MK-801 limits neurovascular dysfunction during experimental allergic encephalomyelitis.
Increased permeability of the blood-brain barrier (BBB) is a characteristic of the demyelinating disease multiple sclerosis and the animal counterpart experimental allergic encephalomyelitis (EAE). In physically traumatized cerebral tissue neurovascular damage, linked with activation of the cerebroendothelial-bound N-methyl-D-aspartate receptor, can be treated with the antagonist MK-801. We have examined the ability of MK-801 to modify BBB leakage and the development of disease during EAE. Prophylactic MK-801, at 0.15 mg kg(-1) body weight suppressed neurovascular breakdown, measured by a dual radioisotope technique, and significantly reduced neurological deficits (P < .05), but not perivascular lesions. A 2-fold increase in administered MK-801 completely prevented abnormal extravasation in cerebella (P < .01) and significantly inhibited BBB disruption in medulla-pons (P < .05) and cervical spinal tissues (P < .01). High-dose treatment also restricted disease development (P < .01) and lesion formation (P < .05). Therapeutic MK-801, at 0.30 mg kg(-1) body weight, completely counteracted neuroendothelial leakage in cerebella (P < .05) and inhibited BBB dysfunction in remaining tissues without restricting inflammatory cell invasion. However, doubling the dose did not further enhance suppression of neurovascular breakdown. Our use of MK-801 to control major features of EAE strongly implicates N-methyl-D-aspartate receptor-dependent mechanisms in disease development and prompts consideration of a role for the receptor in the pathogenesis of human demyelinating conditions.
Bolton
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Pharmacology Group, School of Pharmacy & Pharmacology, University of Bath, United Kingdom.
Paul
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D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects*; D002199:Capillary Permeability; D003345:Corticosterone / Q000097:blood; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology
D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate; D003345:Corticosterone