Abstract
The neuroprotective efficacy of YM872, a novel, highly water-soluble α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor antagonist, was investigated in rats subjected to permanent occlusion of the left middle cerebral artery. The rats were assessed either histologically or neurologically 24 hr or 1 wk after ischemia. YM872 was intravenously infused for either 4 or 24 hr at dose rates of 0 to 20 mg/kg/hr starting 5 min after ischemia to examine the effect of prolonged treatment. YM872 was then infused at 20 mg/kg/hr beginning 0 to 4 hr after ischemia to determine the efficacy time window. Additionally, a 20 mg/kg/hr dose rate of YM872 was infused for 4 hr in single day- or 5-day repetitive-administrations to evaluate long-term benefits of the drug. YM872 significantly reduced infarct volume in both 4- and 24-hr treatment groups measured 24 hr after ischemia. No difference was observed in the degree of protection between length of infusion. Significant neuroprotection was maintained even when drug administration was delayed up to 2 hr after ischemia. A single YM872-administration significantly improved neurological deficit and reduced infarct volume (30%, P < .01) measured 1 wk after ischemia. YM872 treatment did not induce such adverse effects as physiological changes, serious behavioral abnormalities or nephrotoxicity. These data suggest that the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor plays a crucial role in the progression of neuronal damage in the early phase of ischemia and that YM872 may be useful in treating acute ischemic stroke.
Footnotes
-
Send reprint requests to: Dr. Masao Shimizu-Sasamata, Neuroscience Research, Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
- Abbreviations:
- AMPA
- α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid
- ANOVA
- analysis of variance
- MABP
- mean arterial blood pressure
- MCA
- middle cerebral artery
- NBQX
- 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo (f) quinoxaline
- NMDA
- N-methyl-d-aspartate
- TTC
- 2,3,5-triphenyltetrazolium hydrochloride
- VSCC
- voltage-sensitive calcium channel
- YM90K
- 6-(1H-imidazol-1-yl)-7-nitro-2,3(1H, 4H)-quinoxalinedione monohydrochloride
- [Ca++]i
- intracellular Ca++concentration
- Received April 30, 1998.
- Accepted June 17, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|