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Purinergic receptors in cognitive disturbances

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NEUROBIOLOGY OF DISEASE
卷 185, 期 -, 页码 -

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ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2023.106229

关键词

Cognitive disturbances; Purinergic P2X/P2Y receptors; Adenosine A1/A2A receptors; Neurogenerative diseases; Psychiatric disorders

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Purinergic receptors of the ATP/ADP, UTP/UDP and adenosine-sensitive classes play a broad role in cognitive processes, both in normal and disease conditions. Neurodegenerative diseases are associated with the release of high concentrations of ATP, which is enzymatically degraded to adenosine. Activation of P2X7 and A2AR receptors on various protein aggregates contributes to the primary injury, and small molecular antagonists show promise in preventing or mitigating this damage in animal models. Purinergic receptors are also implicated in psychiatric diseases, suggesting their potential as therapeutic targets for cognitive deterioration.
Purinergic receptors (Rs) of the ATP/ADP, UTP/UDP (P2X, P2Y) and adenosine (A1, A2A)-sensitive classes broadly interfere with cognitive processes both under quasi normal and disease conditions. During neurodegenerative illnesses, high concentrations of ATP are released from the damaged neuronal and non-neuronal cells of the brain; then, this ATP is enzymatically degraded to adenosine. Thus, the primary injury in neurodegenerative diseases appears to be caused by various protein aggregates on which a superimposed damage mediated by especially P2X7 and A2AR activation develops; this can be efficiently prevented by small molecular antagonists in animal models of the above diseases, or are mitigated in the respective knockout mice. Dementia is a leading symptom in Alzheimer's disease (AD), and accompanies Parkinson's disease (PD) and Huntington's disease (HD), especially in the advanced states of these illnesses. Animal experimentation suggests that P2X7 and A2ARs are also involved in a number of psychiatric diseases, such as major depressive disorder (MDD), obsessive compulsive behavior, and attention deficit hyperactivity disorder. In conclusion, small molecular antagonists of purinergic receptors are expected to supply us in the future with pharmaceuticals which are able to combat in a range of neurological/psychiatric diseases the accompanying cognitive deterioration.

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