Neuroprotective effect of s-methylisothiourea in transient focal cerebral ischemia in rat.
Over production of NO by nitric oxide synthase (NOS) in the brain parenchyma has been demonstrated to contribute to tissue damage. NO may be toxic by formation of peroxinitrite after a reaction between NO and superoxide appears to be one of the major pathways leading to cell death. Of three types of NOS, nNOS is neurotoxic in early and iNOS in late stage of transient cerebral ischemia (TFCI), while eNOS is neuroprotective in all stages. We examined the neuroprotective effect of a preferential iNOS inhibitor s-methylisothiourea (SMT) at 0, 8, 24 and 48h as multiple injections (30 and 100mg/kg, i.p.) in ischemia and reperfusion injury in a rat model of middle cerebral artery occlusion (2h) and reperfusion (72h). After 2h of ischemia and 72h of reperfusion, animals were sacrificed for studying the infarct volume, brain edema and apoptosis and neuro-behavioral abnormality was assessed at 24, 48 and 72h of reperfusion. SMT reduced significantly the infarct volume, neuro-behavioral abnormality, brain edema, number of apoptotic cells in penumbra and NOx levels in plasma and brain both at 30 and 100mg/kg in dose-dependent manner. The amount of peroxynitrite measured by rhodamine assay was significantly reduced by SMT, as compared to control group. SMT protected Neuro 2a cells against sodium azide-induced damage. It is concluded that, SMT may possibly targeting both constitutive as well as inducible NOS at varying time interval to elicit neuroprotection in TFCI rats.
ArunaDevi
Rathinam
R
Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, Bareilly, U.P. 243 122, India.
Ramteke
Vinod D
VD
Kumar
Saurabh
S
Shukla
Manoj K
MK
Jaganathan
Subramani
S
Kumar
Dinesh
D
Sharma
Anil K
AK
Tandan
Surendra K
SK
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D002546:Ischemic Attack, Transient / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D007550:Isothiuronium / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D009569:Nitric Oxide / Q000096:biosynthesis; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D007550:Isothiuronium; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; C027744:S-methylisothiopseudouronium