Protection with lubeluzole against delayed ischemic brain damage in rats. A quantitative histopathologic study.
OBJECTIVE
Cerebral ischemia may lead to glutamate-induced excitotoxic damage in vulnerable brain areas. Lubeluzole is not an N-methyl-D-aspartate antagonist but prevents postischemic increase in extracellular glutamate concentrations. The present study examined whether lubeluzole, administered after global incomplete ischemia in rats, is capable of preserving the structural integrity of CA1 hippocampus.


METHODS
Ischemia was induced by bilateral carotid artery occlusion and severe hypotension for a duration of 9 minutes. Delayed neuronal cell death was histologically evaluated 7 days later. This was done by scoring acidophilic cell change and coagulative necrosis and by counting the number of surviving neurons in the CA1 subfield. Experiments were performed according to a paired design (13 animals per treatment group).


RESULTS
Posttreatment with lubeluzole (0.31 mg/kg i.v. bolus at 5 minutes and 0.31 mg/kg i.v. infusion during 1 hour) resulted in significant neuroprotection. Whereas in the untreated rats there were 42 (median) viable neurons per millimeter CA1 layer in the left and 69 in the right hemisphere, in the drug-treated rats 99 viable neurons per millimeter were found in the left (P = .002) and 113 in the right hemisphere (P = .013). Histological scores, reflecting altered staining properties of the hippocampal cells, correlated strongly with the quantitative data, reflecting the structural integrity of CA1 pyramidal neurons.


CONCLUSIONS
Lubeluzole, when administered after an ischemic insult in rats, protects vulnerable brain regions against delayed structural injury. The results support the potential clinical use of this new drug in stroke treatment.
Haseldonckx
M
M
Department of Morphology, Life Sciences, Janssen Research Foundation, Beerse, Belgium.
Van Reempts
J
J
Van de Ven
M
M
Wouters
L
L
Borgers
M
M
D000818:Animals; D001925:Brain Damage, Chronic / Q000209:etiology / Q000517:prevention & control*; D002545:Brain Ischemia / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D016893:Carotid Stenosis / Q000150:complications; D016923:Cell Death; D004353:Drug Evaluation, Preclinical; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology*; D008026:Ligation; D008297:Male; D009474:Neurons / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010880:Piperidines / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D012769:Shock / Q000150:complications; D013844:Thiazoles / Q000627:therapeutic use*; D013997:Time Factors
D018696:Neuroprotective Agents; D010880:Piperidines; D013844:Thiazoles; C097722:lubeluzole