Neurorotective Potential Of Limonene In Streptozotocin Induced Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is a neurodegenerative illness that causes higher-order cognitive dysfunctions as well as changes in cognitive, behavioural, and social functioning. Alzheimer's disease is caused by the loss of neuronal connections (Hira et al., 2020). Dementia is a common indication of a progressive decline in brain function. It has the capacity to inflict damage on memory, judgment, and other brain functions. Although dementia primarily affects the elderly, it can also affect persons under the age of 65 (El-Shiekh et al., 2020). Around 55 million individuals worldwide suffer from dementia, with over 60% of them residing in low- and middle-income nations. Every year, approximately 10 million new cases are reported. The expected population will be 82 million in 2030 and it will be around 152 million in 2050, as of older people in the population increases every country according to World Health Organization (Kobierskij, 2021). In India, dementia is estimated to affect 2.7 % of the population. Dementia has a varied prevalence rate in India, ranging from 2 per 1000 to 35 per 1000 people, according to various epidemiological evidences (Choudhary, Ranjan and Asthana, 2021). Every year, almost 10 million new incidents are discovered, with the number estimated to triple by 2050 as a result of demographic shifts toward ageing, as well as increased disability and lower quality of life for people with cognitive impairment (Beydoun and Kivimaki, 2020). We are familiar with the fact that microglia, astrocytes, and pro-inflammatory cytokines are three immune components that are particularly significant in the pathogenesis of AD (Jo et al., 2014). Furthermore, Limonene markedly suppressed the level of proinflammatory cytokines (IL-1β, TNF α and IL-6) and down regulated expressions of cyclooxygenase-2 (COX-2). On the other hand, oxidative stress and its association with cognitive dysfunction is well known(Garwood et al., 2011). Antioxidants help to maintain a healthy balance of oxidants and antioxidants in the body. The key pathways involved for the development of oxidative stress have been identified as mitochondrial failure, metal buildup, hyperphosphorylated tau, inflammation, and beta amyloid formation (Šimić et al., 2016). Oxidative stress is also caused by a lack of antioxidant components in the body, such as Catalase, Superoxide Dismutase (SOD), and Reduced Glutathione (GSH) (Islam et al., 2015). Limonene has antioxidant, anti-inflammatory and anti-apoptotic effect which is also useful in neurological disorders (Athar and Alam, 2012). A recent study investigated the therapeutic effect of limonene against Aβ42-induced neurotoxicity in drosophila, a fruit fly model of AD (Koo, 2019) and improves memory in the scopolamine rat model (Zhou, Fukumoto and Yokogoshi, 2009). Thus, Limonene have better BBB penetration and shows less interaction and side effects. These findings suggest that Limonene is a promising candidate molecule for further investigation into its processes and therapeutic potential in Alzheimer's disease. In the present study, Sprague Dawley rats (250-300 g) were obtained from the Central animals house of Maharaja Ranjit Singh Punjab Technical University, Bathinda, Punjab (India) and divided into 7 groups based on age, weight and sex. AD was induced by STZ (3 mg/kg) administration in rats. Limonene (25, 50, 100 mg/kg, p.o) was administered daily for 13 days from the day of induction. Limonene significantly attenuated the behaviour and biochemical parameter. Biventricular infusion of STZ produced significant impairment in learning and memory, cholinergic hypofunction and elevation in hippocampal oxidative stress in rats. STZ- infused rats showed poor learning and consolidation of memory and the rats were unable to discriminate between familiar & novel objects as evidenced in MWM (Morris water maze) and ORT (Object recognition task). Furthermore, biochemical analysis revealed that Limonene administration significantly attenuated STZ induced biochemical consequences which include lipid peroxidation, associated with oxidative stress perceive the formation of MDA and elevate the nitrite level in the rat brain. In summary, the present study has shown that Limonene is effective in ameliorating i.c.v. Streptozotocin induced behavioural alterations, cholinergic dysfunction and oxidative–nitrative stress. The observed beneficial effects of Limonene in spatial memory processing may be due to its ability to restore cholinergic functions, and its antioxidant mechanisms. However, more studies required to understand the molecular mechanisms of Limonene involved in cognitive enhancement or preventing neurotoxic damage, which could be useful to support its use in neuroprotective pathologies.