Parkinson's disease (PD) is a common
neurodegenerative disorder characterized by progressive and selective death of dopaminergic neurons.
Orexin-A is involved in many biological effects of the body. It has been reported that
orexin-A has protective effects in cellular models of PD. However, little is known about the protective effects of
orexin-A in animal parkinsonian models and the cellular mechanism has not yet been fully clarified. The aim of this study was to evaluate the effects of
orexin-A in
MPTP mice model of PD as well as the possible neuroprotective mechanisms of
orexin-A on dopaminergic neurons. The results from animal experiments demonstrated that
orexin-A attenuated the loss of dopaminergic neurons and the decrease of
tyrosine hydroxylase (TH) expression in the substantia nigra, normalized the striatal dopaminergic fibers, and prevented the depletion of
dopamine and its metabolites in the striatum.
MPTP-treated mice showed
cognitive impairments accompanied with significant motor deficiency.
Orexin-A improved
MPTP-induced impairments in both motor activity and spatial memory. Importantly,
orexin-A increased the
protein level of
brain-derived neurotrophic factor (
BDNF) in dopaminergic neurons of the substantia nigra. Furthermore, the protective effects of
orexin-A on
MPTP parkinsonian mice could be blocked by orexinergic receptor 1 (OX1R) antagonist, SB334867. In another set of experiments with SH-SY5Y dopaminergic cells,
orexin-A significantly induced the expression of
BDNF in a dose and time-dependent manner. The upregulation of
BDNF is mainly concerned with PI3K and PKC signaling pathways via OX1R. The present study demonstrated that
orexin-A exerted
neuroprotective effects on
MPTP parkinsonian mice, which may imply
orexin-A as a potential therapeutic target for PD.