Targeting Kv1.3 channels to reduce white matter pathology after traumatic brain injury

Abstract

Axonal injury is present in essentially all clinically significant cases of traumatic brain injury (TBI). While no effective treatment has been identified to date, experimental TBI models have shown promising axonal protection using immunosuppressants FK506 and Cyclosporine-A, with treatment benefits attributed to calcineurin inhibition or protection of mitochondrial function. However, growing evidence suggests neuroprotective efficacy of these compounds may also involve direct modulation of ion channels, and in particular Kv1.3. The present study tested whether blockade of Kv1.3 channels, using Clofazimine (CFZ), would alleviate TBI-induced white matter pathology in rodents. Postinjury CFZ administration prevented suppression of compound action potential (CAP) amplitude in the corpus callosum of adult rats following midline fluid percussion TBI, with injury and treatment effects primarily expressed in unmyelinated CAPs. Kv1.3 protein levels in callosal tissue extracts were significantly reduced postinjury, but this loss was prevented by CFZ treatment. In parallel, CFZ also attenuated the injury-induced elevation in pro-inflammatory cytokine IL1-β. The effects of CFZ on glial function were further studied using mixed microglia/astrocyte cell cultures derived from P3-5 mouse corpus callosum. Cultures of callosal glia challenged with lipopolysaccharide exhibited a dramatic increase in IL1-β levels, accompanied by reactive morphological changes in microglia, both of which were attenuated by CFZ treatment. These results support a cell specific role for Kv1.3 signaling in white matter pathology after TBI, and suggest a treatment approach based on the blockade of these channels. This therapeutic strategy may be especially efficacious for normalizing neuro-glial interactions affecting unmyelinated axons after TBI.

Dimethyl fumarate improves white matter function following severe hypoperfusion: Involvement of microglia/macrophages and inflammatory mediators

“… 56 Demyelination of axons induced by cuprizone or TBI and compression injury also cause increases in refractoriness. 44 , 49 , 57 , 58 …”

Investigation of left and right lateral fluid percussion injury in C57BL6/J mice: In vivo functional consequences

“…Mice were perfused as described for histology and 40 μm coronal brain sections cut by vibratome were processed for IHC [24] using antibodies for IBA1 (Wako, Abcam; 1:300), and GFAP (Dako, Encor Biotechnology; 1:20,000). Images were collected on a Zeiss 700 confocal microscope for qualitative assessment of each protein.…”

A Kv1.3 channel‐specific blocker alleviates neurological impairment through inhibiting T‐cell activation in experimental autoimmune encephalomyelitis

“…Besides, cumulative studies suggested that Kv1.3 channels took part in the regulation of oligodendrocyte differentiation and maturation . Some Kv1.3 blockers exhibited neuroprotective effects as MBP mRNA decay was completely blocked by the inhibition of Kv1.3 expression . Together, these previous findings indicated that ImK affected the attenuation of oligodendrocyte damage and probably the enhancement of their survival and remyelination.…”