**5. Role of oxidative stress in acrylamide induced neurotoxicity**

The principle mechanism of ACR neurotoxicity is unknown, but some studies have linked it with the reduction in antioxidative capacity and inflammatory responses [7]. Oxidative stress which occurs due to the imbalance between the production and the removal of reactive oxygen species (ROS), free radicals and antioxidants, is evident in neurological disorders like Alzheimer's disease (AD), Huntington's disease (HD) and Parkinson's disease (PD), ataxia, peripheral neuropathy, amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) [37–40]. Antioxidant enzymes like superoxide dismutase (SOD), catalase (CAT), glutathione S-transferase (GST), glutathione peroxidase (GSH-Px) neutralise the effects of free radicals but due to the pro-oxidant effect of ACR, the levels of these enzyme are decreased resulting in an imbalance between the production and removal of free radicals by elevating the oxidative stress markers like ROS and thereby inducing lipid peroxidation (LPO) [33, 41–43] (**Figure 1**). Like many other xenobiotic compounds, ACR is an electrophile that can interact with nucleophiles containing specific residues [43]. It reacts with molecules that consist of bisulfide (SH), azanide (NH2) or hydroxide (OH). Glutathione (GSH) is a thiol that is well known for its free radical and ROS scavenging property [7, 33, 34]. Previous research has established that rats administered with ACR have a significant decrease of GSH in brain tissue when compared to the control group [33, 34, 44, 45]. The reduction in GSH levels results in an increase in levels of ROS that accumulates and induces oxidative stress. GSH is a nonenzymatic

#### **Figure 1.**

*Role of oxidative stress in ACR induced neurotoxicity.*

antioxidant that also acts as a coenzyme for the peroxide decomposition enzyme GSH-Px [7]. Studies also suggest that LPO is an effect of low levels of GSH [46–48]. First-line defence enzymatic antioxidants like SOD, CAT and GSH-Px have reduced in ACR-treated rats [33, 42, 45, 47]. GST is an antioxidant enzyme used to maintain the free radical balance. ACR was shown to enhance GST activity, suggesting an increase in the synthesis of S-conjugates between ACR and GSH [43, 46]. In contrast, a study by [47] reported a decrease in GST activity while measuring ACR-treated rat brains. As a result of the changes in levels and activity of various antioxidant enzymes and molecules, the concentration of total oxidants and antioxidants are increased and decreased respectively [49]. LPO, protein damage and DNA damage are biomarkers for oxidative stress in neurodegenerative diseases [39, 50].
