Re-purposing 5-nonyloxytryptamine and epirubicin as polysialic acid mimetics for protection from MPP+-induced cytotoxicity in human neuronal cells

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

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.

Full text

https://www.xiahepublishing.com/2572-5505/JERP-2024-00038

The study was recently published in the Journal of Exploratory Research in Pharmacology.

Journal of Exploratory Research in Pharmacology (JERP) publishes original innovative exploratory research articles, state-of-the-art reviews, editorials, short communications that focus on novel findings and the most recent advances in basic and clinical pharmacology, covering topics from drug research, drug development, clinical trials and application.

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