1 3 Coenzyme Q10 treatment ameliorates cognitive deficits by modulating 4 mitochondrial functions in surgically induced menopause 5 6 7 Rajat Sandhir ⇑ Q1 , Neha Sethi, Aanchal Aggarwal, Alka Khera 8 Department of Biochemistry, Basic Medical Science Building, Panjab University, Chandigarh 160014, India 9 10 12 article info 13 Article history: 14 Received 28 November 2013 15 Received in revised form 7 April 2014 16 Accepted 16 April 2014 17 Available online xxxx 18 Keywords: 19 Coenzyme Q10 20 Cognition 21 Menopause 22 Mitochondria 23 Ovariectomy 24 Oxidative stress 25 26 abstract 27 The mechanisms associated with cognitive decline in post-menopausal state driven by a loss of ovarian 28 function and reduced estrogen levels are not well understood. The aim of the present study is to inves- 29 tigate the role of mitochondrial dysfunctions in cognitive impairment in post-menopausal state and to 30 evaluate the protective effect of Coenzyme Q10 (CoQ10). A significant decline in cognitive functions 31 was observed in mice after four weeks of ovariectomy as assessed by morris water maze and elevated 32 plus maze. Administration of CoQ10 (10 mg/kg body weight, orally) daily for 4 weeks was found to 33 reverse cognitive deficits observed in ovariectomized (Ovx) mice. The activity of mitochondrial electron 34 transport chain components; NADH: cytochrome reductase, succinate dehydrogenase and cytochrome c 35 oxidase was significantly reduced in the brain of Ovx mice. This was accompanied by higher levels of ROS, 36 protein carbonyls, lipid peroxidation, mitochondrial swelling and reduced activity of aconitase. The levels 37 of GSH were observed to be significantly lowered resulting in reduced redox ratio (GSH/GSSG) in brain of 38 Ovx mice. Activities of antioxidant enzymes; superoxide dismutase and catalase were also found to be 39 reduced in brain of Ovx animals. CoQ10 supplementation to Ovx mice mitigated the mitochondrial dys- 40 functions and oxidative stress. Thus, the data indicates that CoQ10 improves cognitive decline in post- 41 menopausal state by modulating mitochondrial functions and oxidative stress. 42 Ó 2014 Published by Elsevier Ltd. 43 44 45 46 1. Introduction 47 Menopause defines the end of menstrual cycle in women 48 wherein ovaries are almost completely devoid of follicles with dra- 49 matic decrease in ovarian hormones; estrogen and progesterone 50 (Sarrel, 2002). Menopause induced decline in estrogen level can 51 lead to various physiological changes that include dyslipidemia 52 and impaired glucose tolerance which have been implicated in 53 increased risk of cardiovascular disease (Rossouw et al., 2007). In 54 addition, osteoporosis is widely prevalent in post-menopausal 55 women (Frenkel et al., 2010). Intriguingly, recent evidence sug- 56 gests that post menopausal condition is associated with negative 57 neurological outcomes (Rocca et al., 2010). Various experimental 58 and clinical studies have documented that post-menopausal 59 females suffer from cognitive decline and dementia (Gibbs, 2000; 60 Shumaker et al., 2003). It was reported that women who under- 61 went bilateral ovariectomy underperformed on certain memory 62 tasks (Nappi et al., 1999). Estrogen administration has been found 63 to be effective in improving cognitive functions in Alzheimer’s dis- 64 ease and in women with surgically-induced menopause (Monk and 65 Brodaty, 2000; Phillips and Sherwin, 1992). Many researchers have 66 suggested that these neurological defects have a mitochondrial eti- 67 ology thereby affecting various functions of the brain Q2 (Chaturvedi 68 and Beal, 2013) (Irwin et al., 2008). 69 Mitochondria play a central role in regulating viability and 70 death of neurons, and mitochondrial dysfunction has been shown 71 to contribute to neuronal death seen in Alzheimer’s and Parkin- 72 son’s disease (Abou-Sleiman et al., 2006; Hirai et al., 2001). During 73 menopause or post-menopause state, reduction in estrogen levels 74 accentuates oxidative stress through impaired mitochondrial func- 75 tions leading to cognitive decline (Brinton, 2008). Estrogen supple- 76 mentation has been shown to increase the levels of cytochrome c 77 oxidase (complex IV) thus enhancing electron transport chain 78 and preventing oxidative leakage and damage which can impact 79 mitochondrial functions (Nilsen and Brinton, 2004). This increased 80 complex IV activity may underlie the estrogen-induced increase in 81 mitochondrial respiration and ATP production. Estrogen has also 82 been found to maintain mitochondrial calcium homeostasis and 83 increase the expression of Bcl-2 thereby preventing neuronal apop- 84 tosis (Nilsen and Diaz Brinton, 2003). Depletion of estrogen can 85 cause mitochondrial oxidative stress and dysfunctions causing 86 neuronal loss (Evsen et al., 2013). However, long-term use of estro- 87 gen in the postmenopausal period may increase the risk of http://dx.doi.org/10.1016/j.neuint.2014.04.011 0197-0186/Ó 2014 Published by Elsevier Ltd. ⇑ Corresponding author. Tel.: +91 172 2534131; fax: +91 172 2541022. E-mail address: sandhir@pu.ac.in (R. Sandhir). Neurochemistry International xxx (2014) xxx–xxx Contents lists available at ScienceDirect Neurochemistry International journal homepage: www.elsevier.com/locate/nci NCI 3568 No. of Pages 8, Model 5G 28 April 2014 Please cite this article in press as: Sandhir, R., et al. Coenzyme Q10 treatment ameliorates cognitive deficits by modulating mitochondrial functions in surgically induced menopause. Neurochem. Int. (2014), http://dx.doi.org/10.1016/j.neuint.2014.04.011