Abstract
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.
Highlights
Parkinson’s disease is the second most common chronic neurodegenerative disease characterized by progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) (Hornykiewicz and Kish, 1987)
Double-labeling immunofluorescence showed that both orexinergic receptor 1 (OX1R) and orexinergic receptor 2 (OX2R) were colocalized with tyrosine hydroxylase (TH) on the dopaminergic neurons in the SNpc
The present study identified that orexin-A exerts neuroprotective effects on MPTP-induced mouse model of Parkinson’s disease (PD)
Summary
Parkinson’s disease is the second most common chronic neurodegenerative disease characterized by progressive loss of dopaminergic neurons in the SNpc (Hornykiewicz and Kish, 1987). The incidence of PD in the population over 55 years old is about 1% and the cardinal symptoms of PD include resting tremor, bradykinesia, muscle rigidity, postural instability, and usually companied. The most common treatment for PD is symptom management. The dopamine precursor levodopa is the most widely used clinical drug (Hornykiewicz, 1975), which could only attenuate the symptoms, but fails to halt the progressive degeneration of dopaminergic neurons in the substantia nigra. Many efforts were devoted to find endogenous neuroprotective mediators to stop or reverse the degenerative changes of dopaminergic neurons in the substantia nigra
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