Mitochondria are a crucial target for the actions of neurotoxins, causing symptoms of Parkinson’s disease in various experimental animal models, and also neuroprotectors. There is evidence that mitochondrial dysfunction induced by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) influences functioning of the ubiquitin-proteasomal system (UPS) responsible for selective proteolytic degradation of proteins from various intracellular compartments (including mitochondria) and neuroprotective effects of certain anti-Parkisonian agents (monoamine oxidase inhibitors) may be associated with their effects on the UPS. In this study, we have investigated the effect of the neurotoxin MPTP and neuroprotector isatin, and their combination on the profile of ubiquitinated brain mitochondrial proteins. The development of movement disorders induced by MPTP administration caused dramatic changes in the profile of ubiquitinated proteins associated with mitochondria. Pretreatment with the neuroprotector isatin decreased manifestations of MPTP-induced Parkinsonism, and had a significant impact on the profile of ubiquitinated mitochondrial proteins (including oxidative modified proteins). Administration of isatin alone to intact mice also influenced the profile of ubiquitinated mitochondrial proteins, and increased the proportion of oxidized proteins carrying the ubiquitination signature. These alterations in the ubiquitination of mitochondrial proteins observed within 2 h after administration of MPTP and isatin obviously reflect immediate short-term biological responses to these treatments.

Experiments on adult Wistar rats with streptozotocin-induced diabetes showed that antihyperglycemic activity of an original nootropic and neuroprotective drug Noopept (N-phenylacetyl-L-prolylglycine ethyl ester) is more pronounced under conditions of oral application than after intraperitoneal injection. These data provided a basis for studying the effect of Noopept on major indexes of the incretin system. Streptozotocin was shown to decrease the concentrations of incretin GLP-1 and insulin in the blood. Noopept had a normalizing effect on these parameters. This influence of Noopept was not related to the inhibition of a major enzyme metabolizing incretins (dipeptidyl peptidase IV). A reference drug sitagliptin also increased the contents of incretins and insulin, which was associated with the inhibition of dipeptidyl peptidase IV. It is known that GLP-1 increases NGF expression in the insular system. Our results suggest that the increase in incretin activity contributes to the antiapoptotic effect of Noopept on pancreatic β cells. The mechanism for an increase in blood GLP-1 level after oral application of Noopept requires further investigations.

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A single intraperitoneal administration of 50 and 100 mg/kg mexidolum and subchronic intraperitoneal administration of 100 mg/kg mexidolum significantly enhances the physical performance of animals in the forced swim test. Subchronic intraperitoneal administration of 100 mg/kg of the comparison drug mildronatum enhances the physical performance of animals, while intraperitoneal administration at a lower dose (50 mg/kg) has no effect. The effect of mexidolum at a dose of 50 and 100 mg/kg is comparable with the effect of mildronatum in a dose of 100 mg/kg.

In rats with carrageenan-induced paw edema, diclofenac sodium significantly reduces exudation after ten-day preventive oral administration at a dose of 10 mg/kg but not 5 mg/kg. Mexidol at a dose of 100 mg/kg in combination with diclofenac sodium at a dose of 5 mg/kg (preventively orally, during 10 days, once a day) reduces paw edema during the first two out of four hours of its recording compared with the control group. However, ten-day preventive oral administration of mexidol at a dose of 100 mg/kg (once a day) increases the severity of carrageenan-induced paw edema in rats at four hours after the injection of the phlogogen.

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