Long-term effects of clomethiazole in a model of global ischemia.
The failure of neuroprotective drugs in clinical trials has raised questions about the predictive value of animal models. To address this issue we reexamined the efficacy of clomethiazole using functional and histological outcome measures in combination with long-term survival times. Gerbils were exposed to 5 min of global ischemia and received 400 mg/ml clomethiazole (via osmotic minipump) plus a bolus injection (60 mg/kg) 30 min after ischemia. Brain temperature was maintained at approximately 36.5 degrees C during ischemia and for the first 30 min after ischemia, and was monitored in all groups for 24 h. Subgroups of clomethiazole-treated gerbils had their temperatures regulated in the normothermic range while in other animals temperature was not controlled. Open-field habituation tests were conducted 5, 10, 30, and 60 days after occlusion. CA1 cell counts and CA1 slice recordings were done at the conclusion of behavioral testing. Clomethiazole significantly attenuated CA1 cell loss at 10-, 30-, and 60-day survival. A modest reduction in habituation deficits was evident only on Day 10 (P < 0.05). Similarly, field potential amplitude was not maintained in the rostral CA1 region. Clomethiazole produced mild hypothermia that developed over several hours. Based on short-term CA1 cell counts, clomethiazole provided significant histological protection with limited functional preservation. Neuroprotection disappeared when longer survival times (60 day) were employed and temperature confounds eliminated. These data demonstrate the necessity of utilizing more clinically relevant survival times and carefully monitoring/regulating postischemic temperature when assessing potential neuroprotective compounds.
Chaulk
Dana
D
Basic Medical Sciences, Faculty of Medicine, Memorial University, St. John's, A1B 3V6, Newfoundland, Canada.
Wells
Jennifer
J
Evans
Suzanne
S
Jackson
David
D
Corbett
Dale
D
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000503:physiopathology; D002452:Cell Count; D002719:Chlormethiazole / Q000494:pharmacology*; D004195:Disease Models, Animal; D018450:Disease Progression; D004558:Electric Stimulation; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005260:Female; D005849:Gerbillinae; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D066298:In Vitro Techniques; D009474:Neurons / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D013037:Spatial Behavior / Q000187:drug effects; D013995:Time
D018696:Neuroprotective Agents; D002719:Chlormethiazole