Neuroprotective effects of the GABA A receptor partial agonist U-101017 in 3-acetylpyridine-treated rats Vimala H. Sethy*, Haiyan Wu, Jo A. Oostveen, Edward D. Hall CNS Research 7251-209-508, Pharmacia and Upjohn, Inc., 301 Henrietta Street, Kalamazoo, MI 49001, USA Received 26 November 1996; revised version received 15 April 1997; accepted 23 April 1997 Abstract The neuroprotective effects of U-101017, [7-chloro-5-[cis-3,5-dimethylpiperazine)carbonyl]-imidazole[1,5a]quinoline-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 mmol/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 tempera- ture. 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.  1997 Elsevier Science Ireland Ltd. Keywords: 3-Acetylpyridine; Neuroprotective effects; g-Aminobutyric acid The balance between the activity of excitatory and inhi- bitory neurotransmission may be essential for the mainte- nance of normal neuronal anatomical structure and physiological functions in the brain. Pyramidal cells of the hippocampus respond to both excitatory and inhibitory inputs via activation of glutamate and g-aminobutyric acid (GABA) receptors, respectively. Likewise, glutamate and aspartate are the excitatory, and GABA is the inhibitory, neurotransmitters for the Purkinje cells of the cerebellum [5,16,28]. Persistent imbalance in the activity of these neu- rotransmitters may be responsible for the degeneration of neurons following ischemia and anoxia. For instance, it has been demonstrated that there is an elevation of extracellular glutamate and aspartate in the hippocampus and striatum during transient forebrain ischemia [2,6]. On the other hand, several other mediators of cerebral ischemia, includ- ing calcium, arachidonic acid and oxygen radicals, decrease the GABA A response in vitro [19–21]. In addition, reduc- tion in the mRNA of GABA A receptor subunits (a1 and b2) occurs immediately after reperfusion and prior to the degen- eration of hippocampal CA 1 neurones following transient forebrain ischemia in the gerbil. Thus, an increase in exci- tatory and a decrease in inhibitory neurotransmitter activ- ities may be responsible for the degeneration of neurons. This is further supported by neuroprotective effects of drugs which block the action of excitatory aminoacids (MK 801) or enhance the effect of GABA (diazepam) [10,26]. U-101017 [(7-chloro-5-[cis-3,5-dimethylpiperazine)car- bonyl]-imidazole[1,5a]quinoline-3-carboxylate)] is a novel anxiolytic which competes with [ 3 H]flunitrazepam for bind- ing to cerebral cortical membrane preparations [23]. In a 1 b 2 g 2 and a 3 b 2 g 2 GABA A receptor complexes, U-101017 has a biphasic effect on GABA-induced increases in Cl - flux. At a low concentration (1 mm), U-101017 potentiates and at high concentrations (1 mm) inhibits GABA-induced Cl - current in these GABA A receptor subtypes. Flumazenil, an antagonist of the GABA A receptors, blocks the potentiat- ing effect of U-101017 on GABA-induced chloride current [8]. Consistent with this unique physiological effect, U- Neuroscience Letters 228 (1997) 45–49 0304-3940/97/$17.00  1997 Elsevier Science Ireland Ltd. All rights reserved PII S0304-3940(97)00353-4 * Corresponding author. Tel.: +1 616 8337694; fax: +1 616 8332525.