Investigating the neuroprotective effect of exercise; the role of redox homeostasis

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Precision Medicine: Pathology to Population HealthThe aim of this project is to explore oxidative stress as a mechanism by which exercise offers protection for the brain. Oxidative stress is central to brain health, and arises when oxidants (produced by metabolic processes) overwhelm antioxidants (produced by the body as a defence). The balance between oxidants and antioxidants is referred to as redox balance and redox balance is key for cell function. Redox disturbance and more specifically, oxidative stress has been directly linked to mental disorders such as schizophrenia and depression, cognitive decline, and neurodegenerative pathology including dementia.Exercise can perturb oxidative stress and may rebalance the redox disturbances that are seen in disorders of mental health. Furthermore, exercise is known to be neuroprotective. We propose that this neuroprotective capacity is due to the ability of exercise to regulate redox balance. We have shown that glutathione (GSH) in the brain can be measured using non-invasive MR spectroscopy (Wood, Yucel et al. 2009). In a recent pilot study we have shown that we can detect changes in GSH following exercise, and that these changes appear to be exercise intensity dependent.Study 1 - What is the optimal exercise to perturb brain GSH? In a cross-over study design, we will assess the effect of moderate (MOD, 60%VO2 max); high (HIGH, 80%VO2 max); very high intensity interval exercise (HIIT; 4 x 1min intervals at 100% VO2 max with 2-min recovery between each interval) on brain GSH in healthy sedentary (older age 65-75 yrs and young 18-35 yrs) participant groups. Bouts will randomized in order and will be separated by at least 7 days to ensure any adaptive effect of a previous bout has been lost. Study 2 - Can exercise perturb brain GSH in disease?Participants for study 2 will be recruited from two clinical groups: 1) Older age adults (65-75 years) with a diagnosis of md-aMCI will be recruited via the memory clinics at the Barberry Hospital (Birmingham and Solihull Mental Health Trust). 2) Young adults with first episode psychosis (18-35 years) will be recruited via Early Intervention Services in Birmingham and Solihull. All will be currently treated and not acutely unwell.Study 2 will employ a 12-week exercise intervention, with duration and intensity identified by study 1 as having most potential for perturbing brain GSH. Brain GSH will be assessed by glutathione-specific MR spectroscopy using MEGA-PRESS and spectral editing (Terpstra, Henry et al. 2003). Data from our pilot study shows that we can measure exercise-induced change in brain GSH using this technique. To provide context to brain oxidative stress, red blood cell GSH, and white cell thioredoxin and peroxyredoxin, will be assessed. Blood markers of neuroprotection (IGF-1 and BDNF) will also be assessed. A battery of neuropsychological tests will explore measures of cognitive function that are routinely used in clinical practice. In MCI we will assess attention, working memory, episodic memory, and executive function (Haller, Missonnier et al. 2013). In first episode psychosis we will assess psychopathology and cognitive function, with a particular focus on positive symptoms (Firth, Cotter et al. 2015) and on verbal memory. We hypothesize that the HIGH exercise bout will be identified by study 1 as the optimal exercise to increase brain GSH following a period of exercise training.This research will allow us to better understand how exercise could be used in the management of conditions such as depression and schizophrenia, and in prevention or retardation of the progression of neurodegeneration.