Abstract
ATP is a (co)transmitter and signaling molecule in the CNS. It acts at a multitude of ligand-gated cationic channels termed P2X to induce rapid depolarization of the cell membrane. Within this receptor-channel family, the P2X7 receptor (R) allows the transmembrane fluxes of Na+, Ca2+, and K+, but also allows the slow permeation of larger organic molecules. This is supposed to cause necrosis by excessive Ca2+ influx, as well as depletion of intracellular ions and metabolites. Cell death may also occur by apoptosis due to the activation of the caspase enzymatic cascade. Because P2X7Rs are localized in the CNS preferentially on microglia, but also at a lower density on neuroglia (astrocytes, oligodendrocytes) the stimulation of this receptor leads to the release of neurodegeneration-inducing bioactive molecules such as pro-inflammatory cytokines, chemokines, proteases, reactive oxygen and nitrogen molecules, and the excitotoxic glutamate/ATP. Various neurodegenerative reactions of the brain/spinal cord following acute harmful events (mechanical CNS damage, ischemia, status epilepticus) or chronic neurodegenerative diseases (neuropathic pain, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis) lead to a massive release of ATP via the leaky plasma membrane of neural tissue. This causes cellular damage superimposed on the original consequences of neurodegeneration. Hence, blood-brain-barrier permeable pharmacological antagonists of P2X7Rs with excellent bioavailability are possible therapeutic agents for these diseases. The aim of this review article is to summarize our present state of knowledge on the involvement of P2X7R-mediated events in neurodegenerative illnesses endangering especially the life quality and duration of the aged human population.
Highlights
ATP, originally thought to be solely the universal energy currency of cells, was discovered and characterized by Geoffrey Burnstock [1], as an extracellular non-adrenergic, non-cholinergic (NANC) neurotransmitter in smooth muscle organs such as the taenia coli
The aim of the present review is to summarize the state of our present knowledge on a special subtype of P2XRs, the P2X7R, in the amplification of CNS damage during neurodegeneration and the elucidation of P2X7R antagonists as possible pharmacological means to alleviate the deleterious consequences of this group of illnesses for mankind
Given that serum amyloid A is detected in the brain of Alzheimer’s Disease (AD) patients, these results provide a further mechanism for the P2X7R-related microglial neurotoxicity during AD
Summary
ATP, originally thought to be solely the universal energy currency of cells, was discovered and characterized by Geoffrey Burnstock [1], as an extracellular non-adrenergic, non-cholinergic (NANC) neurotransmitter in smooth muscle organs such as the taenia coli. In addition to its transmitter function in the nervous system, purine and pyrimidine nucleotides were recognized to act as signaling molecules coordinating the function of almost every cell in the animal/human organism. Geoffrey Burnstock’s primary interest in the last period of his life was in neurodegeneration and -regeneration. He wrote many conceptual review articles on the involvement of ATP in brain injury, stroke, ischemia, epilepsy, chronic pain, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis and amyotrophic lateral sclerosis [8,9]. The aim of the present review is to summarize the state of our present knowledge on a special subtype of P2XRs, the P2X7R, in the amplification of CNS damage during neurodegeneration and the elucidation of P2X7R antagonists as possible pharmacological means to alleviate the deleterious consequences of this group of illnesses for mankind
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