Axonal protection achieved in a model of multiple sclerosis using lamotrigine.
Axonal degeneration is a major cause of permanent disability in multiple sclerosis (MS). Recent observations from our and other laboratories suggest that sodium accumulation within compromised axons is a key, early step in the degenerative process, and hence that limiting axonal sodium influx may represent a mechanism for axonal protection in MS. Here we assess whether lamotrigine, a sodium channel-blocking agent, is effective in preventing axonal degeneration in an animal model of MS, namely chronic-relapsing experimental autoimmune encephalomyelitis (CR-EAE). When administered from 7 days post-inoculation, lamotrigine provided a small but significant reduction in the neurological deficit present at the termination of the experiments (averaged over three independent experiments; vehicle: 3.5+/-2.7; lamotrigine: 2.6+/-2.0, P<0.05) and preserved more functional axons in the spinal cord (measured as mean compound action potential area; vehicle: 31.7 microV.ms+/-23.0; lamotrigine: 42.9+/-27.4, P<0.05). Histological examination of the thoracic spinal cord (n=71) revealed that lamotrigine treatment also provided significant protection against axonal degeneration (percentage degeneration in dorsal column; vehicle: 33.5 %+/-38.5; lamotrigine: 10.4 %+/-12.5, P<0.01). The findings suggest that lamotrigine may provide a novel avenue for axonal protection in MS.
Bechtold
David A
DA
Department of Clinical Neuroscience, King's College London, Guy's Campus, National Hospital for Neurology and Neurosurgery, London, UK.
Miller
Sandra J
SJ
Dawson
Angela C
AC
Sun
Yue
Y
Kapoor
Raju
R
Berry
David
D
Smith
Kenneth J
KJ
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D000077213:Lamotrigine; D008297:Male; D009103:Multiple Sclerosis / Q000150:complications* / Q000188:drug therapy; D009410:Nerve Degeneration / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control*; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D051381:Rats; D013116:Spinal Cord / Q000187:drug effects / Q000503:physiopathology; D018709:Statistics, Nonparametric; D013997:Time Factors; D014227:Triazines / Q000627:therapeutic use*
D018696:Neuroprotective Agents; D014227:Triazines; D000077213:Lamotrigine