Modulation of blood-brain barrier dysfunction and neurological deficits during acute experimental allergic encephalomyelitis by the N-methyl-D-aspartate receptor antagonist memantine.
Previous studies by us have strongly indicated a role for the N-methyl-D-aspartate (NMDA) receptor in the pathogenesis of experimental allergic encephalomyelitis (EAE) and, moreover, the loss of blood-brain barrier (BBB) integrity implicit in the disease. The current investigation has used the NMDA receptor antagonist memantine to modify the neurological course of EAE and, in particular, prevent BBB breakdown. Memantine was administered orally either semiprophylactically, from day 7 postinoculation (PI), or therapeutically, 10 to 11 days PI. Semiprophylactic administration of drug at 60 mg/kg b.wt. significantly restored BBB integrity, reduced symptoms, and limited inflammatory lesions (p < 0.05), when assessed 12 days PI. Higher concentrations of memantine did not notably advance disease improvements observed at 60 mg/kg b.wt., and 40-mg/kg b.wt. doses only reduced histological scores (p < 0.05). Therapeutic application of memantine was found to be as effective as semiprophylactic dosing. Administration of drug at 60 mg/kg b.wt. was demonstrated as the optimum dose, significantly reducing disease, BBB permeability, and lesions (p < 0.01). Extended studies revealed that, after cessation of memantine treatment using either dosing regime, any subsequent appearance of disease was suppressed in severity and duration. We have provided further strong evidence in support of a role for the NMDA receptor in the development of EAE and, in particular, the loss of BBB function and recruitment of inflammatory cells. Moreover, memantine is therapeutically efficacious, suggesting the NMDA receptor as a viable pharmacological target for future treatment of human neurological conditions such as multiple sclerosis.
Paul
Carolyn
C
Department of Pharmacy and Pharmacology, University of Bath, Bath, UK. carolyn.paul@luton.ac.uk
Bolton
Christopher
C
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects*; D001835:Body Weight / Q000187:drug effects; D003345:Corticosterone / Q000097:blood; D018450:Disease Progression; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology; D004912:Erythrocytes / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D008559:Memantine / Q000494:pharmacology* / Q000627:therapeutic use; D009422:Nervous System Diseases / Q000503:physiopathology*; D051381:Rats; D011917:Rats, Inbred Lew; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D012711:Serum Albumin, Radio-Iodinated; D013116:Spinal Cord / Q000473:pathology
D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D012711:Serum Albumin, Radio-Iodinated; D008559:Memantine; D003345:Corticosterone