Brain concentrations of kynurenic acid after a systemic neuroprotective dose in the gerbil model of global ischemia.
1. Kynurenic acid (KYNA) is a kynurenine metabolite and a broad spectrum excitatory amino acid antagonist that has been shown to be neuroprotective in models of cerebral ischemia, when administered exogenously. However, the actual concentration required in the CNS to evoke significant neuroprotection has never been assessed. 2. The purpose of this study was to address this question in the gerbil model of forebrain ischemia. KYNA (400-1600 mg/kg) or vehicle were administered i.p. 15 min before 5 min bilateral carotid occlusion. 3. Seven days after reperfusion, ischemia-induced hippocampal nerve cell loss (95% in vehicle-treated) was significantly lower in KYNA-treated gerbils (65% and 52% at 1000 and 1200 mg/Kg, respectively, P < 0.01). Treatment with 1000 mg/kg produced brain KYNA concentrations that were dramatically elevated (135.9 and 42.3 microM in CSF and whole brain, vs 0.032 and 0.16 microM in controls, at 15 min after ischemia), as measured in a separate group of transcardially-perfused gerbils. Cerebral KYNA concentrations tended to return to basal values 2 hours after reperfusion. 4. These results indicate that KYNA has a marked neuroprotective effect in a model of forebrain ischemia. This activity is associated with KYNA concentrations in the brain and CSF that are compatible with the in vitro affinity of the compound for ionotropic glutamate receptors.
Salvati
P
P
CNS Preclinical Research, Pharmacia & Upjohn SpA, Nerviano, MI, Italy.
Ukmar
G
G
Dho
L
L
Rosa
B
B
Cini
M
M
Marconi
M
M
Molinari
A
A
Post
C
C
D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005849:Gerbillinae; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002546:Ischemic Attack, Transient / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D007736:Kynurenic Acid / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016548:Prosencephalon; D015424:Reperfusion; D013997:Time Factors; D014018:Tissue Distribution
D018696:Neuroprotective Agents; D007736:Kynurenic Acid