Protective Effect of Antioxidants on Neuronal Dysfunction and Plasticity in Huntington’s Disease

Hindawi Oxidative Medicine and Cellular Longevity Volume 2017, Article ID 3279061, 15 pages https://doi.org/10.1155/2017/3279061 Review Article Protective Effect of Antioxidants on Neuronal Dysfunction and Plasticity in Huntington’s Disease Thirunavukkarasu Velusamy,1,2 Archana S. Panneerselvam,3 Meera Purushottam,4 Muthuswamy Anusuyadevi,5 Pramod Kumar Pal,6 Sanjeev Jain,4 Musthafa Mohamed Essa,7 Gilles J. Guillemin,8 and Mahesh Kandasamy3,9 1 Department of Biotechnology, Bharathiar University, Coimbatore, Tamil Nadu, India DBT Ramalingaswami Re-Entry Fellowship Programme, Department of Biotechnology (DBT), New Delhi, India 3 Laboratory of Stem Cells and Neuroregeneration, Department of Animal Science, School of Life Sciences, Bharathidasan University, Tiruchirappalli, Tamil Nadu, India 4 Department of Psychiatry, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, Karnataka, India 5 Molecular Gerontology Laboratory, Department of Biochemistry, School of Life Sciences, Bharathidasan University, Tiruchirappalli, Tamil Nadu, India 6 Department of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, Karnataka, India 7 Department of Food Science and Nutrition, CAMS, Sultan Qaboos University, Muscat, Oman 8 Neuroinflammation Group, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia 9 UGC-Faculty Recharge Program (UGC-FRP), University Grant Commission, New Delhi, India 2 Correspondence should be addressed to Gilles J. Guillemin; and Mahesh Kandasamy; Received 29 July 2016; Revised 9 November 2016; Accepted 5 December 2016; Published 12 January 2017 Academic Editor: Vladimir Jakovljevic Copyright © 2017 Thirunavukkarasu Velusamy et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Huntington’s disease (HD) is characterised by movement disorders, cognitive impairments, and psychiatric problems. The abnormal generation of reactive oxygen species and the resulting oxidative stress-induced mitochondrial damage in neurons upon CAG mutations in the HTT gene have been hypothesized as the contributing factors of neurodegeneration in HD. The potential use of antioxidants against free radical toxicity has been an emerging field in the management of ageing and many neurodegenerative disorders. Neural stem cells derived adult neurogenesis represents the regenerative capacity of the adult brain. The process of adult neurogenesis has been implicated in the cognitive functions of the brain and is highly modulated positively by different factors including antioxidants. The supportive role of antioxidants to reduce the severity of HD via promoting the functional neurogenesis and neuroprotection in the pathological adult brain has great promise. This review comprehends the recent studies describing the therapeutic roles of antioxidants in HD and other neurologic disorders and highlights the scope of using antioxidants to promote adult neurogenesis in HD. It also advocates a new line of research to delineate the mechanisms by which antioxidants promote adult neurogenesis in HD. 1. Introduction Huntington’s disease (HD) is an autosomal dominant neurodegenerative syndrome associated with abnormal CAG expansions in the Huntington (HTT) gene [1–3]. The mutant HTT contains polymorphic CAG repeats in excess of 39 in exon 1 of the gene present in the short arm of the chromosome 4 [3–5]. The CAG mutations ultimately result in the abnormal expansion of polyglutamine (polyQ) tracts in the HTT protein, which leads to misfolding and loss of protein function [6, 7]. The polyQ expansion has been identified to be the primary inducer of degeneration of medium spiny neurons (MSNs) in the striatum and leads to neurodegeneration to other regions of brain, including 2 the cortex, hippocampus, hypothalamus, and brain stem in a progressive manner [7–9]. The epidemiology of HD suggests that the disease occurs worldwide, but its prevalence varies depending upon genetic diversity and geographical regions [9, 10]. The rate of incidence of HD is considerably higher in the Caucasian population than the Asian population. While an estimate shows the prevalence and increasing trend of HD in Western Europe, Australia, North America, and the United Kingdom, India represents a large number of total HD cases in Asia [11, 12]. Single nucleotide polymorphism (SNP) at the HTT locus in association with the genetic diversity, lifestyle, food, and environmental factors is presumed to be the reasons for the variations in the frequency of HD among the human population [13]. HD has been characterised by choreiform movements, dystonia, cognitive deficits, and psychiatric problems [14]. These symptoms have been accompanied by neurodegeneration along with an abnormal level of neurotransmitters, microglial activation, reactive astrogliosis, and impaired neurogenesis [15]. Recently, HD patients have also been characterised with different types of behavioural, motor, and aggressive symptoms [16, 17]. All the abovementioned problems aggravate the development of HD and contribute to gradual deterioration of the physical abilities and mental processes. Importantly, people with HD have problems in taking care of their daily routine, such as food consumption, due to difficulty in swallowing (dysphagia), which may occur during the later stages of the disease. Further, abnormalities in energy metabolism caused by mitochondrial dysfunctions add to severity of the disease. The loss of muscle function in the mandibular regions, pharynx, and oesophagus could lead to disorders like bruxism (grinding the teeth), failure to intake of food and choking, which could ultimately lead to death [16, 18]. Currently, there are no available treatments that can delay the onset or arrest the progression of the disease, while the focus of medical care is limited to merely managing the neurological symptoms of HD. This is mainly due to lack of knowledge about the underlying biology of the disease. Of the few therapeutic options available for the treatment of HD, tetrabenazine has been an approved drug by the Food and Drug Administration (FDA) for minimising the clinical symptoms of involuntary movements [19–23]. Other treatment strategies for HD include administration of antipsychotic and antidepressant drugs [21, 22]. Antipsychotic drugs like haloperidol [23], fluphenazine [24], clonazepam [25], amantadine [26], and levetiracetam [27] might help in controlling panic attacks, aggression, and choreiform movements, while antidepressants like fluoxetine [28], sertraline [29, 30], nortriptyline [31], and lithium [32] are used to stabilize depression, anxiety associated mood swings, and negative thoughts. In addition, riluzole is frequently used as a neuroprotective drug to control glutamatergic neurotransmi (...truncated)