Is Ecto-nucleoside Triphosphate Diphosphohydrolase (NTPDase)-based Therapy of Central Nervous System Disorders Possible?

Abstract

Extracellular nucleotides and nucleosides are signalling molecules acting in all tissues and organs, including the central nervous system (CNS). A wide variety of effects, exerted by ecto-purines, requires that their levels, and ATP in particular, must be precisely controlled. Under physiological conditions, concentration of ecto-purines is regulated by a complex cascade of ecto-enzymes, including ecto-NTPDases (nucleoside triphosphate diphosphohydrolases), ecto-NPPs (nucleotide pyrophosphohydrolases/phosphodiesterases), ectoalkaline phosphatases, and ecto-5'nucleotidase. Adenylate kinase, transferring the phosphate moiety between nucleotides, also plays a role in controlling ecto-purines concentration. Disturbances in the elements of purinergic pathway within the CNS underlie the induction and amplification of many neurological pathologies. ATP released in bulk from the cells, and not degraded by less efficient or dysfunctional ecto-nucleotidases, triggers excitotoxic damage and neuro-inflammation in the brain tissue. High ATP concentration activating specific receptors has been shown to be involved in various disorders throughout CNS, including brain injury and ischemia, neuro-inflammation, epilepsy as well as neuropathic pain and migraine. Taking the above mentioned influence of ATP into consideration, the modulation of ecto-NTPDase activity or its site-targeted delivery seems a good therapeutic method. The availability of effective brain-targeted drug-delivery system is one of the most significant challenges facing potential NTPDase-based treatment of CNS disorders. The application of genetically engineered stem cells as carrier vehicles offers a promising strategy for the efficient delivery of the enzyme to CNS tissues.