Neuroprotective effects of the GABA(A) receptor partial agonist U-101017 in 3-acetylpyridine-treated rats.
The neuroprotective effects of U-101017, [7-chloro-5-[cis-3,5-dimethylpiperazine)carbonyl]-imidazole[1,5a]quinoli ne-3-carboxylate], a GABA(A) receptor partial agonist, were investigated in 3-acetylpyridine (3-AP) treated Wistar rats. A significant (P < 0.01) reduction in both cGMP and ATP in the cerebellum was observed at 96 h after treatment with 3-AP (500 micromol/kg i.p.). Oral administration of U-101017 before and after treatment with 3-AP significantly attenuated 3-AP-induced decreases in cGMP and ATP, and this effect was dose related. Consistent with the neurochemical effect, U-101017 prevented 3-AP-induced loss of motor coordination. Treatment with U-101017 partially, but significantly (P < 0.01) prevented the loss of inferior olivary neurons. U-101017 had no significant effect on body temperature. Thus, hypothermia was not involved in neuroprotective effects of U-101017. Co-administration of flumazenil with each treatment of U-101017 blocked the neuroprotective effect of U-101017, indicating that it mediated neuroprotection via the benzodiazepine binding sites on the GABA(A) receptor complex. Delayed administration of U-101017 at various time intervals after treatment with 3-AP demonstrated a significant neuroprotective effect even at 8 h, suggesting that this drug has a wide therapeutic window.
Sethy
V H
VH
CNS Research 7251-209-508, Pharmacia and Upjohn, Inc., Kalamazoo, MI 49001, USA.
Wu
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H
Oostveen
J A
JA
Hall
E D
ED
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005442:Flumazenil / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology; D058785:GABA-A Receptor Agonists; D008297:Male; D009068:Movement / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009847:Olivary Nucleus / Q000166:cytology / Q000187:drug effects; D011725:Pyridines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011804:Quinolines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
C104547:7-chloro-5((cis-3,5-dimethylpiperazine)carbonyl)imidazo(1,5a)quinoline-3-carboxylate; D018757:GABA Modulators; D058785:GABA-A Receptor Agonists; D018696:Neuroprotective Agents; D011725:Pyridines; D011804:Quinolines; C010835:3-acetylpyridine; D005442:Flumazenil; D000255:Adenosine Triphosphate; D006152:Cyclic GMP