G-Protein-Coupled Receptors in CNS: A Potential Therapeutic Target for Intervention in Neurodegenerative Disorders and Associated Cognitive Deficits

Overview

Journal Cells

Publisher MDPI

Specialties Biochemistry
Biophysics
Cell Biology
Molecular Biology

Date 2020 Feb 28

PMID 32102186

Citations 40

Authors

Shofiul Azam

Md Ezazul Haque

Md Jakaria

Song-Hee Jo

In-Su Kim

Dong-Kug Choi

Affiliations

Soon will be listed here.

Abstract

Neurodegenerative diseases are a large group of neurological disorders with diverse etiological and pathological phenomena. However, current therapeutics rely mostly on symptomatic relief while failing to target the underlying disease pathobiology. G-protein-coupled receptors (GPCRs) are one of the most frequently targeted receptors for developing novel therapeutics for central nervous system (CNS) disorders. Many currently available antipsychotic therapeutics also act as either antagonists or agonists of different GPCRs. Therefore, GPCR-based drug development is spreading widely to regulate neurodegeneration and associated cognitive deficits through the modulation of canonical and noncanonical signals. Here, GPCRs' role in the pathophysiology of different neurodegenerative disease progressions and cognitive deficits has been highlighted, and an emphasis has been placed on the current pharmacological developments with GPCRs to provide an insight into a potential therapeutic target in the treatment of neurodegeneration.

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References

Wootten D, Christopoulos A, Sexton P . Emerging paradigms in GPCR allostery: implications for drug discovery. Nat Rev Drug Discov. 2013; 12(8):630-44. DOI: 10.1038/nrd4052. View

Mazzola C, Micale V, Drago F . Amnesia induced by beta-amyloid fragments is counteracted by cannabinoid CB1 receptor blockade. Eur J Pharmacol. 2003; 477(3):219-25. DOI: 10.1016/j.ejphar.2003.08.026. View

Gabryelewicz T, Masellis M, Berdynski M, Bilbao J, Rogaeva E, St George-Hyslop P . Intra-familial clinical heterogeneity due to FTLD-U with TDP-43 proteinopathy caused by a novel deletion in progranulin gene (PGRN). J Alzheimers Dis. 2010; 22(4):1123-33. PMC: 5045304. DOI: 10.3233/JAD-2010-101413. View

Liu Y, Hu J, Wu J, Zhu C, Hui Y, Han Y . α7 nicotinic acetylcholine receptor-mediated neuroprotection against dopaminergic neuron loss in an MPTP mouse model via inhibition of astrocyte activation. J Neuroinflammation. 2012; 9:98. PMC: 3416733. DOI: 10.1186/1742-2094-9-98. View

Nirogi R, Ajjala D, Aleti R, Rayapati L, Pantangi H, Boggavarapu R . Development and validation of sensitive LC-MS/MS method for the quantification of SUVN-502 and its metabolite and its application for first in human pharmacokinetic study. J Pharm Biomed Anal. 2017; 145:423-430. DOI: 10.1016/j.jpba.2017.04.005. View

Fakhfouri G, Ahmadiani A, Rahimian R, Grolla A, Moradi F, Haeri A . WIN55212-2 attenuates amyloid-beta-induced neuroinflammation in rats through activation of cannabinoid receptors and PPAR-γ pathway. Neuropharmacology. 2012; 63(4):653-66. DOI: 10.1016/j.neuropharm.2012.05.013. View

Tang X, Wang Y, Li D, Luo J, Liu M . Orphan G protein-coupled receptors (GPCRs): biological functions and potential drug targets. Acta Pharmacol Sin. 2012; 33(3):363-71. PMC: 4077139. DOI: 10.1038/aps.2011.210. View

Jicha G, Nelson P . Management of frontotemporal dementia: targeting symptom management in such a heterogeneous disease requires a wide range of therapeutic options. Neurodegener Dis Manag. 2011; 1(2):141-156. PMC: 3172080. DOI: 10.2217/nmt.11.9. View

Halliday G, Leverenz J, Schneider J, Adler C . The neurobiological basis of cognitive impairment in Parkinson's disease. Mov Disord. 2014; 29(5):634-50. PMC: 4049032. DOI: 10.1002/mds.25857. View

10.

Selkoe D . The therapeutics of Alzheimer's disease: where we stand and where we are heading. Ann Neurol. 2015; 74(3):328-36. DOI: 10.1002/ana.24001. View

11.

Maher-Edwards G, Zvartau-Hind M, Hunter A, Gold M, Hopton G, Jacobs G . Double-blind, controlled phase II study of a 5-HT6 receptor antagonist, SB-742457, in Alzheimer's disease. Curr Alzheimer Res. 2010; 7(5):374-85. DOI: 10.2174/156720510791383831. View

12.

Caraci F, Molinaro G, Battaglia G, Giuffrida M, Riozzi B, Traficante A . Targeting group II metabotropic glutamate (mGlu) receptors for the treatment of psychosis associated with Alzheimer's disease: selective activation of mGlu2 receptors amplifies beta-amyloid toxicity in cultured neurons, whereas dual activation of.... Mol Pharmacol. 2010; 79(3):618-26. DOI: 10.1124/mol.110.067488. View

13.

Young S, Ervin F, Pihl R, Finn P . Biochemical aspects of tryptophan depletion in primates. Psychopharmacology (Berl). 1989; 98(4):508-11. DOI: 10.1007/BF00441950. View

14.

Sutton L, Orlandi C, Song C, Oh W, Muntean B, Xie K . Orphan receptor GPR158 controls stress-induced depression. Elife. 2018; 7. PMC: 5823542. DOI: 10.7554/eLife.33273. View

15.

Westbrook A, Braver T . Dopamine Does Double Duty in Motivating Cognitive Effort. Neuron. 2016; 89(4):695-710. PMC: 4759499. DOI: 10.1016/j.neuron.2015.12.029. View

16.

Benhamu B, Martin-Fontecha M, Vazquez-Villa H, Pardo L, Lopez-Rodriguez M . Serotonin 5-HT6 receptor antagonists for the treatment of cognitive deficiency in Alzheimer's disease. J Med Chem. 2014; 57(17):7160-81. DOI: 10.1021/jm5003952. View

17.

Matsumoto M, Saito T, Takasaki J, Kamohara M, Sugimoto T, Kobayashi M . An evolutionarily conserved G-protein coupled receptor family, SREB, expressed in the central nervous system. Biochem Biophys Res Commun. 2000; 272(2):576-82. DOI: 10.1006/bbrc.2000.2829. View

18.

Mendelsohn D, Riedel W, Sambeth A . Effects of acute tryptophan depletion on memory, attention and executive functions: a systematic review. Neurosci Biobehav Rev. 2009; 33(6):926-52. DOI: 10.1016/j.neubiorev.2009.03.006. View

19.

Heng B, Aubel D, Fussenegger M . An overview of the diverse roles of G-protein coupled receptors (GPCRs) in the pathophysiology of various human diseases. Biotechnol Adv. 2013; 31(8):1676-94. DOI: 10.1016/j.biotechadv.2013.08.017. View

20.

Beal M, Ferrante R, Swartz K, Kowall N . Chronic quinolinic acid lesions in rats closely resemble Huntington's disease. J Neurosci. 1991; 11(6):1649-59. PMC: 6575424. View