Talampanel(LY300164)

Talampanel (LY300164) is a non-competitive antagonist of AMPA-receptor [1] [2] [3].

The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA receptor) is a ionotropic transmembrane receptor for glutamate, which is involved in fast synaptic transmission in the central nervous system (CNS) [1].

Talampanel (LY300164) is a non-competitive AMPA-receptor antagonist. In primary rat hippocampal cultures, LY300164 dose-dependently attenuated kainic acid (KA)-excitotoxicity with IC50 value of 4 μM [2].

In male Mongolian gerbils with bilateral carotid artery occlusion, LY300164 (10 mg/kg) orally administration reduced responses to AMPA by 68% but reduced responses to NMDA only by 9%. LY300164 (10 mg/kg) administered orally or intravenously immediately after the occlusion exhibited good protection with 24% and 20% of the neurones surviving, respectively [1]. In mice with transient focal cerebral ischemia/reperfusion, talampanel significantly reduced the infarct size by 33.1%. Also, talampanel significantly reduced the amount of TUNEL-positive cells and caspase-3 active cells [3].

References:
[1].  Lodge D, Bond A, O'Neill MJ, et al. Stereoselective effects-of 2,3-benzodiazepines in vivo: electrophysiology and neuroprotection studies. Neuropharmacology, 1996, 35(12): 1681-1688.
[2].  May PC, Robison PM, Fuson KS. Stereoselective neuroprotection by novel 2,3-benzodiazepine non-competitive AMPA antagonist against non-NMDA receptor-mediated excitotoxicity in primary rat hippocampal cultures. Neurosci Lett, 1999, 262(3): 219-221.
[3].  Denes L, Szilágyi G, Gál A, et al. Talampanel a non-competitive AMPA-antagonist attenuates caspase-3 dependent apoptosis in mouse brain after transient focal cerebral ischemia. Brain Res Bull, 2006, 70(3): 260-262.

Talampanel, a novel noncompetitive AMPA antagonist, is neuroprotective after traumatic brain injury in rats.[Pubmed:11686490]

J Neurotrauma. 2001 Oct;18(10):1031-8.

Talampanel [(R)-7-acetyl-5-(4-aminophenyl)-8,9-dihydro-8-methyl-7H-1,3-dioxolo[4,5-h][2,3] benzodiazepine] is an orally active noncompetitive antagonist of the AMPA subtype of glutamate excitatory amino acid receptors. The purpose of this study was to determine whether treatment with talampanel would protect in a rat model of traumatic brain injury (TBI). Twenty-four hours prior to TBI, a fluid-percussion interface was positioned parasagittally over the right cerebral cortex. On the following day, fasted rats were anesthetized with 3% halothane, 70% nitrous oxide, and a balance of oxygen; mechanically ventilated and physiologically regulated; and subjected to right parieto-occipital parasagittal fluid-percussion injury (1.5-2.0 atm). The agent (talampanel, bolus infusion of 4 mg/kg followed by infusion of 4 mg/kg/h over 72 h) or vehicle was administered i.v. starting at either 30 min or 3 h after trauma. Seven days after TBI, brains were perfusion-fixed, coronal sections at various levels were digitized, and contusion areas were measured. Treatment with talampanel, when instituted 30 min after trauma, significantly reduced total contusion area compared to vehicle-treated rats (0.54 +/- 0.25 vs. 1.79 +/- 0.42 mm2, respectively). When talampanel treatment was begun at 3 h, the neuroprotective effect of the drug was lost. In addition, treatment with talampanel starting at 30 min significantly attenuated neuronal damage in all three subsectors of the hippocampal CA1 sector compared to vehicle-treated rats (normal-neuron counts, right (ipsilateral) medial CA1: 80.3 +/- 2.0 [talampanel] vs. 66.3 +/- 2.1 [vehicle] (mean +/- SEM); middle CA1: 71.5 +/- 2.0 vs. 60.3 +/- 2.2; lateral CA1: 74.5 +/- 3.0 vs. 63.0 +/- 3.2, respectively). By contrast, when talampanel treatment was begun at 3 h, normal pyramidal-neuron counts were almost identical in both groups. Our findings document that talampanel therapy instituted 30 min after trauma significantly reduces histological damage.

The AMPA/kainate receptor antagonist, LY 300164, increases the anticonvulsant effects of diazepam.[Pubmed:10882038]

Naunyn Schmiedebergs Arch Pharmacol. 2000 Jun;361(6):629-35.

The aim of this study was to evaluate the influence of 7-acetyl-5-(4-aminophenyl)-8,9-dihydro-8-methyl-7H-1,3-dioxolo(4,5 H)-2,3-benzodiazepine (LY 300164), a selective non-competitive antagonist at alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate receptors, on the protection provided by diazepam against electrically- and chemically-evoked seizures in rodents. LY 300164 (2 mg/kg) was devoid of any significant action upon each seizure parameter in kindled rats (seizure severity, seizure duration, after-discharge duration). LY 300164 (5 mg/kg) exerted a significant anticonvulsive effect as regards seizure and after-discharge durations. Combined treatment with LY 300164 (2 mg/kg) and diazepam (0.3125-1.25 mg/kg) resulted in the clear-cut anticonvulsive activity. It is noteworthy that the antiseizure potency of the combined treatment (diazepam 1.25 mg/kg plus LY 300164 2 mg/kg) was comparable to that of diazepam (10-20 mg/kg) alone. The combination of diazepam (1.25 mg/kg) with LY 300164 (2 mg/kg) did not induce any significant motor impairment in the rotorod test or memory deficit in the passive-avoidance task. In contrast, diazepam alone (10-20 mg/kg) had pronounced adverse effects in kindled animals. LY 300164 (up to 2 mg/kg) did not influence the threshold for electro- and pentylenetetrazol-induced convulsions but potentiated the anticonvulsive action of diazepam in the maximal electroshock and pentylenetetrazol test in mice, the ED50s of the benzodiazepine being reduced from 13 to 8.7 and from 0.29 to 0.049 mg/kg, respectively. As shown in the passive-avoidance task, combination of LY 300164 (2 mg/kg) with diazepam (8.7 mg/ kg) produced significant motor and long-term memory impairment. Diazepam alone (at the dose equal to its ED50 against maximal electroshock) also caused motor and memory deficits in mice. Interaction at the pharmacokinetic level, at least in plasma, can be excluded, because LY 300164 (2 mg/kg) did not affect the free plasma diazepam concentration. In conclusion, LY 300164 potentiates the protective action of diazepam in some animal models of seizures. This profitable interaction may create a new approach for the treatment of drug resistant epilepsy or status epilepticus.

LY 300164, a novel antagonist of AMPA/kainate receptors, potentiates the anticonvulsive activity of antiepileptic drugs.[Pubmed:9832379]

Eur J Pharmacol. 1998 Oct 23;359(2-3):103-9.

LY 300164 [7-acetyl-5-(4-aminophenyl)-8,9-dihydro-8-methyl-7H-1,3-dioxolo(4, 5H)-2,3-benzodiazepine], administered intraperitoneally up to 2 mg/kg, did not influence the threshold for electroconvulsions. In doses of 2.5-4 mg/kg, LY 300164 significantly raised the threshold. In subprotective doses against electroconvulsions, this excitatory amino acid receptor antagonist enhanced the protective activity of intraperitoneally given valproate, carbamazepine and diphenylhydantoin against maximal electroshock-induced convulsions in mice. The anticonvulsive action of phenobarbital was potentiated by LY 300164 only at 2 mg/kg. The non-N-methyl-D-aspartate receptor antagonist did not affect the plasma levels of the antiepileptic drugs, so a pharmacokinetic interaction is not probable. Combined treatment with LY 300164 (2 mg/kg) and the antiepileptics studied (providing 50% protection against maximal electroshock) did not impair the motor performance of mice, evaluated in the chimney test. Valproate, at its ED50 of 280 mg/kg against maximal electroshock, produced motor impairment. As shown in the passive avoidance task, combination of LY 300164 (2 mg/kg) with valproate or diphenylhydantoin resulted in impairment of long-term memory. Alone among the antiepileptics, valproate (280 mg/kg) and phenobarbital (28.5 mg/kg) disturbed long-term memory. The results suggest that blockade of glutamate-mediated events via non-NMDA receptors leads to enhancement of the anticonvulsive activity of conventional antiepileptics. Some combinations of LY 300164 with antiepileptic drugs were superior to these antiepileptics alone in terms of their lack of adverse effects.