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СпутникиРНSpaceXРоскосмосNASAIntroduction. Parkinson's disease (PD) is a widespread neurodegenerative disorder characterized by the progressive loss of dopaminergic (DA) neurons in the nigrostriatal system of the brain. Since current PD therapy is predominantly symptomatic, there is an urgent need to develop novel disease-modifying therapeutic strategies. Neurotrophins represent promising candidates for this role. Specifically, neurotrophin-3 (NT-3) improves the survival and functional state of DA neurons during neurodegenerative processes. However, the clinical application of neurotrophins is limited by their low bioavailability. At the Federal research center for innovator and emerging biomedical and pharmaceutical technologies, low-molecular-weight dimeric dipeptide mimetics of NT-3 were synthesized based on the central β-turn fragment of its loop 4. These include GTS-301LL (bis-(N-monosuccinyl-L-asparaginyl-L-asparagine) hexamethylenediamine), GTS-304LL (bis-(N-monoglutaryl-L-asparaginyl-L-asparagine) hexamethylenediamine) and its LD-stereoisomer.Objective. To evaluate the neuroprotective activity of the obtained mimetics on human neuroblastoma SH-SY5Y cells under conditions of 6-OHDAinduced toxicity (a cell model of PD).Methods. The dipeptides were added to the culture medium at concentrations ranging from 10−5 to 10−8 M, either 24 hours before or immediately after 6-OHDA exposure. NT-3 (100 ng/mL) was used as a positive control.Results. NT-3 improved cell viability when added both 24 hours before and immediately after the neurotoxin. Among the NT-3 mimetics, GTS-301LL and GTS-304LL exhibited the most pronounced neuroprotective activity, increasing cell viability at a concentration of 10−5 M when added 24 hours before 6-OHDA, and at concentrations of 10−5 to 10−7 M when added after 6-OHDA. GTS-304LD showed neuroprotective activity only when added 24 hours prior to 6-OHDA at the concentrations range 10−5 – 10−6 M.Conclusion. These findings indicate that further investigation of the antiparkinsonian activity of dipeptide mimetics of NT-3 loop 4 is highly promising.
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