ZJM-289, a novel nitric oxide donor, alleviates the cerebral ischaemic-reperfusion injury in rats.
1. Current studies indicate that nitric oxide (NO) plays a dual role as both a protective and pathogenic factor in focal cerebral ischaemia depending on the level, location, source and environment. The present study hypothesized that the NO donor ZJM-289 could inhibit cerebral ischaemia-reperfusion (I/R) injury and investigated the mechanism of the beneficial events. 2. Adult male rats were randomly divided into four groups: (i) sham operated; (ii) I/R (ischaemia for 90 min and reperfusion for 24 h) treated with vehicle; (iii) I/R treated with 0.1 mmol/kg body weight ZJM-289; and (iv) I/R treated with 0.2 mmol/kg body weight ZJM-289. We evaluated the changes in brain infarction, brain-water content, neurological deficits and histopathology. Western blot analysis was used to study the expression of endothelial nitric oxide synthase (eNOS) and neuronal nitric oxide synthase (nNOS) in the brain after I/R. The levels of NO and cyclic guanosine monophosphate (cGMP) were also determined. 3. ZJM-289 reduced infarct volume and brain-water content in ischemic brains and promoted functional recovery. Western blotting showed significant inhibition of nNOS in ZJM-289 treated rats compared with untreated rats. However, eNOS expression in the ischemic brain was enhanced in the ZJM-289 groups. The cGMP and NO levels increased in the ZJM-289 groups after I/R. The study showed that ZJM-289 could alleviate cerebral injury after I/R through inhibition of nNOS and stimulation of the NO/soluble guanylate cyclase/cGMP pathway. Therefore, a suitable NO donor might be an effective candidate for the treatment of acute stroke by neuroprotection.
Zhuang
Pei
P
Department of Pharmacology, China Pharmaceutical University, Nanjing, China.
Ji
Hui
H
Zhang
Yi-Hua
YH
Min
Zhen-Li
ZL
Ni
Qing-Gui
QG
You
Ran
R
D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002934:Cinnamates / Q000737:chemistry / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D008297:Male; D018696:Neuroprotective Agents / Q000737:chemistry / Q000627:therapeutic use; D009566:Nitrates / Q000737:chemistry / Q000627:therapeutic use*; D020030:Nitric Oxide Donors / Q000737:chemistry / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
C554089:(2-(1-diethylaminoacetoxy)pentyl)benzoic acid (2-methoxy-4-(2-(4-nitrooxybutoxycarbonyl)vinyl))phenyl ester; D002934:Cinnamates; D018696:Neuroprotective Agents; D009566:Nitrates; D020030:Nitric Oxide Donors