KM-34, a Novel Antioxidant Compound, Protects against 6-Hydroxydopamine-Induced Mitochondrial Damage and Neurotoxicity

Abstract

The etiology of Parkinson’s disease is not completely understood and is believed to be multifactorial. Neuronal disorders associated to oxidative stress and mitochondrial dysfunction are widely considered major consequences. The aim of this study was to investigate the effect of the synthetic arylidenmalonate derivative 5-(3,4-dihydroxybenzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (KM-34), in oxidative stress and mitochondrial dysfunction induced by 6-hydroxydopamine (6-OHDA). Pretreatment (2 h) with KM-34 (1 and 10 μM) markedly attenuated 6-OHDA-induced PC12 cell death in a concentration-dependent manner. KM-34 also inhibited H2O2 generation, mitochondrial swelling, and membrane potential dissipation after 6-OHDA-induced mitochondrial damage. In vivo, KM-34 treatment (1 and 2 mg/Kg) reduced percentage of asymmetry (cylinder test) and increased the vertical exploration (open field) with respect to untreated injured animals; KM-34 also reduced glial fibrillary acidic protein overexpression and increased tyrosine hydroxylase-positive cell number, both in substantia nigra pars compacta. These results demonstrate that KM-34 present biological effects associated to mitoprotection and neuroprotection in vitro, moreover, glial response and neuroprotection in SNpc in vivo. We suggest that KM-34 could be a putative neuroprotective agent for inhibiting the progressive neurodegenerative disease associated to oxidative stress and mitochondrial dysfunction.

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Acknowledgments

This work was partially supported by CAPES/MES (Brazil-Cuba) project 178/12 2, titled: “Estudo de compostos derivados de arilidenmalonatos e de benzodiazepinas em modelos experimentais de enfermidade de Parkinson, com énfase nos mecanismos neuroinflamatórios, mitocondriais, antioxidantes e apoptótico” and by CAPES/MES (Brazil-Cuba) Project 09-061 “Sistemas heterocíclicos policondensados com potencial atividade antiparasitaria: leishmania e malaria.” Ochoa-Rodriguez E. is indebted to both CAPES/MES projects for contributing to Brazil-Cuba scientific cooperation and particularly for partially funding the synthesis and biological evaluations of different synthetic compounds.

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Fonseca-Fonseca, L.A., Nuñez-Figueredo, Y., Sánchez, J.R. et al. KM-34, a Novel Antioxidant Compound, Protects against 6-Hydroxydopamine-Induced Mitochondrial Damage and Neurotoxicity. Neurotox Res 36, 279–291 (2019). https://doi.org/10.1007/s12640-017-9851-5

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Keywords

  • KM-34
  • Arylidenmalonate derived
  • Mitochondria
  • Neuroprotection
  • Parkinson’s disease