The Hidden Notes of Redox Balance in Neurodegenerative Diseases

Abstract

Reactive oxygen species (ROS) are versatile molecules that, even if produced in the background of many biological processes and responses, possess pleiotropic roles categorized in two interactive yet opposite domains. In particular, ROS can either function as signaling molecules that shape physiological cell functions, or act as deleterious end products of unbalanced redox reactions. Indeed, cellular redox status needs to be tightly regulated to ensure proper cellular functioning, and either excessive ROS accumulation or the dysfunction of antioxidant systems can perturb the redox homeostasis, leading to supraphysiological concentrations of ROS and potentially harmful outcomes. Therefore, whether ROS would act as signaling molecules or as detrimental factors strictly relies on a dynamic equilibrium between free radical production and scavenging resources. Of notice, the mammalian brain is particularly vulnerable to ROS-mediated toxicity, because it possesses relatively poor antioxidant defenses to cope with the redox burden imposed by the elevated oxygen consumption rate and metabolic activity. Many features of neurodegenerative diseases can in fact be traced back to causes of oxidative stress, which may influence both the onset and progression of brain demise. This review focuses on the description of the dual roles of ROS as double-edge sword in both physiological and pathological settings, with reference to Alzheimer’s and Parkinson’s diseases.

Intracellular Molecular Targets and Signaling Pathways Involved in Antioxidative and Neuroprotective Effects of Cannabinoids in Neurodegenerative Conditions

“…Oxidative stress develops when the production of ROS overwhelms the endogenous capabilities of the antioxidative defense provided by diverse enzymatic and non-enzymatic mechanisms. Non-enzymatic antioxidants (e.g., GSH and vitamins) and antioxidant enzymes (catalase, SOD, glutathione peroxidase, and thioredoxin) are critically involved in redox regulation and the maintenance of redox homeostasis [ 155 , 156 , 157 , 158 , 159 , 160 ]. In comparison with other tissues, the brain is particularly vulnerable to oxidative damage due to its high rate of oxygen consumption, limited antioxidative defense, presence of metal ions that are able to initiate redox cycling and the formation of highly dangerous and very reactive hydroxyl radicals via Fenton chemistry, and the high amount of polyunsaturated fatty acids (PUFAs) that are prone to oxidation, together with the post-mitotic nature of neurons [ 161 , 162 ].…”

“…Furthermore, THC-rich extracts may promote glucose utilization and the activity of gluconeogenic enzymes in the rat brain [ 224 ]. Glucose homeostasis is usually disturbed in neurodegenerative diseases, partially as a result of the oxidative damage of enzymes participating in glycolysis, the Krebs cycle, and oxidative phosphorylation, and the impairment of glucose utilization largely contributes to the progression of pathological changes [ 159 ]. THC-rich extracts increased glucose uptake and suppressed oxidative stress levels, as evidenced by enhanced GSH levels, increased SOD and catalase activity, reduced lipid peroxidation, and NO production [ 224 ].…”

Translational repression ofNox4mRNA via the EI24-RTRAF interaction is crucial for hydrogen peroxide homeostasis and insulin synthesis

“…Therefore, cells have evolved numerous antioxidant systems to maintain basal ROS at a normal, non-toxic level. This is especially essential for cells with relatively weak intrinsic antioxidant defenses, like neurons (Lee et al, 2021;Piccirillo et al, 2022) and pancreatic beta cells (Eguchi et al, 2021;Lenzen, 2017). Thus, regulating the expression levels of enzymes that constitutively produce ROS is crucial for maintaining redox homeostasis, particularly for pancreatic beta cells, that have high energy demands and engage in metabolic and redox crosstalk.…”