Adenosinergic approaches to stroke therapeutics.

Basic neuroscience research findings during the past five years have established a clear relationship between the excitatory amino acid (EAA) neurotransmitters (glutamic and aspartic acid) and various pathological states. A major mechanism of neural tissue degeneration following cerebral ischemia, and perhaps other neurodegenerative diseases, seems to involve overactivity of the EAA system in brain. This process is called delayed excitotoxicity and it has become a focal point for the design of new drugs that inhibit its course (EAA receptor blockers). Very recently it has been shown that it is possible to block delayed excitotoxicity using adenosine A1 receptor agonists which inhibit EAA release pre-synaptically. This approach is very effective in reducing post-stroke neurological damage in a number of animal models and has certain advantages when compared to the EAA receptor blocker strategy. Adenosine agonists not only inhibit excitotoxicity but they also block granulocyte activation and the capillary no-reflow phenomenon which results. An additional adenosinergic approach involves brain permeable adenosine uptake blockers which would serve to increase adenosine levels somewhat selectively at ischemic foci thereby inhibiting EAA release. The adenosinergic approach to stroke therapeutics may be a potentially effective strategy for new drug development in neurology, and may have general applicability to other neurodegenerative disease states where excitotoxicity is being implicated.