Neuroprotective effects of the GABA(A) receptor partial agonist U-101017 in 3-acetylpyridine-treated rats.

Abstract

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.

• Authors: V H Sethy, H Wu, J A Oostveen, E D Hall
• Journal: Neuroscience letters (Neurosci Lett) Vol. 228 Issue 1 Pg. 45-9 (May 30 1997) ISSN: 0304-3940 [Print] Ireland
• PMID: 9197284 (Publication Type: Journal Article)

Chemical References

• 7-chloro-5((cis-3,5-dimethylpiperazine)carbonyl)imidazo(1,5a)quinoline-3-carboxylate
• GABA Modulators
• GABA-A Receptor Agonists
• Neuroprotective Agents
• Pyridines
• Quinolines
• 3-acetylpyridine
• Flumazenil
• Adenosine Triphosphate
• Cyclic GMP

Topics

• Adenosine Triphosphate (metabolism)
• Animals
• Body Temperature (drug effects)
• Cerebellum (drug effects, metabolism)
• Cyclic GMP (metabolism)
• Dose-Response Relationship, Drug
• Flumazenil (pharmacology)
• GABA Modulators (pharmacology)
• GABA-A Receptor Agonists
• Male
• Movement (drug effects)
• Neuroprotective Agents (pharmacology)
• Olivary Nucleus (cytology, drug effects)
• Pyridines (antagonists & inhibitors, pharmacology)
• Quinolines (antagonists & inhibitors, pharmacology)
• Rats
• Rats, Wistar
• Time Factors