Background: Alzheimer's disease (AD) is the most common form of dementia worldwide, with approximately 6 million American cases in 2020. The clinical signs of AD include cognitive dysfunction, apathy, anxiety and neuropsychiatric signs, and pathogenetic mechanisms that involve amyloid peptide-β extracellular accumulation and tau hyperphosphorylation. Unfortunately, current drugs to treat AD can provide only symptomatic relief but are not disease-modifying molecules able to revert AD progression. The endogenous modulator adenosine, through A2A receptor activation, plays a role in synaptic loss and neuroinflammation, which are crucial for cognitive impairment and memory damage. Objective: In this review, recent advances covering A2A adenosine receptor antagonists will be extensively reviewed, providing a base for the rational design of future A2A inhibitors. Method: Herein, the literature on A2A adenosine receptors and their role in synaptic plasticity and neuroinflammation as well as the effects of A2A antagonism in animal models of AD and in humans are reviewed. Furthermore, current chemical and structure-based strategies are presented. Results: Caffeine, the most widely consumed natural product stimulant and an A2A antagonist, improves human memory. Similarly, synthetic A2A receptor antagonists, as described in this review, may provide a means to fight AD. Conclusion: This review highlights the clinical potential of A2A adenosine receptor antagonists as a novel approach to treat patients with AD.

A2A Adenosine Receptor Antagonists in Neurodegenerative Diseases

Merighi, Stefania
Primo
;
Borea, Pier Andrea
Secondo
;
Varani, Katia;Vincenzi, Fabrizio;Gessi, Stefania
Ultimo
2022

Abstract

Background: Alzheimer's disease (AD) is the most common form of dementia worldwide, with approximately 6 million American cases in 2020. The clinical signs of AD include cognitive dysfunction, apathy, anxiety and neuropsychiatric signs, and pathogenetic mechanisms that involve amyloid peptide-β extracellular accumulation and tau hyperphosphorylation. Unfortunately, current drugs to treat AD can provide only symptomatic relief but are not disease-modifying molecules able to revert AD progression. The endogenous modulator adenosine, through A2A receptor activation, plays a role in synaptic loss and neuroinflammation, which are crucial for cognitive impairment and memory damage. Objective: In this review, recent advances covering A2A adenosine receptor antagonists will be extensively reviewed, providing a base for the rational design of future A2A inhibitors. Method: Herein, the literature on A2A adenosine receptors and their role in synaptic plasticity and neuroinflammation as well as the effects of A2A antagonism in animal models of AD and in humans are reviewed. Furthermore, current chemical and structure-based strategies are presented. Results: Caffeine, the most widely consumed natural product stimulant and an A2A antagonist, improves human memory. Similarly, synthetic A2A receptor antagonists, as described in this review, may provide a means to fight AD. Conclusion: This review highlights the clinical potential of A2A adenosine receptor antagonists as a novel approach to treat patients with AD.
2022
Merighi, Stefania; Borea, Pier Andrea; Varani, Katia; Vincenzi, Fabrizio; Jacobson, Kenneth A; Gessi, Stefania
File in questo prodotto:
File Dimensione Formato  
Curr Med Chem.pdf

solo gestori archivio

Descrizione: Full text editoriale
Tipologia: Full text (versione editoriale)
Licenza: NON PUBBLICO - Accesso privato/ristretto
Dimensione 1.15 MB
Formato Adobe PDF
1.15 MB Adobe PDF   Visualizza/Apri   Richiedi una copia
nihms-1776846.pdf

accesso aperto

Descrizione: Post-printq
Tipologia: Post-print
Licenza: Creative commons
Dimensione 841.41 kB
Formato Adobe PDF
841.41 kB Adobe PDF Visualizza/Apri

I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11392/2474894
Citazioni
  • ???jsp.display-item.citation.pmc??? 13
  • Scopus 24
  • ???jsp.display-item.citation.isi??? 24
social impact