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Background and objectives Despite significant advances in Parkinson's disease (PD) treatment, it remains incurable, with limited therapeutic options. Currently, repurposing already tested, safe drugs has emerged as an effective therapeutic strategy against various neurodegenerative diseases, including PD. Using a drug-repurposing approach, the current study investigated the neuroregenerative potential of polysialic acid mimicking compounds, 5-nonyloxytryptamine oxalate (5-NOT) and Epirubicin (Epi), an anti-cancer drug, in 1-methyl-4-phenylpyridinium (MPP + )-treated human neuroblastoma SH-SY5Y cells as a PD model.
Methods The excitotoxic model was established by exposing SH-SY5Y cells to 500 μM of MPP + and subsequently treating them with the test compounds. The effect of MPP + -induced toxicity on cellular and nuclear morphology, as well as on the expression of neuroplasticity and cell survival proteins, were studied by immunostaining, gelatin zymogram, and Western blot assays. Results Treatment with 5-NOT and Epi significantly promoted the survival of MPP + -challenged SH-SY5Y cells and prevented changes in their cellular and nuclear morphology by regulating the expression of microtubule-associated protein (MAP-2) and polysialylated-neural cell adhesion molecule (PSA-NCAM) and NCAM synaptic plasticity proteins.
Further, 5-NOT and Epi treatment also protected SH-SY5Y cells by restoring levels of nitric oxide, matrix metalloproteinase, and stress response proteins. Interstingly, 5-NOT attenuated MPP + -induced toxicity in SH-SY5Y cells by regulating the intrinsic protein kinase AKT/BAD apoptotic pathway and the P-38 MAP kinase synaptic plasticity pathway. Conclusions Related Stories Scientists discover key genes for regenerating cells in the ear and eye High-fat diet linked to increased breast cancer metastasis risk Study: Rural cancer patients cross state lines for specialized care The present data provides compelling evidence for the potential beneficial role of 5-NOT as a glycomimetic drug candidate targeting the neurodegeneration of dopamine neurons, a hallmark feature of patients suffering from PD.
The study's outcome is also supported by our previous findings in spinal cord injury ( in vivo study) and neurodegenerative disease in vitro models of glutamate-induced excitotoxicity. Identification of novel compounds from small molecule libraries mimicking the functions of PSA may offer new therapeutic avenues for PD and other neurodegenerative diseases. Xia & He Publishing Inc.
https://www.xiahepublishing.com/2572-5505/JERP-2024-00038.
