The neuronal nitric oxide synthase inhibitor, TRIM, as a neuroprotective agent: effects in models of cerebral ischaemia using histological and magnetic resonance imaging techniques.
Most neuroprotective compounds that appear promising in the pre-clinical phase of testing are subsequently dismissed as relatively ineffective when entered into large-scale clinical trials. Many pre-clinical studies of potential neuroprotective candidates evaluate efficacy in only one or possibly two different models of ischaemia. In this study we examined the effects of 1,2-trifluoromethylphenyl imidazole (TRIM), a novel neuronal nitric oxide synthase (nNOS) inhibitor, in three models of cerebral ischaemia (global gerbil, global rat and focal rat). In addition, to follow the progression of the pathology, we also compared traditional histology methods with more advanced magnetic resonance imaging (MRI) as endpoint measures for neurological damage and neuroprotection. TRIM (50 mg/kg i.p.) prevented ischaemia-induced hippocampal damage following global ischaemia in gerbils when administered before or immediately post-occlusion, but failed to protect when administration was delayed until 30 min post-occlusion. Further studies indicated that the compound (administered at 50 mg/kg, i.p., immediately after occlusion) also protected in a rat four-vessel occlusion (4-VO) model using both histological and diffusion-weighted (DW) imaging techniques. In a final study, TRIM (50 mg/kg i.p. 30 min after occlusion) provided a significant reduction in infarct volume at 4 and 24 h as measured using diffusion-weighted (DW) and proton density (PD)-weighted magnetic resonance imaging (MRI). This was confirmed using histological techniques. These studies confirm that nNOS inhibitors may have utility in stroke and provide evidence that combined magnetic resonance and histological methods can provide a powerful method of assessing neuronal damage in rodent models of cerebral ischaemia.
Haga
Kristin K
KK
Department of Clinical Neuroscience, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK.
Gregory
Lloyd J
LJ
Hicks
Caroline A
CA
Ward
Mark A
MA
Beech
John S
JS
Bath
Phillip W
PW
Williams
Steven C R
SC
O'Neill
Michael J
MJ
D000818:Animals; D002545:Brain Ischemia / Q000145:classification / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D020212:Carotid Artery Injuries / Q000150:complications / Q000473:pathology; D002470:Cell Survival; D002544:Cerebral Infarction / Q000209:etiology / Q000517:prevention & control; D004195:Disease Models, Animal; D005849:Gerbillinae; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D007093:Imidazoles / Q000627:therapeutic use*; D066298:In Vitro Techniques; D008279:Magnetic Resonance Imaging; D008297:Male; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar; D013194:Staining and Labeling; D013778:Tetrazolium Salts / Q000378:metabolism; D013997:Time Factors
D007093:Imidazoles; D018696:Neuroprotective Agents; D013778:Tetrazolium Salts; C098186:1-(2-trifluoromethylphenyl)imidazole; C009591:triphenyltetrazolium; D019001:Nitric Oxide Synthase