Blocking connexin43 expression reduces inflammation and improves functional recovery after spinal cord injury.
After traumatic CNS injury, a cascade of secondary events expands the initial lesion. The gap-junction protein connexin43 (Cx43), which is transiently up-regulated, has been implicated in the spread of 'bystander' damage. We have used an antisense oligodeoxynucleotide (asODN) to suppress Cx43 up-regulation in two rat models of spinal cord injury. Within 24 h of compression injury, rats treated with Cx43-asODN scored higher than sense-ODN and vehicle-treated controls on behavioural tests of locomotion. Their spinal cords showed less swelling and tissue disruption, less up-regulation of astrocytic GFAP, and less extravasation of fluorescently-labelled bovine serum albumin and neutrophils. The locomotor improvement was sustained over at least 4 weeks. Following partial spinal cord transection, Cx43-asODN treatment reduced GFAP immunoreactivity, neutrophil recruitment, and the activity of OX42(+) microglia in and around the lesion site. Cx43 has many potential roles in the pathophysiology of CNS injury and may be a valuable target for therapeutic intervention.
Cronin
Michael
M
Research Department of Cell and Developmental Biology, University College London, London, UK.
Anderson
Patrick N
PN
Cook
Jeremy E
JE
Green
Colin R
CR
Becker
David L
DL
D000818:Animals; D039481:CD11b Antigen / Q000378:metabolism; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology; D018031:Connexin 43 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D008124:Locomotion / Q000187:drug effects; D008297:Male; D017628:Microglia / Q000187:drug effects; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology*; D013119:Spinal Cord Injuries / Q000150:complications* / Q000188:drug therapy / Q000473:pathology; D013997:Time Factors
D039481:CD11b Antigen; D018031:Connexin 43; D005904:Glial Fibrillary Acidic Protein; D020319:Oligodeoxyribonucleotides, Antisense