Overexpression of ORX or MCH Protects Neurological Function Against Ischemic Stroke

Overview

Journal Neurotox Res

Publisher Springer

Specialty Neurology

Date 2022 Jan 11

PMID 35013906

Authors

Gang Wu

Xian Zhang

ShiJun Li

Dan Zhou

Jie Bai

Hanxiang Wang

Qing Shu

Affiliations

Soon will be listed here.

Abstract

In recent years, orexin (ORX) and melanin-concentrating hormone (MCH) have been demonstrated to exert neuroprotective roles in cerebral ischemia. Hence, this study investigated the regulatory function of ORX and MCH in neurological function following ischemic stroke and explored the molecular mechanism underlying these functions. A rat model of ischemic stroke was developed by middle cerebral artery occlusion (MCAO), and Longa scoring was employed to evaluate the degree of neurological function deficit. The expression patterns of ORX and MCH were examined by real-time polymerase chain reaction in the brain tissues of rats with ischemic stroke induced by middle cerebral artery occlusion (MCAO). Moreover, electroencephalography (EEG) analysis and high-performance liquid chromatography (HPLC) were respectively performed to detect rapid-eye movement (REM) sleep, the glutamate (Glu) uptake, and the expression of γ-aminobutyric acid B receptor (GABA). Immunoblotting was performed to test the levels of autophagic markers LC3, BECLIN-1, and p62. Immunohistochemistry (IHC) staining and TUNEL assays were respectively used to assess the autophagy and neuronal apoptosis. Results demonstrated that ORX and MCH were lowly expressed in brain of rats with ischemic stroke. ORX or MCH overexpression decreased neuronal apoptosis and autophagy, and improved the sleep architecture of post-stroke rats, while rescuing Glu uptake and GABA expression. ORX or MCH upregulation exerted protective effects on neurological function. Taken together, ORX and/or MCH protect against ischemic stroke in a rat model, highlighting their value as targets for the clinical treatment of ischemic stroke.

Citing Articles

Inclusion of hypocretin-1 improved performance of poor sleep quality prediction for elderly patients with acute ischemic stroke: a prospective cohort study.

Fu T, Zhang W, Guo R, He S, Yu S, Wang H Front Aging Neurosci. 2025; 16():1509846.

PMID: 39839304 PMC: 11747788. DOI: 10.3389/fnagi.2024.1509846.

References

Clark I, Vissel B . Inflammation-sleep interface in brain disease: TNF, insulin, orexin. J Neuroinflammation. 2014; 11:51. PMC: 3994460. DOI: 10.1186/1742-2094-11-51. View

Denk H, Stumptner C, Abuja P, Zatloukal K . Sequestosome 1/p62-related pathways as therapeutic targets in hepatocellular carcinoma. Expert Opin Ther Targets. 2019; 23(5):393-406. DOI: 10.1080/14728222.2019.1601703. View

Flores A, Saravia R, Maldonado R, Berrendero F . Orexins and fear: implications for the treatment of anxiety disorders. Trends Neurosci. 2015; 38(9):550-9. DOI: 10.1016/j.tins.2015.06.005. View

Gonzalez J, Iordanidou P, Strom M, Adamantidis A, Burdakov D . Awake dynamics and brain-wide direct inputs of hypothalamic MCH and orexin networks. Nat Commun. 2016; 7:11395. PMC: 4844703. DOI: 10.1038/ncomms11395. View

Harada S, Yamazaki Y, Tokuyama S . Orexin-A suppresses postischemic glucose intolerance and neuronal damage through hypothalamic brain-derived neurotrophic factor. J Pharmacol Exp Ther. 2012; 344(1):276-85. DOI: 10.1124/jpet.112.199604. View

Henny P, Brischoux F, Mainville L, Stroh T, Jones B . Immunohistochemical evidence for synaptic release of glutamate from orexin terminals in the locus coeruleus. Neuroscience. 2010; 169(3):1150-7. PMC: 2914109. DOI: 10.1016/j.neuroscience.2010.06.003. View

Huang L, Li Q, Wen R, Yu Z, Li N, Ma L . Rho-kinase inhibitor prevents acute injury against transient focal cerebral ischemia by enhancing the expression and function of GABA receptors in rats. Eur J Pharmacol. 2017; 797:134-142. DOI: 10.1016/j.ejphar.2017.01.021. View

Jego S, Glasgow S, Herrera C, Ekstrand M, Reed S, Boyce R . Optogenetic identification of a rapid eye movement sleep modulatory circuit in the hypothalamus. Nat Neurosci. 2013; 16(11):1637-43. PMC: 4974078. DOI: 10.1038/nn.3522. View

Jiang Y, Yang S, Tao J, Lin Z, Ye X, You Y . Opposing needling promotes behavior recovery and exerts neuroprotection via the cAMP/PKA/CREB signal transduction pathway in transient MCAO rats. Mol Med Rep. 2016; 13(3):2060-70. PMC: 4768950. DOI: 10.3892/mmr.2016.4773. View

10.

Jin R, Xiao A, Chen R, Granger D, Li G . Inhibition of CD147 (Cluster of Differentiation 147) Ameliorates Acute Ischemic Stroke in Mice by Reducing Thromboinflammation. Stroke. 2017; 48(12):3356-3365. PMC: 5726599. DOI: 10.1161/STROKEAHA.117.018839. View

11.

Khandelwal P, Yavagal D, Sacco R . Acute Ischemic Stroke Intervention. J Am Coll Cardiol. 2016; 67(22):2631-44. DOI: 10.1016/j.jacc.2016.03.555. View

12.

Kim S, Jo K, Hong K, Han S, Suh H . GABA and l-theanine mixture decreases sleep latency and improves NREM sleep. Pharm Biol. 2019; 57(1):65-73. PMC: 6366437. DOI: 10.1080/13880209.2018.1557698. View

13.

Li A, Zhang H, Han H, Zhang W, Yang S, Huang Z . LC3 promotes the nuclear translocation of the vitamin D receptor and decreases fibrogenic gene expression in proximal renal tubules. Metabolism. 2019; 98:95-103. DOI: 10.1016/j.metabol.2019.06.008. View

14.

Magi S, Piccirillo S, Amoroso S . The dual face of glutamate: from a neurotoxin to a potential survival factor-metabolic implications in health and disease. Cell Mol Life Sci. 2019; 76(8):1473-1488. PMC: 11105246. DOI: 10.1007/s00018-018-3002-x. View

15.

Mahler S, Moorman D, Smith R, James M, Aston-Jones G . Motivational activation: a unifying hypothesis of orexin/hypocretin function. Nat Neurosci. 2014; 17(10):1298-303. PMC: 4335648. DOI: 10.1038/nn.3810. View

16.

Matsuura K, Kabuto H, Makino H, Ogawa N . Pole test is a useful method for evaluating the mouse movement disorder caused by striatal dopamine depletion. J Neurosci Methods. 1997; 73(1):45-8. DOI: 10.1016/s0165-0270(96)02211-x. View

17.

Pace M, Adamantidis A, Facchin L, Bassetti C . Role of REM Sleep, Melanin Concentrating Hormone and Orexin/Hypocretin Systems in the Sleep Deprivation Pre-Ischemia. PLoS One. 2017; 12(1):e0168430. PMC: 5218733. DOI: 10.1371/journal.pone.0168430. View

18.

Sanchart C, Rattanaporn O, Haltrich D, Phukpattaranont P, Maneerat S . Enhancement of gamma-aminobutyric acid (GABA) levels using an autochthonous Lactobacillus futsaii CS3 as starter culture in Thai fermented shrimp (Kung-Som). World J Microbiol Biotechnol. 2017; 33(8):152. DOI: 10.1007/s11274-017-2317-3. View

19.

Schneeberger M, Tan K, Nectow A, Parolari L, Caglar C, Azevedo E . Functional analysis reveals differential effects of glutamate and MCH neuropeptide in MCH neurons. Mol Metab. 2018; 13:83-89. PMC: 6026325. DOI: 10.1016/j.molmet.2018.05.001. View

20.

Seifinejad A, Li S, Mikhail C, Vassalli A, Pradervand S, Arribat Y . Molecular codes and in vitro generation of hypocretin and melanin concentrating hormone neurons. Proc Natl Acad Sci U S A. 2019; 116(34):17061-17070. PMC: 6708384. DOI: 10.1073/pnas.1902148116. View