Abstract
Several chronic neuroinflammatory diseases, including Parkinson’s disease (PD), have the so-called ‘redox imbalance’ in common, a dynamic system modulated by various factors. Among them, alteration of the mitochondrial functionality can cause overproduction of reactive oxygen species (ROS) with the consequent induction of oxidative DNA damage and apoptosis. Considering the failure of clinical trials with drugs that eliminate ROS directly, research currently focuses on approaches that counteract redox imbalance, thus restoring normal physiology in a neuroinflammatory condition. Herein, we used SH-SY5Y cells treated with 6-hydroxydopamine (6-OHDA), a neurotoxin broadly employed to generate experimental models of PD. Cells were pre-treated with the Rho-modulating Escherichia coli cytotoxic necrotizing factor 1 (CNF1), before the addition of 6-OHDA. Then, cell viability, mitochondrial morphology and dynamics, redox profile as well as autophagic markers expression were assessed. We found that CNF1 preserves cell viability and counteracts oxidative stress induced by 6-OHDA. These effects are accompanied by modulation of the mitochondrial network and an increase in macroautophagic markers. Our results confirm the Rho GTPases as suitable pharmacological targets to counteract neuroinflammatory diseases and evidence the potentiality of CNF1, whose beneficial effects on pathological animal models have been already proven to act against oxidative stress through an autophagic strategy.
Highlights
Parkinson’s disease (PD) is the second most common neurodegenerative disease, disabling millions worldwide
Among the hallmarks in the pathogenesis of PD, a crucial role is played by neuroinflammation and redox imbalance, the latter being a dynamic system that may change via many factors [2], including mitochondria that are central to energy metabolism
The results showed that cytotoxic necrotizing factor 1 (CNF1) per se did not introduce any significant GSH perturbations within cells, whereas 6-OHDA exposure induced a 46% drop in GSH concentration compared to controls (Figure 4A)
Summary
Parkinson’s disease (PD) is the second most common neurodegenerative disease, disabling millions worldwide. Anti-oxidants that directly target mitochondria though apparently are more efficacious in animal models are still unexplored in terms of their benefits in humans [13,14,15,16] and, may eliminate physiologically-relevant ROS [13,14,15,16] that act as key molecules in different signaling pathways [12] To face this problem and eliminate the production of pathological ROS, an effective strategy could be focused on mitochondrial dynamics, since the maintenance of a balanced fission/fusion cycle can prevent the accumulation of damaged and fragmented mitochondria and eliminate the production of pathological ROS [17]
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