Elsevier

Neuroscience Letters

Volume 741, 10 January 2021, 135480
Neuroscience Letters

Increased plasma orexin-A concentrations are associated with the non-motor symptoms in Parkinson’s disease patients

https://doi.org/10.1016/j.neulet.2020.135480Get rights and content

Highlights

  • The occurrence of Parkinson's disease is usually accompanied by hypothalamic damage.

  • Orexin-A is produced by the hypothalamus and the periphery.

  • Elevated plasma orexin-A levels were observed in early stages of Parkinson's disease.

  • Plasma orexin-A levels may decrease with the progression of Parkinson's disease.

  • Orexin-A plays an important role in non-motor symptoms of Parkinson's disease.

Abstract

Background

Orexin, a neuropeptide primarily secreted by neurons in the lateral hypothalamus, has been implicated in Parkinson’s disease (PD). Studies on the relationship between plasma orexin-A levels and PD are rare.

Objectives

This study aimed to assess levels of plasma orexin-A in the progression of PD and to evaluate the correlation between orexin-A levels and non-motor symptoms.

Methods

Enzyme-linked immunosorbent assay was used to determine plasma orexin-A levels in 117 healthy controls and 121 PD patients, including those with early (n = 68), medium (n = 40) and advanced (n = 13) stages of the disease. Evaluation of motor symptoms and non-motor symptoms in PD patients, such as sleep disorders, cognitive dysfunction, neuropsychiatric symptoms, autonomic nervous dysfunction, hyposmia and PD-related pain, were assessed by the associated scales.

Results

Plasma orexin-A levels were significantly higher in PD patients compared to healthy controls. Orexin-A levels were elevated in early-stage and medium-stage PD compared to healthy controls, but were decreased in advanced-stage PD. Orexin-A levels were negatively correlated with the Unified Parkinson’s Disease Rating Scale Part III scores, disease duration, and dopamine receptor agonist doses, and were positively correlated with the Pittsburgh Sleep Quality Index, REM-sleep Behavior Disorder Questionnaire, 14-item Hamilton Anxiety Scale, Mini-Mental State Examination, and Non-motor Symptom Scale items 22–24 scores.

Conclusions

We found for the first time that plasma orexin-A levels were increased in early-stage and medium-stage PD and were decreased in advanced-stage PD. Furthermore, orexin-A levels were correlated with the non-motor symptoms of insomnia, REM-sleep behavior disorder, anxiety, cognitive dysfunction, and renal dysfunction.

Introduction

Parkinson’s disease (PD), which is characterized by resting tremor, bradykinesia and rigidity, is a common neurodegenerative disease involving the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) [1] and accompanied by various manifestations of non-motor symptoms (NMSs) in different stages of the disease, such as sleep disorders, neuropsychiatric symptoms, cognitive dysfunction, and autonomic nervous dysfunction. The pathogenesis of PD is not clear, and its occurrence is usually accompanied by varying degrees of hypothalamic damage. In addition to hypothalamic degeneration with age or disease progression, it is also related to the existence of Lewy bodies, a pathophysiological marker of PD, in the hypothalamus [[2], [3], [4]]. Orexin is a neuropeptide synthesized by orexin neurons in the lateral hypothalamic area. Its activity, primarily found in the hypothalamus, decreases with aging and is closely related to many neurodegenerative diseases, including PD [5,6].

Orexin is present in human body in two forms, orexin-A and orexin-B. The binding of orexin-A and orexin-B to G-protein-coupled receptors, such as orexin receptor type 1 (OX1R) and orexin receptor type 2 (OX2R), is associated with various physiological processes [6,7]. Orexin is widely involved in the regulation of sleep, wakefulness, cognition, mood, energy homeostasis, and visceral functions [[7], [8], [9]]. Fronczek [10] previously reported that PD patients exhibit significant loss of orexin neurons and decreased levels of orexin-A in ventricular cerebrospinal fluid (CSF) on postmortem examination, indicating a key role for orexin-A in the progression of PD. Studies have demonstrated the neuroprotective effects of orexin-A in animal and cellular models of PD, including upregulating the expression of hypoxia inducible factor 1α, and reducing cell death and the formation of alpha-synuclein aggregates induced by MPP+ [11].

Kukkonen’s report shows that orexin and orexin receptors are also expressed in peripheral tissues, such as the gastrointestinal tract, endocrine pancreas, adipose tissue, and adrenal glands [8], implying that peripheral systems also play important roles in the regulation of orexin. Orexin-A can cross the blood-brain barrier (BBB) by a simple diffusion method, possessing a variety of properties, such as lipid, solubility, high stability and a resistance to degradation [12]. Thus, an increasing number of studies have focused on the detection of orexin-A in peripheral blood [[13], [14], [15]]. Evidence indicates that orexin-A levels measured in human plasma reflect not only peptides derived from the brain but also peripherally produced peptides [8,16]. Previous studies measured orexin-A levels in the CSF of PD patients and attempted to correlate the orexin-A levels with the severity of PD [10,[17], [18], [19]]. However, studies on plasma orexin-A levels in PD patients are rare, and little is known about the possible relationship between orexin-A levels and non-motor symptoms in PD patients.

In this study, we aimed to assess plasma orexin-A levels in PD patients with different clinical characteristics and in healthy controls to determine whether orexin-A is a candidate peripheral biomarker of PD. As a secondary objective, we aimed to explore the correlation between plasma orexin-A levels and motor or non-motor symptoms in PD patients, evaluating a more in-depth effect of orexin-A on PD.

Section snippets

Subject recruitment

A total of 121 PD patients and 117 healthy controls were enrolled in our study in Henan Province, China from 2018 to 2019. Patients were diagnosed by two experienced neurologists at Henan Provincial People’s Hospital, according to the International Parkinson and Movement Disorder Society Clinical Diagnostic Criteria [20]. Exclusion criteria were as follows: (1) Diagnosis of any neurological disease except PD (Alzheimer disease, epilepsy, cerebrovascular disease, severe head trauma, etc.); (2)

Demographic data and plasma orexin-A levels in healthy controls and PD patients

No differences were found in age, gender, or years of education between the PD and control groups, while MMSE scores of the PD group were significantly lower than those of the control group (Table 1).

Levels of plasma orexin-A in PD patients were significantly higher than in healthy controls (Table 1; Fig. 1A). According to the H–Y classification, PD patients were divided into early-stage (n = 68), medium-stage (n = 40) and advanced-stage PD (n = 13), and there were significant differences

Discussion

As Parkinson’s disease progresses, the hypothalamus shows varying degrees of damage [2]. Therefore, we hypothesized that orexin-A, which is secreted by the lateral hypothalamus, would decrease in the plasma of PD patients. Interestingly, our study first found an increase in peripheral orexin-A levels in PD patients. After H–Y classification, only early-stage and medium-stage PD patients exhibited increased orexin-A levels, while patients in advanced-stage PD had decreased orexin-A levels.

Conclusions

We found that high levels of plasma orexin-A are present only in early-stage and medium-stage PD, whereas in advanced-stage PD they are significantly decreased. These findings suggest that monitoring orexin-A levels may be a potential treatment or prevention strategy for PD. Plasma orexin-A levels can also be used to assess the likelihood of PD-related non-motor symptoms, such as anxiety, insomnia, RBD, cognitive dysfunction, and renal dysfunction. Finally, to elucidate the clinical

Funding

This work was supported by research grants from: Science and Technology Department of Henan Province (192102310085); Henan Provincial Commission of Health and Family Planning (201701018).

CRediT authorship contribution statement

Shen Huang: Conceptualization, Methodology, Writing - original draft, Writing - review & editing. Zhenxiang Zhao: Formal analysis, Writing - review & editing. Jianjun Ma: Conceptualization, Resources, Supervision, Project administration, Writing - review & editing. Shiyu Hu: Formal analysis, Investigation. Linyi Li: Formal analysis, Investigation. Zhidong Wang: Validation. Wenhua Sun: Validation. Xiaoxue Shi: Data curation. Mingjian Li: Data curation. Jinhua Zheng: Formal analysis, Writing -

Declaration of Competing Interest

The authors report no declarations of interest.

Acknowledgments

We would like to thank all the subjects in this study.

References (32)

  • F.N. Emamzadeh et al.

    Parkinson’s disease: biomarkers, treatment, and risk factors

    Front. Neurosci.

    (2018)
  • J. Li et al.

    The hypocretins/orexins: integrators of multiple physiological functions

    Br. J. Pharmacol.

    (2014)
  • J.P. Kukkonen

    Physiology of the orexinergic/hypocretinergic system: a revisit in 2012

    Am. J. Physiol. Cell Physiol.

    (2013)
  • M.H. James et al.

    Role of the Orexin/Hypocretin system in stress-related psychiatric disorders

    Curr. Top. Behav. Neurosci.

    (2017)
  • R. Fronczek et al.

    Hypocretin (orexin) loss in Parkinson’s disease

    Brain

    (2007)
  • A.J. Kastin et al.

    Orexin A but not orexin B rapidly enters brain from blood by simple diffusion

    J. Pharmacol. Exp. Ther.

    (1999)
  • Cited by (14)

    • Parkinson disease: Protective role and function of neuropeptides

      2022, Peptides
      Citation Excerpt :

      Significant differences in the levels of orexin-A have been found in the CSF of late-stage PD patients. Both CSF and plasma studies in PD showed a decreasing trend in orexin levels with the increasing severity of the PD, as measured by the Unified Parkinson’s Disease Rating Scale Part III (UPDRS III) [36,37]. Drourot et al. also found further decrease in CSF orexins levels in a longitudinal study for 4 and 5 years in 2 PD patients [37].

    • Etiologies of insomnia in Parkinson's disease – Lessons from human studies and animal models

      2022, Experimental Neurology
      Citation Excerpt :

      At any rate, none of the above studies correlated orexin levels with insomnia or sleep fragmentation. A recent study reported increased plasma orexin levels in PD insomnia (Huang et al., 2021), making the putative relationship between orexinergic neuronal loss and insomnia in PD even less straight-forward. Rodent works examining sleep/wakefulness alterations in animals that underwent combined dopaminergic and orexinergic lesions do not support a direct role for orexinergic neuronal loss in insomnia when an additional dopaminergic deficit is present.

    • The role of orexin in Parkinson's disease

      2024, Journal of Neuroscience Research
    View all citing articles on Scopus
    View full text