Edaravone, the first known free radical scavenger, has demonstrated cellular protective properties in animals and humans. Owing to its antioxidant activity, edaravone modulates oxidative damage in various diseases, especially neurodegenerative diseases. In 2015, edaravone was approved in Japan to treat amyotrophic lateral sclerosis. The distinguishing pathogenic features of neurodegenerative diseases include high reactive oxygen species levels and mitochondrial dysfunction. However, the correlation between mitochondria and edaravone has not been elucidated. This review highlights recent studies on novel therapeutic perspectives of edaravone in terms of its effect on oxidative stress and mitochondrial function.

Amyotrophic lateral sclerosis (ALS) is a common neurodegenerative disease characterized by progressive motor neuron degeneration. Although several studies on genes involved in ALS have substantially expanded and improved our understanding of ALS pathogenesis, the exact molecular mechanisms underlying this disease remain poorly understood. Glycogen synthase kinase 3 (GSK3) is a multifunctional serine/threonine-protein kinase that plays a critical role in the regulation of various cellular signaling pathways. Dysregulation of GSK3β activity in neuronal cells has been implicated in the pathogenesis of neurodegenerative diseases. Previous research indicates that GSK3β inactivation plays a neuroprotective role in ALS pathogenesis. GSK3β activity shows an increase in various ALS models and patients. Furthermore, GSK3β inhibition can suppress the defective phenotypes caused by SOD, TDP-43, and FUS expression in various models. This review focuses on the most recent studies related to the therapeutic effect of GSK3β in ALS and provides an overview of how the dysfunction of GSK3β activity contributes to ALS pathogenesis.

Environmental high-temperature heat exposure is linked to physiological stress such as disturbed protein homeostasis caused by endoplasmic reticulum (ER) stress. Abnormal proteostasis in neuronal cells is a common pathological factor of Parkinson’s disease (PD). Chronic heat stress is thought to induce neuronal cell death during the onset and progression of PD, but the exact role and mechanism of ER stress and the activation of the unfolded protein response (UPR) remains unclear. Here, we showed that chronic heat exposure induces ER stress mediated by the PKR-like eukaryotic initiation factor 2α kinase (PERK)/eIF2α phosphorylation signaling pathway in Drosophila neurons. Chronic heat-induced eIF2α phosphorylation was regulated by PERK activation and required for neuroprotection from chronic heat stress. Moreover, the attenuated protein synthesis by eIF2α phosphorylation was a critical factor for neuronal cell survival during chronic heat stress. We further showed that genetic downregulation of PERK, specifically in dopaminergic (DA) neurons, impaired motor activity and led to DA neuron loss. Therefore, our findings provide in vivo evidence demonstrating that chronic heat exposure may be a critical risk factor in the onset of PD, and eIF2α phosphorylation mediated by PERK may contribute to the protection of DA neurons against chronic heat stress in Drosophila.

Polyphenols are secondary metabolites of plants, fruits, and vegetables. They act as antioxidants against free radicals from UV light, pathogens, parasites, and oxidative stress. In Drosophila models, feeding with various polyphenols results in increased antioxidant capacity and prolonged lifespan. Therefore, dietary polyphenols have several health advantages for preventing many human diseases, including cardiovascular diseases, cancer, and neurodegenerative diseases. However, the exact role of polyphenols in neurodegenerative diseases is still yet to be completely defined. This review focuses on the most recent studies related to the therapeutic effect of polyphenols in neurodegenerative disease management and provides an overview of novel drug discovery from various polyphenols using the Drosophila model.

Transactive response DNA-binding protein-43 (TDP-43) is involved in the pathology of familial and sporadic amyotrophic lateral sclerosis (ALS). TDP-43-mediated ALS models in mice, Drosophila melanogaster, and zebrafish exhibit dysfunction of locomotor function, defective neuromuscular junctions, and motor neuron defects. There is currently no effective cure for ALS, and the underlying mechanisms of TDP-43 in ALS remain poorly understood. In this study, a genetic screen was performed to identify modifiers of human TDP-43 (hTDP-43) in a Drosophila model, and glutathione S-transferase omega 2 (GstO2) was found to be involved in hTDP-43 neurotoxicity. GstO2 overexpressed on recovered defective phenotypes resulting from hTDP-43, including defective neuromuscular junction (NMJ) boutons, degenerated motor neuronal axons, and reduced larvae and adult fly locomotive activity, without modulating the levels of hTDP-43 protein expression. GstO2 modulated neurotoxicity by regulating reactive oxygen species (ROS) produced by hTDP-43 in the Drosophila model of ALS. Our results demonstrated that GstO2 was a key regulator in hTDP-43-related ALS pathogenesis and indicated its potential as a therapeutic target for ALS.

Although mitochondrial dysfunction is associated with the development and progression of diabetic nephropathy (DN), its mechanisms are poorly understood, and it remains debatable whether mitochondrial morphological change is a cause of DN. In this study, a Drosophila DN model was established by treating a chronic high-sucrose diet that exhibits similar phenotypes in animals. Results showed that flies fed a chronic high-sucrose diet exhibited a reduction in lifespan, as well as increased lipid droplets in fat body tissue. Furthermore, the chronic high-sucrose diet effectively induced the morphological abnormalities of nephrocytes in Drosophila. High-sucrose diet induced mitochondria fusion in nephrocytes by increasing Opa1 and Marf expression. These findings establish Drosophila as a useful model for studying novel regulators and molecular mechanisms for imbalanced mitochondrial dynamics in the pathogenesis of DN. Furthermore, understanding the pathology of mitochondrial dysfunction regarding morphological changes in DN would facilitate the development of novel therapeutics.