New 8-hydroxyquinoline derivatives as promising therapeutic approaches targeting neurodegeneration

Abstract

Background: Alzheimer's disease, Parkinson's disease, and Amyotrophic lateral sclerosis are recognized as the most prevalent neurodegenerative diseases (NDs), presenting a huge burden for society. These diseases share common pathophysiological mechanisms, such oxidative stress, dysfunction in iron metabolism, ferroptosis, and protein misfolding [1-4]. Given their powerful metal chelating and antioxidant properties, 8-hydroxyquinoline (8-HQs) derivatives have emerged as attractive therapeutic approaches for the development of innovative therapies for NDs [5]. Objective: To assess, in vitro, the neuroprotective effects of 12 newly synthesized 8-HQs with iron chelation and radical scavenging capacity, using differentiated neuronal SH-SY5Y cells as an in vitro model. Methods: The cytotoxicity of 8-HQs was initially evaluated using the MTT reduction and neutral red uptake assays, 24 hours after exposure, to select non-cytotoxic concentrations. The neuroprotective effects of the 8-HQs against the cytotoxicity induced by iron (III), erastin (a ferroptosis inducer), or by the combination of the two aggressors, were then evaluated. Their capacity to decrease tert-butyl hydroperoxide (t-BHP)-induced cytotoxicity was also investigated, aiming to elucidate the potential of the novel 8-HQs derivatives to counteract oxidative stress. The most promising 8-HQs were also tested for their ability to protect against the neurotoxin 1-methyl-4-phenylpyridinium (MPP⁺), which is frequently used to mimic Parkinson's disease in in vitro models [6]. Results: Some of the 8-HQs significantly protected SH-SY5Y cells against the cytotoxicity induced by iron (III), erastin, or by the combined effects iron (III) + erastin. Moreover, several 8-HQs also remarkably reduced the cytotoxic effects induced by both t-BHP and MPP⁺. Conclusions: The 8-HQs showed outstanding neuroprotective properties against the harmful effects induced by distinct chemical aggressors, highlighting their potential to become effective disease-modifying agents for counteracting neurodegeneration.