P2X receptory a jejich role v neurodegenerativních onemocněních

Abstract

P2X receptors are trimeric, extracellular ATP-activated, ion channels involved in a wide range of pathophysiological processes. This thesis focuses on their distribution, structure and function, with particular attention given to the P2X7 receptor and its role in neuroinflammation and neurodegenerative diseases. P2X7 emerges as a key element linking extracellular damage signals to the activation of the NLRP3 inflammasome, cytokine production and regulation of cell death. In the context of Alzheimer's disease, P2X7 contributes to amyloidogenesis, impairs microglial clearance of amyloid-β plaques and modulates the hyperphosphorylation and spreading of tau protein. In Parkinson's disease, the P2X7 receptor mediates the neurotoxic effects of extracellular α-synuclein through oxidative stress, mitochondrial dysfunction and promotion of neuroinflammation via the NLRP3 inflammasome. The P2X4 receptor is presented in the thesis as a modulator of microglial chemotaxis and the development of neuropathic pain. Despite promising results in preclinical models, the clinical application of P2X receptor antagonists remains limited by their insufficient selectivity and poor penetration across the blood-brain barrier. Keywords: purinergic signalling, extracellular ATP, P2X7 receptor, inflammatory pain, neuroinflammation