Protection from hypoxic and N-methyl-D-aspartate injury with azelastine, a leukotriene inhibitor.
The 5-lipoxygenase metabolites, leukotrienes, increase in concentration during cerebral ischemia. Azelastine is a new anti-allergic agent which inhibits leukotriene C4 synthesis and release. We examined the neuroprotective properties of azelastine using the hippocampal slice. Azelastine 15 microM significantly protected CA1 evoked responses from hypoxic injury, with CA1 population spike amplitude recovering to a mean 76 +/- 13% in azelastine treated slices, compared to 4 +/- 3% recovery in paired unmedicated slices. The EC50 for this azelastine hypoxic protection was 9.8 microM. Azelastine additionally protected against injury induced by N-methyl-D-aspartate (NMDA), but not non-NMDA glutamate receptor agonists. No hypoxic protection was afforded by diphenhydramine 50 microM, suggesting that azelastine protection did not occur through histamine H1 receptor blockade. The finding of protection with azelastine against hypoxic and NMDA-induced injury suggests that leukotriene production is a common pathway in these forms of neuronal injury, and that leukotriene inhibition may be a useful neuroprotective strategy.
Wallis
R A
RA
Department of Neurology, UCLA.
Panizzon
K L
KL
D000818:Animals; D004155:Diphenhydramine / Q000494:pharmacology; D004594:Electrophysiology; D006624:Hippocampus / Q000187:drug effects* / Q000502:physiology; D000860:Hypoxia / Q000503:physiopathology*; D066298:In Vitro Techniques; D017997:Leukotriene C4 / Q000378:metabolism*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D016202:N-Methylaspartate / Q000494:pharmacology*; D010793:Phthalazines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011969:Receptors, Histamine H1 / Q000187:drug effects
D016859:Lipoxygenase Inhibitors; D010793:Phthalazines; D011969:Receptors, Histamine H1; D017997:Leukotriene C4; D016202:N-Methylaspartate; D004155:Diphenhydramine; C020976:azelastine