[Decrease in the glutamate release may contribute to the neuroprotective action of the novel neuroleptic drug dilept].

Dilept (GZR-123, N-caproyl-L-prolyl-L-tyrosine methyl ester), designed and synthesized at the Zakusov Institute of Pharmacology, was chosen as one of the most effective compounds from a series of N-acylprolyltyrosine derivatives having common pharmacophores with beta-turn of neurotensin (NT(8-13)) and repeating the structure of a nonpeptide prototype, the atypical neuroleptic sulpiride. The aim of this study was to evaluate the effect of dilept on the level of spontaneous and K(+)-stimulated release of glutamate. The experiments were performed in vitro on the cortical brain slices of male Wistar rats. Dilept used in concentrations 10(-5) and 10(-6) mole/liter did not affect the spontaneous release of glutamate though markedly decreased the K(+)-stimulated release. A decrease in the glutamate release under the action of the neuroleptic could contribute to the neuroprotective activity of dilept.

[Neuroprotective activity of the proline-containing dipeptide noopept on the model of brain ischemia induced by the middle cerebral artery occlusion].

The influence of noopept (N-phenylacetyl-L-prolylglycine ethyl ester, GVS-111) on the extent of ischemic cortical stroke was investigated in experiments on white mongrel male rats with ischemia induced by a combination of the middle cerebral artery occlusion with ipsilateral common carotid artery ligation. Animals were treated with noopept (0.5 mg/kg, i.p.) according to the following schedule: 15 min and 2, 24, and 48 h after the occlusion. Test rats were decapitated 72 h after occlusion, brains were extracted and frozen, and thin brain slices were stained with 2,3,5-triphenyltetrazolium chloride. The slices were scanned and processed using Auc 1 computer program, which estimates the percentage of damaged area relative to that of the whole ipsilateral hemisphere. The conditions of coagulation the distal segment of middle cerebral artery were selected, which caused necrosis localized in the fronto-parietal and dorso-lateral regions of the brain cortex without any damage of subcortical structures. The extent of the brain damage in control group (treated by saline) was 18.6%, while that in the group treated with noopept was 12.2%, thus demonstrating a decrease in the infarction area by 34.5% (p < 05). The data on noopept efficacy on the model of the extensive ischemic injury of brain cortex show that this drug has good prospects for use in the neuroprotective treatment of stroke.

[The new tripeptoid neurotensin analog dilept selectively affects dopamine turnover in nucleus accumbens and hypothalamus].

The effects of dilept (N-caproyl-L-prolyl-L-tyrosine methyl ester) - a new peptidomimetic of neurotensine - on the level of monoamines and their main metabolites in four functionally important brain structures has been studied upon single and subchronic administration in intact rats and in those pretreated with the NMDA receptor blocker ketamine. Repeated administration of dilept favors the accumulation of DOPAC and accelerates the dopamine (DA) turnover in nucleus accumbens, as manifested by an increase in the DOPAC/DA ratio. The opposite effect (decrease in the DOPAC/DA ratio) was observed in the hypothalamus, where the subchronic treatment with dilept completely inhibited the activating action of ketamine on the DA turnover. The selective influence of dilept on the dopaminergic system activity in nucleus accumbens (but not in striatum), together with the previously obtained behavioral data, suggest that dilept is a new atypical neuroleptic producing no extrapyramidal side effects.