Abstract
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.
Footnotes
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Send reprint requests to: Dr. C. Bolton, Pharmacology Group, School of Pharmacy & Pharmacology, University of Bath, Claverton Down, Bath, UK, BA2 7AY.
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↵1 The investigation was supported financially by The Multiple Sclerosis Society of Great Britain and Northern Ireland.
- Abbreviations:
- BBB
- blood-brain barrier
- bwt
- body weight
- CNS
- central nervous system
- EAE
- experimental allergic encephalomyelitis
- EVBE
- extravascular blood equivalent
- 125I
- 125iodine
- 111In
- 111indium
- MS
- multiple sclerosis
- NMDA
- N-methyl-d-aspartate
- NO
- nitric oxide
- PBS
- phosphate-buffered saline
- PI
- postinoculation
- HEPES
- N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid
- Received December 3, 1996.
- Accepted March 24, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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