstract

We previously demonstrated that activated microglia release excessive glutamate through gap junction hemichannels and identified a novel gap junction hemichannel blocker, INI-0602, that was proven to penetrate the blood-brain barrier and be an effective treatment in mouse models of amyotrophic lateral sclerosis and Alzheimer disease. Spinal cord injury causes tissue damage in two successive waves. The initial injury is mechanical and directly causes primary tissue damage, which induces subsequent ischemia, inflammation, and neurotoxic factor release resulting in the secondary tissue damage. These lead to activation of glial cells. Activated glial cells such as microglia and astrocytes are common pathological observations in the damaged lesion. Activated microglia release glutamate, the major neurotoxic factor released into the extracellular space after neural injury, which causes neuronal death at high concentration. In the present study, we demonstrate that reduction of glutamate-mediated exitotoxicity via intraperitoneal administration of INI-0602 in the microenvironment of the injured spinal cord elicited neurobehavioral recovery and extensive suppression of glial scar formation by reducing secondary tissue damage. Further, this intervention stimulated anti-inflammatory cytokines, and subsequently elevated brain-derived neurotrophic factor. Thus, preventing microglial activation by a gap junction hemichannel blocker, INI-0602, may be a promising therapeutic strategy in spinal cord injury.

A Multicenter Randomized Controlled Trial Evaluating a Cx43-Mimetic Peptide in Cutaneous Scarring

“…Animal model studies have also shown that Cx43 hemichannel blockade reduced infarct size after myocardial infarction (Hawat et al, 2012; Wang et al, 2013) and decreased glial scarring in both ischemic stroke (Davidson et al, 2015) and spinal cord injury models (Umebayashi et al, 2014). In the context of skin healing and hypertrophic scarring or keloid formation, modulation of Cx43 expression levels has been shown to control the balance between fibroblast proliferation and apoptosis, as well as extracellular matrix deposition (Lu et al, 2007).…”

Inhibition of glial hemichannels by boldine treatment reduces neuronal suffering in a murine model of Alzheimer's disease

“…Interestingly, the use of a derivative of CBX, INI‐0602, which inhibits glutamate release from microglial cells by blocking activated Cx32 HCs, improved memory impairment in another FAD mouse model (Takeuchi et al, ). This drug also led to behavioral amelioration in other models of neurodegenerative diseases, ALS and PD (Suzuki, Ono, & Sawada, ; Takeuchi et al, ), and in spinal cord injury (Umebayashi et al, ). The underlying mechanisms were attributed to the inhibitory effect of INI‐0602 on microglial Cx32 HCs (Takeuchi et al, ) although direct evidence is lacking.…”

Microglia in neuropathology caused by protozoan parasites

“…In the uninjured adult brain, microglial cells typically have a small cell body endowed with numerous radial extensions, which are highly ramified. Microglial cells occupy cellular microdomains which do not overlap, and which accordingly are only sparsely interconnected by junctions, although they are equipped with gap junctional hemichannels (Orellana et al, 2009;Umebayashi et al, 2014). Such cells were formerly termed 'resting' or 'quiescent' microglia.…”