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Therapeutic potential of extracellular ATP and P2 receptors in nervous system diseases.

ABSTRACT: Extracellular adenosine 5 inch-triphosphate (ATP) is a key signaling molecule present in the central nervous system (CNS), and now is receiving greater attention due to its role as a messenger in the CNS during different physiological and pathological events. ATP is released into the extracellular space through vesicular exocytosis or from damaged and dying cells. Once in the extracellular environment, ATP binds to the specific receptors termed P2, which mediate ATP effects and are present broadly in both neurons and glial cells. There are P2X, the ligand-gated ionotropic receptors, possessing low affinity for ATP and responsible for fast excitatory neurotransmission, and P2Y, the metabotropic G-protein-coupled receptors, possessing high affinity for ATP. Since massive extracellular release of ATP often occurs after stress, brain ischemia and trauma, the extracellular ATP is considered relating to or involving in the pathological processes of many nervous system diseases. Conversely, the trophic functions have also been extensively described for the extracellular ATP. Therefore, extracellular ATP plays a very complex role in the CNS and its binding to P2 receptors can be related to toxic and/or beneficial effects. In this review, we described the extracellular ATP acting via P2 receptors as a potent therapeutic target for treatment of nervous system diseases.

SUBMITTER: Tu J

PROVIDER: S-EPMC5552493 | biostudies-other | 2009 Feb

REPOSITORIES: biostudies-other

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Project description:The complement system plays critical roles in development, homeostasis, and regeneration in the central nervous system (CNS) throughout life; however, complement dysregulation in the CNS can lead to damage and disease. Complement proteins, regulators, and receptors are widely expressed throughout the CNS and, in many cases, are upregulated in disease. Genetic and epidemiological studies, cerebrospinal fluid (CSF) and plasma biomarker measurements and pathological analysis of post-mortem tissues have all implicated complement in multiple CNS diseases including multiple sclerosis (MS), neuromyelitis optica (NMO), neurotrauma, stroke, amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). Given this body of evidence implicating complement in diverse brain diseases, manipulating complement in the brain is an attractive prospect; however, the blood-brain barrier (BBB), critical to protect the brain from potentially harmful agents in the circulation, is also impermeable to current complement-targeting therapeutics, making drug design much more challenging. For example, antibody therapeutics administered systemically are essentially excluded from the brain. Recent protocols have utilized "Trojan horse" techniques to transport therapeutics across the BBB or used osmotic shock or ultrasound to temporarily disrupt the BBB. Most research to date exploring the impact of complement inhibition on CNS diseases has been in animal models, and some of these studies have generated convincing data; for example, in models of MS, NMO, and stroke. There have been a few recent clinical trials of available anti-complement drugs in CNS diseases associated with BBB impairment, for example the use of the anti-C5 monoclonal antibody (mAb) eculizumab in NMO, but for most CNS diseases there have been no human trials of anti-complement therapies. Here we will review the evidence implicating complement in diverse CNS disorders, from acute, such as traumatic brain or spine injury, to chronic, including demyelinating, neuroinflammatory, and neurodegenerative diseases. We will discuss the particular problems of drug access into the CNS and explore ways in which anti-complement therapies might be tailored for CNS disease.

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Therapeutic potential of extracellular ATP and P2 receptors in nervous system diseases.

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