Augmentation of nitrite therapy in cerebral ischemia by NMDA receptor inhibition.
Our recent work suggested that early infusion of nitrite might represent a novel therapeutic approach for acute ischemic stroke. In this study, we sought to examine the therapeutic time window of nitrite in an experimental stroke model, and to develop combined strategies for augmenting its protective effects. Nitrite was infused at various times after ischemia to rats subjected to transient or permanent focal ischemia. Nitrite was infused with memantine to prevent the potential toxicity. Infarct volumes, functional outcomes, microhypoxic areas, and oxidative stress were measured. Nitrite reduced the infarction volume and enhanced functional recovery when administered within 3 and 1.5h in the transient and permanent model, respectively. Combined therapy with nitrite and memantine prolonged the time window up to 4.5h. The potential oxidative toxicities of nitrite were significantly inhibited by memantine. The combination therapy of nitrite and memantine may be a feasible therapeutic approach for acute ischemic stroke.
Jung
Keun-Hwa
KH
Department of Neurology, Stem Cell Laboratory, Clinical Research Institute, Seoul National University Hospital, 28, Yongon-dong, Chongro-gu, Seoul 110-744, South Korea.
Chu
Kon
K
Lee
Soon-Tae
ST
Park
Hee-Kwon
HK
Kim
Jin-Hee
JH
Kang
Kyung-Muk
KM
Kim
Manho
M
Lee
Sang Kun
SK
Roh
Jae-Kyu
JK
D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use*; D008297:Male; D008559:Memantine / Q000627:therapeutic use*; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D012977:Sodium Nitrite / Q000627:therapeutic use*; D020521:Stroke / Q000188:drug therapy*
D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; D012977:Sodium Nitrite; D008559:Memantine