Calorie restriction (CR) protects against neurodegeneration in Parkinson’s disease, however the mechanisms behind this neuroprotection remain unknown. Ghrelin is a gut hormone with neuroprotective effects in Parkinson’s disease and CR increases plasma ghrelin concentrations. Hence we hypothesized that elevated endogenous ghrelin during CR prevents nigrostriatal neurodegeneration in the MPTP mouse model of Parkinson’s disease. We placed ghrelin wildtype (WT) and knockout (KO) mice on CR or ad libitum diet followed by treatment with MPTP or Saline. As a measure of nigrostriatal degeneration we used stereology to examine tyrosine hydroxylase (TH) number and volume by immunohistochemistry and striatal dopamine/metabolites by HPLC. MPTP treatment in WT mice reduced TH neuronal number and volume in the SNpc in both ad lib and CR mice with a greater loss in ad lib animals, indicating the neuroprotective effect of CR. However, CR did not attenuate TH cell or volume loss after MPTP in KO mice, suggesting increased ghrelin mediates the neuroprotective effect of CR. In WT mice, CR prevented the increase in astrocyte number observed in ad libitum WT mice after MPTP treatment. However, KO mice still exhibited a significant increase in astrocytes after MPTP treatment, which may reflect a greater need to remove degenerating TH neurons in KO mice relative to WT mice.

In order to understand the cellular mechanisms through which ghrelin acts to reduce neurodegeneration, we injected C57/Bl6 mice with ghrelin. We measured AMPK phosphorylation in these mice as AMPK is a known downstream signalling target for ghrelin in the hypothalamus. There was a significant elevation in pAMPK and TH levels in the Substantia nigra and Striatum which was ghrelin-dependent. Together, our data reveals that endogenous ghrelin mediates the neuroprotective effects of CR on the nigrostriatal dopamine system and we attempt to map a pathway by which ghrelin mediates this neuroprotection.