Lubeluzole protects sensorimotor function and reduces infarct size in a photochemical stroke model in rats.
Posttreatment with lubeluzole, the S-isomer of a novel 3,4-difluoro benzothiazole, potently rescued tactile/proprioceptive hindlimb placing reactions contralateral to unilateral thrombotic infarcts in the hindlimb area of the parietal sensorimotor neocortex of rats. Administered at 5 min postinfarct, a single i.v. bolus of lubeluzole was three times as potent as the racemate, whereas the R-isomer was inactive. Neurological protection was near-maximal for treatment delays through 1 hr postinfarct, but declined with longer delays. However, when administered at 6 hr, 1.25 mg/kg i.v. still protected 60% of infarcted rats. An i.v. bolus followed by a 1-hr i.v. infusion produced equieffective neurologic protection at both 6- and 3-hr delays. This optimal lubeluzole regimen, started at 5 min postinfarct, reduced infarct volume by 22 to 24% at 4 hr postinfarct and by 28% at 7 days postinfarct. Again, the R-isomer was inactive. Down-regulation of the glutamate-activated nitric oxide synthase pathway leading to neurotoxicity and neuronal death may constitute a neuroprotective mechanism of action for lubeluzole.
De Ryck
M
M
Janssen Research Foundation, Department of Neuropsychopharmacology, Beerse, Belgium.
Keersmaekers
R
R
Duytschaever
H
H
Claes
C
C
Clincke
G
G
Janssen
M
M
Van Reet
G
G
D000818:Animals; D001921:Brain / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects* / Q000502:physiology; D002544:Cerebral Infarction / Q000188:drug therapy*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009553:Nimodipine / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D010777:Photochemistry; D010880:Piperidines / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism; D013844:Thiazoles / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use
D018696:Neuroprotective Agents; D010880:Piperidines; D013844:Thiazoles; D009553:Nimodipine; D016291:Dizocilpine Maleate; D019001:Nitric Oxide Synthase; C097722:lubeluzole