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Orexin-A Exerts Neuroprotective Effects via OX1R in Parkinson's Disease
Mei-Fang Liu1,2, Yan Xue1, Cui Liu1
1Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, Qingdao University, Qingdao, China.
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.
Insights
Orexin-A shows neuroprotective effects in Parkinson's disease (PD) animal models by preserving dopaminergic neurons and improving motor and cognitive functions. Its mechanism involves upregulating brain-derived neurotrophic factor (BDNF) via orexin receptor 1 (OX1R).
Area of Science:
- Neuroscience
- Neuropharmacology
- Cell Biology
Background:
- Parkinson's disease (PD) involves progressive dopaminergic neuron loss.
- Orexin-A demonstrates protective effects in cellular PD models.
- The in vivo protective mechanisms and effects of orexin-A in PD animal models remain unclear.
Purpose of the Study:
- To investigate the neuroprotective effects of orexin-A in a mouse model of Parkinson's disease (MPTP model).
- To elucidate the underlying cellular mechanisms of orexin-A's neuroprotection, focusing on dopaminergic neurons.
Main Methods:
- MPTP-induced Parkinson's disease model in mice.
- Administration of orexin-A and an orexin receptor 1 (OX1R) antagonist (SB334867).
- Assessment of dopaminergic neuron survival, tyrosine hydroxylase (TH) expression, dopamine levels, motor function, and spatial memory.
- In vitro studies using SH-SY5Y dopaminergic cells to examine BDNF expression and signaling pathways (PI3K, PKC).
Main Results:
- Orexin-A significantly attenuated dopaminergic neuron loss and TH reduction in the substantia nigra.
- Orexin-A normalized striatal dopaminergic fibers and dopamine levels.
- Orexin-A improved motor activity and spatial memory deficits in MPTP-treated mice.
- Orexin-A increased BDNF protein levels in dopaminergic neurons, an effect blocked by the OX1R antagonist.
- In vitro, orexin-A dose- and time-dependently induced BDNF expression via PI3K and PKC signaling through OX1R.
Conclusions:
- Orexin-A exerts significant neuroprotective effects in an MPTP mouse model of Parkinson's disease.
- The neuroprotection is mediated by the upregulation of BDNF through the OX1R pathway.
- Orexin-A represents a potential therapeutic target for Parkinson's disease treatment.