Ghrelin is the metabolic link connecting calorie restriction to neuroprotection

PERSPECTIVE Ghrelin is the metabolic link connecting calorie restriction to neuroprotection Parkinson's disease (PD) is the second most common neu-rodegenerative disease whereby the number of diagnosed patients rises by 3–4% each year creating an ever-expanding social, medical and financial burden. Symptoms such as rigidity, postural instability and bradykinesia are due to diminished levels of dopamine within the brain. More specifically dopamine cell bodies are located in the substantia nigra (SN) and dopamine is released in the striatum. Motor dys-function becomes evident with a 70–80% loss of dopamine in the striatum. The cause of PD is currently unknown and hence most treatments are aimed at minimizing symptoms not preventing the cause. However, it is known that metabolic status, more specifically calorie restriction is neuropro-tective in PD (Bayliss and Andrews, 2013). Calorie restriction (CR), or reducing calories without causing malnutrition is beneficial in a number of pathological conditions including diabetes, cancer and neurodegener-ation. Primates with a chronic overall 30% reduction in food intake were found to be resistant to the MPTP model of PD (Maswood et al., 2004). This study highlights that CR is neu-roprotective however, the difficulty to adhere to CR necessitates an alternate method to recapitulate the neuroprotective benefits of CR. Evidence from cells treated with serum from CR rats suggests that a hormonal factor improves mitochon-drial function and cell viability (Lopez-Lluch et al., 2006). One hormone that is elevated with prolonged fasting and promptly falls post-prandially is ghrelin. Ghrelin plays a role in maintaining steady blood glucose levels during fasting and also has many other non-metabolic functions including enhanced learning and memory (Diano et al., 2006) and neuroprotection in PD (Andrews et al., 2009; Bayliss et al., 2016). For this reason we hypothesized that CR elicits neu-roprotective actions in PD by elevating ghrelin levels in the bloodstream. To address this hypothesis we used mice unable to produce the hormone ghrelin, reduced their calorie intake by 30% and exposed them to the MPTP model of PD. MPTP is used to selectively target dopaminergic neurons and inhibit complex I of the electron transport chain. This results in selective destruction of dopamine neurons thus mimicking the human condition. In normal mice (denoted Ghrelin WT) CR diminished the loss of dopamine neurons, enhanced do-pamine turnover and reduced gliosis after MPTP. However, in mice lacking ghrelin (Ghrelin KO) CR had no neuropro-tective effects. This data strongly implicates ghrelin as a metabolic hormone responsible for …