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Protective effects of zonisamide against rotenone-induced neurotoxicity
Salvatore Condello1, Monica Currò, Nadia Ferlazzo
1Department of Biomedical Sciences and Morphological and Functional Imaging, University of Messina, AOU Policlinico "G. Martino", Via C. Valeria, 98125, Messina, Italy.
Abstract:
Zonisamide (ZNS), an antiepileptic drug having beneficial effects also against Parkinson's disease symptoms, has proven to display an antioxidant effects in different experimental models. In the present study, the effects of ZNS on rotenone-induced cell injury were investigated in human neuroblastoma SH-SY5Y cells differentiated towards a neuronal phenotype. Cell cultures were exposed for 24 h to 500 nM rotenone with or without pre-treatment with 10-100 μM ZNS. Then, the following parameters were analyzed: (a) cell viability; (b) intracellular reactive oxygen species production; (c) mitochondrial transmembrane potential; (d) cell necrosis and apoptosis; (e) caspase-3 activity. ZNS dose-dependently suppressed rotenone-induced cell damage through a decrease in intracellular ROS production, and restoring mitochondrial membrane potential. Similarly to ZNS effects, the treatment with N-acetyl-cysteine (100 μM) displayed significant protective effects against rotenone-induced ROS production and Δψm at 4 and 12 h respectively, reaching the maximal extent at 24 h. Additionally, ZNS displayed antiapoptotic effects, as demonstrated by flow cytometric analysis of annexin V/propidium iodide double staining, and significant attenuated rotenone-increased caspase 3 activity. On the whole, these findings suggest that ZNS preserves mitochondrial functions and counteracts apoptotic signalling mechanisms mainly by an antioxidant action. Thus, ZNS might have beneficial effect against neuronal cell degeneration in different experimental models involving mitochondrial dysfunction.
Insights
Zonisamide (ZNS), an antiepileptic drug, protects neuronal cells from rotenone-induced damage by reducing oxidative stress and preserving mitochondrial function. These findings suggest ZNS may benefit neurodegenerative diseases involving mitochondrial dysfunction.
Area of Science:
- Neuroscience
- Pharmacology
- Biochemistry
Background:
- Zonisamide (ZNS) is an antiepileptic drug with demonstrated antioxidant effects.
- Parkinson's disease and other neurodegenerative conditions involve mitochondrial dysfunction and oxidative stress.
Purpose of the Study:
- To investigate the neuroprotective effects of Zonisamide (ZNS) against rotenone-induced cell injury in human neuroblastoma SH-SY5Y cells.
- To elucidate the mechanisms underlying ZNS's protective effects, focusing on oxidative stress and mitochondrial function.
Main Methods:
- Human neuroblastoma SH-SY5Y cells were exposed to rotenone with or without ZNS pre-treatment.
- Assessed cell viability, intracellular reactive oxygen species (ROS) production, mitochondrial membrane potential (Δψm), and apoptosis markers (caspase-3 activity, Annexin V/propidium iodide staining).
- Compared ZNS effects with N-acetyl-cysteine, a known antioxidant.
Main Results:
- Zonisamide dose-dependently reduced rotenone-induced cell damage, decreased intracellular ROS production, and restored mitochondrial membrane potential.
- ZNS exhibited antiapoptotic effects, significantly attenuating caspase-3 activity and reducing cell death.
- N-acetyl-cysteine showed similar protective effects on ROS and Δψm, supporting an antioxidant mechanism for ZNS.
Conclusions:
- Zonisamide preserves mitochondrial function and counteracts apoptosis, primarily through its antioxidant properties.
- ZNS demonstrates potential therapeutic benefits for neuronal degeneration associated with mitochondrial dysfunction.
- These findings support ZNS as a potential treatment for neurodegenerative diseases like Parkinson's.
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