Adenosine (Figure 4) is an endogenous neuromodulatory agent that has anticonvulsant activity in a variety of animal models.45 Using hippocampal microdialysis probes, adenosine levels were found to be increased 6-31-fold in patients with intractable complex partial epilepsy during seizures,46 suggesting that compounds that mimic adenosine effects, e.g., synthetic adenosine analogs, or facilitate its actions, e.g., adenosine kinase (AK) inhibitors, may be potent and effect AEDs.47 However, as in many other therapeutic areas where modulation of adenosine function has been viewed as a therapeutic option, e.g., neuropathic pain, stroke, asthma, chronic obstructive pulmonary disease (COPD), sleep promotion (see 6.06 Sleep), etc., the efficacy of adenosine and its analogs have been accompanied by unmanageable side effects including sedation and hypotension.48 A novel approach to circumventing the side effects of adenosine has been an 'ex vivo gene therapy' approach, tailoring the local delivery of adenosine to an epileptic focus by implanting encapsulated fibroblasts.49 An extension of this approach has been to engineer mouse myoblasts to release adenosine by genetic inactivation of AK.50 In this latter instance, kindled mice grafted with adenosine-releasing implants had complete protection from convulsive seizures with a corresponding reduction in EEG after discharges for periods up to and in excess of 3 weeks without evidence of desensitization or sedation. Efforts are now ongoing to engineer adult stem cells from skin or bone marrow that can produce adenosine to generate autologous therapeutic grafts with a potential lifespan of up to 500 days.50
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