Abstract
Despite major advances in a variety of neuroscientific research fields, the majority of neurodegenerative and neurological diseases are poorly controlled by currently available drugs, which are largely based on a neurocentric drug design. Research from the past 5 years has established a central role of glia to determine how neurons function and, consequently, glial dysfunction is implicated in almost every neurodegenerative and neurological disease. Glial cells are key regulators of the brain's endogenous neuroprotectant and anticonvulsant adenosine. This review will summarize how glial cells contribute to adenosine homeostasis and how glial adenosine receptors affect glial function. We will then move on to discuss how glial cells interact with neurons and the vasculature, and outline new methods to study glial function. We will discuss how glial control of adenosine function affects neuronal cell death, and its implications for epilepsy, traumatic brain injury, ischemia, and Parkinson's disease. Eventually, glial adenosine-modulating drug targets might be an attractive alternative for the treatment of neurodegenerative diseases. There are, however, several major open questions that remain to be tackled.
Highlights
In mammals, purine de novo synthesis proceeds via formation of IMP, which is converted into AMP; there is no de novo synthesis pathway for adenosine
It was shown long ago that 50nucleotidase tended to accumulate in areas of a lesion,[26] and we know that CD73, the ecto50nucleotidase, is highly expressed in microglial cells, as is the ecto-NTPDase, CD39.27
Using double immunohistochemistry analysis, we demonstrated that A2AR expression is induced in microglial cells and astrocytes of mouse substantia nigra at 24 h after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication
Summary
Despite major advances in a variety of neuroscientific research fields, the majority of neurodegenerative and neurological diseases are poorly controlled by currently available drugs, which are largely based on a neurocentric drug design. Research from the past 5 years has established a central role of glia to determine how neurons function and, glial dysfunction is implicated in almost every neurodegenerative and neurological disease. We will discuss how glial control of adenosine function affects neuronal cell death, and its implications for epilepsy, traumatic brain injury, ischemia, and Parkinson’s disease. The role of ATP and adenosine as critically important signaling molecules has become appreciated.[2,3] This awareness that a multiplicity of signals other than those principally involved in nerve–nerve communication play a role in neurodegenerative disease has meant that we have to consider other cells than neurons as critically important players. The present brief review will focus on adenosine (and to a lesser extent ATP) signaling, and the role of glial cells in neurodegenerative disease. The review will feature results from the authors‘ own work more prominently than would be motivated from an objective standpoint
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