**1. Introduction**

Oxidative stress is considered as a detrimental condition for normal brain functioning. Since the brain uses chemically diverse reactive species for signal transmission, it is susceptible to oxidative stress [1]. The human brain consists of more than 86 billion neurons and over 250–300 billion glial +cells, which consume over 20% of the total basal oxygen [2,3]. The mitochondria in the brain use the inspired basal oxygen to reduce O2 to H2O to support adenosine triphosphate (ATP) synthesis [4]. The electron transport chain in the mitochondria is not efficient and leakage of reactive oxygen species (ROS) from the mitochondria occurs when there is excess of oxygen [5]. Redox signaling in the brain functions as an intrinsic sensor to oxidative stress, when signals go awry during pathological conditions. Brain tissue has a high rate of oxidative metabolic activity, intense production of reactive oxygen metabolites, relatively low levels of antioxidants, low repair capacity, non-replicating neuronal cells, and a high membrane surface to cytoplasm ratio [6]. The cellular antioxidant system that prevents tissue damage is composed of endogenous and exogenous antioxidants that have the ability to reduce different chemicals. In biological antioxidant defense systems, both endogenous and exogenous antioxidants are classified into enzymatic antioxidants and non-enzymatic antioxidants, including oxidative enzyme inhibitors, antioxidant enzyme cofactors, ROS/RNS scavengers, and transition metal chelators [7,8]. These two main antioxidant systems play an important role in maintaining the balance between pro-oxidant and antioxidant agents in the brain and in mitigating oxidative stress [9]. The present review focuses on enzymatic and non-enzymatic antioxidant mechanisms in the brain and examines the relative advantages of antioxidant compounds for the treatment of various brain

diseases. Therefore, this review will describe selective antioxidants shown to have neuroprotective effects that limit neurodegenerative disease.

### **2. Factors That Contribute to Vulnerability of the Brain to Oxidative Stress**

Free radicals or other reactive molecules disturb cellular energy metabolism and cause oxidative stress. Endogenous redox imbalance by pro-oxidant and antioxidant agents occurs as a result of free radicals, which play an important role in oxidative stress, cell death, and tissue damage. Increased free radical production due to excess pro-oxidant mechanisms can react with lipids, proteins, nucleic acids, and other biomolecules which can alter their structure and function. A high concentration of polyunsaturated fatty acids exists in membrane lipids in the brain [10]. These are sources of decomposition reaction in the form of lipid peroxidation, in which a single initiating free radical can precipitate the destruction of adjacent molecules. Polyunsaturated fatty acids especially serve as major biological targets for oxidative damage induced by ROS. Other candidate molecules that serve as biological targets of free radicals are nucleic acids. Breaks in DNA or modified bases can result in aberrant gene expression and cell death [11]. Moreover, free radicals can also oxidize the backbone and side chains of proteins, thereby disrupting the function of enzymes, receptors, neurotransmitters, and structural proteins by oxidative modification [12]. Highly reactive oxygen radicals are produced in the brain as a result of interactions between various transition metals and their reducing equivalents. Transition metals including iron, copper, zinc, and manganese, are associated with increased free radical production by the Fenton reaction [13,14]. Since the brain has abundant lipid content, high energy requirements, and weak antioxidant capacity, it is an easy target for excessive oxidative insults. Specifically, ROS increase susceptibility to neuronal damage and functional decline via brain oxidation in Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), cerebrovascular disorders, psychiatric disorders, and other neurodegenerative diseases [6,13,15] (Figure 1).

Considering a detailed perspective on signaling, the rationale underlying the vulnerability of the neurons in the brain to oxidative stress are as follows: In redox signaling, O2 <sup>−</sup>/H2O2 generation by the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 induces the activation of signaling proteins via sulfenic acid formation [16,17]. The brain is dependent on Ca2<sup>+</sup> signaling for synaptic plasticity, a fundamental brain function, and it expends considerable amounts of ATP to maintain intracellular Ca2<sup>+</sup> homeostasis. Synaptic terminal glutamate-induced Ca2<sup>+</sup> transients activate neuronal nitric oxide synthase (nNOS)-mediated NO· generation, and additionally, Ca2<sup>+</sup> overloaded in the mitochondria induces O2 <sup>−</sup>/H2O2 generation which can lead to ONOO· production and excitotoxicity [18–20]. Particularly, the mitochondria generate O2 − in complex I and complex III and the monoamine oxidase enzyme isoform catalyzes H2O2 generation during metabolism [21–23]. The human brain consumes over 25% circulating glucose to support neuronal function; however, protein inactivation by the formation of advanced end glycation products (AGE) due to decreased glycolytic rates can cause glucose-induced oxidative stress [24,25]. Neurotransmitters with a catechol group render the brain sensitive to oxidative stress. Redox-active transition metals catalyze the auto-oxidation of dopamine to a semiquinone radical during neurotransmitter oxidation [26–28]. The mature neurons of the brain have abundant and multiple mechanisms that promote long-term neuronal survival and prevent cell death; however, the brain has a comparatively weak endogenous antioxidant defense system relative to other tissues and is susceptible to imbalance in redox homeostasis. For instance, neurons with 50 times lower catalase content than hepatocytes have constrained glutathione peroxidase 4 (GPX4) activity (owing to low glutathione [GSH] content) and a modest antioxidant defense mechanism [29–31]. Microglia monitor neuronal activity for removal of unhealthy cells, neuronal wiring during development, and activity dependent synaptic plasticity. They generate O2 − via NADPH oxidase 2 (NOX2) within an end-foot process, thus influencing brain oxidation [32,33]. Redox-active transition metals, such as Fe2<sup>+</sup> and Cu+, are enriched in the brain and therefore contribute to ferroptosis by catalyzing peroxyl (ROO· ) and alkoxyl (RO· ) radical generation [34,35]. Lipid peroxidation,

which involves initiation, oxygenation, propagation, and termination, occurs within the neuronal cell membrane [36]. The brain uses nNOS and NOX isoforms to maintain essential functions. However, nNOS/NOX expression is associated with NO· generation, which can be spatially co-generated while producing ONOO· [37,38]. In summary, these interconnected, myriad factors render the brain vulnerable to oxidative stress. Furthermore, excessive production of reactive species and insufficient activity of antioxidant defense systems have been implicated in the pathogenesis of neurodegeneration.

**Figure 1.** Development of various diseases by the pathophysiology of oxidative stress in the brain. Balance and imbalance between pro-oxidants and antioxidants against reactive oxygen species production induce oxidative stress and are consequently involved in neuronal damage resulting in the neurodegenerative diseases.
