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Adenosinergic Pathway in Parkinson’s Disease: Recent Advances and Therapeutic Perspective

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Abstract

Parkinson’s disease (PD) is a neurodegenerative disease characterized pathologically by α-synuclein (α-syn) aggregation. In PD, the current mainstay of symptomatic treatment is levodopa (L-DOPA)-based dopamine (DA) replacement therapy. However, the development of dyskinesia and/or motor fluctuations which is relevant to levodopa is restricting its long-term utility. Given that the ability of which is to modulate the striato-thalamo-cortical loops and function to modulate basal ganglia output, the adenosinergic pathway (AP) is qualified as a potential promising non-DA target. As an indispensable component of energy production pathways, AP modulates cellular metabolism and gene regulation in both neurons and neuroglia cells through the recognition and degradation of extracellular adenosine. In addition, AP is geared to the initiation, evolution, and resolution of inflammation as well. Besides the above-mentioned crosstalk between the adenosine and dopamine signaling pathways, the functions of adenosine receptors (A1R, A2AR, A2BR, and A3R) and metabolism enzymes in modulating PD pathological process have been extensively investigated in recent decades. Here we reviewed the emerging findings focused on the function of adenosine receptors, adenosine formation, and metabolism in the brain and discussed its potential roles in PD pathological process. We also recapitulated clinical studies and the preclinical evidence for the medical strategies targeting the Ado signaling pathway to improve motor dysfunction and alleviate pathogenic process in PD. We hope that further clinical studies should consider this pathway in their monotherapy and combination therapy, which would open new vistas to more targeted therapeutic approaches.

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Abbreviations

PD:

Parkinson’s disease

L-DOPA:

Levodopa

DA:

Dopamine

AP:

Adenosinergic pathway

LBs:

Lewy bodies

Ado:

Adenosine

ATP:

Adenosine triphosphate

CNS:

Central nerve system

ARs:

Adenosine receptors

GPCRs:

G protein-coupled receptors

AC:

Adenylate cyclase

PDE:

Phosphodiesterase

ENT:

Equilibrative nucleoside transporters

AK:

Adenylate kinase

NDPK:

Nucleoside-diphosphate kinase

ADA:

Adenosine deaminase

PKA:

cAMP-dependent protein kinase

D2R:

Dopamine D2 receptor

FDA:

Food and Drug Administration

TJMs:

Tremulous jaw movements

MSNs:

Medium spiny neurons

RECAP:

Retrosynthetic Combinatorial Analysis Procedure

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Funding

The project was supported by the Department of Health of Hebei Province (Grant No.20190505). The project was supported by the S&T Program of Hebei (No. 22377798D).

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  1. Yuan Zhao and Xin Liu contributed equally to this work.

Authors and Affiliations

  1. Department of Geriatrics, The Second Hospital of Hebei Medical University, 215 Hepingxi Road, Shijiazhuang, 050000, Hebei, People’s Republic of China

    Yuan Zhao & Guofeng Yang

  2. Department of Neurosurgery, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, People’s Republic of China

    Xin Liu & Guofeng Yang

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  1. Yuan Zhao
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  2. Xin Liu
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  3. Guofeng Yang
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YZ and XL prepared the manuscript and designed the figures. GF reviewed the manuscript. All authors approved the final manuscript.

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Correspondence to Guofeng Yang.

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Zhao, Y., Liu, X. & Yang, G. Adenosinergic Pathway in Parkinson’s Disease: Recent Advances and Therapeutic Perspective. Mol Neurobiol 60, 3054–3070 (2023). https://doi.org/10.1007/s12035-023-03257-3

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