Adenosine Augmentation Therapy

Excerpt

Adenosine is an endogenous anticonvulsant that is controlled by an astrocyte-based adenosine cycle and expression levels of its key negative regulator adenosine kinase (ADK). Astrogliosis, a pathological hallmark of the epileptic brain, is universally accompanied by overexpression of ADK and resulting adenosine deficiency. Thereby deregulated ADK provides a molecular link between astrogliosis and neuronal dysfunction in epilepsy. Since overexpression of ADK and resulting adenosine deficiency are sufficient to initiate spontaneous recurrent seizures, focal adenosine augmentation therapies (AATs) constitute a rational approach for the suppression and prevention of seizures. Systemic pharmacological AATs using either ADK inhibitors or adenosine A₁ receptor agonists are effective in seizure suppression, however accompanied by wide-spread, largely cardiovascular, side-effects that can only be avoided via focal delivery approaches. As therapeutic tools to achieve focal AAT, stem cells have been engineered to release therapeutic amounts of adenosine using RNA interference or gene targeting technology. In rodent models, stem cell-derived brain-implants provide robust protection from induced and spontaneous seizures through the paracrine delivery of adenosine. Most recently, silk-based polymers have been bioengineered to release adenosine with the goal to translate focal AATs into clinical applications.