Comparative neuroprotective properties of the benzodiazepine receptor full agonist diazepam and the partial agonist PNU-101017 in the gerbil forebrain ischemia model.
Recent studies have demonstrated the neuroprotective properties of the novel imidazoquinoline benzodiazepine receptor partial agonist, PNU-101017, in the gerbil forebrain ischemia model. The compound effectively reduces delayed post-ischemic (5 min bilateral carotid occlusion) hippocampal CA1 neuronal degeneration even when its administration is withheld until 4 h after reperfusion and the effect is unrelated to hypothermia. The purpose of the present study was to determine the comparative abilities of PNU-101017 versus the full agonist diazepam to attenuate post-ischemic CA1 damage. Male gerbils were treated either 30 min before ischemia induction or immediately after reperfusion with an initial dose of PNU-101017 (30 mg/kg i.p.) or diazepam (10 mg/kg i.p.) with a second dose being given at 2 h after reperfusion. Possible hypothermic effects of either compound were prevented by external heating. In vehicle (0.05 N HCl)-treated gerbils, the loss of hippocampal CA1 neurons at 5 days was 85%. PNU-101017 pretreatment reduced the loss to 50% (p<0.05 vs. vehicle) whereas pretreatment with diazepam attenuated damage to only 17% (p<0.001 vs. vehicle). Delaying treatment with PNU-101017 until just after reperfusion still resulted in a reduction in CA1 degeneration statistically that was indistinguishable from that seen with pretreatment. In contrast, diazepam post-treatment did not significantly decrease CA1 neuronal loss. These results suggest that a benzodiazepine receptor partial agonist may have greater neuroprotective practicality than a full agonist for the treatment of global cerebral ischemia. The mechanistic basis for this difference may relate to the partially pro-excitatory neuronal response to endogenous GABA before and after neuronal insult.
Central Nervous System Research, Pharmacia & Upjohn, Kalamazoo, MI 49001, USA. halle@aa.wl.com
E D
ED
Hall
T J
TJ
Fleck
J A
JA
Oostveen
D000818:Animals; D002545:Brain Ischemia / Q000473:pathology*; D003975:Diazepam / Q000494:pharmacology*; D018755:GABA Agonists / Q000494:pharmacology*; D058785:GABA-A Receptor Agonists; D005849:Gerbillinae; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D008297:Male; D009410:Nerve Degeneration / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016548:Prosencephalon / Q000098:blood supply*; D011804:Quinolines / Q000494:pharmacology*
C104547:7-chloro-5((cis-3,5-dimethylpiperazine)carbonyl)imidazo(1,5a)quinoline-3-carboxylate; D018755:GABA Agonists; D058785:GABA-A Receptor Agonists; D018696:Neuroprotective Agents; D011804:Quinolines; D003975:Diazepam