Targeting Kv1.3 channels to reduce white matter pathology after traumatic brain injury.
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.
Department of Anatomy and Neurobiology, School of Medicine, Virginia Commonwealth University Medical Center, Richmond, VA 23298, United States.
Thomas M
TM
Reeves
Department of Anatomy and Neurobiology, School of Medicine, Virginia Commonwealth University Medical Center, Richmond, VA 23298, United States.
Patricia A
PA
Trimmer
Department of Anatomy and Neurobiology, School of Medicine, Virginia Commonwealth University Medical Center, Richmond, VA 23298, United States.
Beverly S
BS
Colley
Department of Anatomy and Neurobiology, School of Medicine, Virginia Commonwealth University Medical Center, Richmond, VA 23298, United States.
Linda L
LL
Phillips
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000831:Animals, Newborn; D000070642:Brain Injuries, Traumatic / Q000150:complications* / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002478:Cells, Cultured; D002991:Clofazimine / Q000494:pharmacology; D003337:Corpus Callosum / Q000187:drug effects / Q000378:metabolism; D016572:Cyclosporine / Q000627:therapeutic use; D004195:Disease Models, Animal; D004558:Electric Stimulation; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D051664:Kv1.3 Potassium Channel / Q000378:metabolism*; D056784:Leukoencephalopathies / Q000188:drug therapy / Q000209:etiology* / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016559:Tacrolimus / Q000627:therapeutic use
C100745:Aif1 protein, rat; D002135:Calcium-Binding Proteins; D007166:Immunosuppressive Agents; D051664:Kv1.3 Potassium Channel; D008840:Microfilament Proteins; D026902:Potassium Channel Blockers; D016572:Cyclosporine; D002991:Clofazimine; D016559:Tacrolimus
Compound action potentials; Glial cell culture; Inflammation; Microglia; Recovery of function; White matter injury