Detlev Boison

Seizure Suppression by Adenosine A1 Receptor Activation in a Mouse Model of Pharmacoresistant Epilepsy

Summary:u2003 Purpose: Because of the high incidence of pharmacoresistance in the treatment of epilepsy (20–30%), alternative treatment strategies are needed. Recently a proof‐of‐principle for a new therapeutic approach was established by the intraventricular delivery of adenosine released from implants of engineered cells. Adenosine‐releasing implants were found to be effective in seizure suppression in a rat model of temporal lobe epilepsy. In the present study, activation of the adenosine system was applied as a possible treatment for pharmacoresistant epilepsy.

Suppression of Kindled Seizures by Paracrine Adenosine Release from Stem Cell-Derived Brain Implants

Summary:u2002 Purpose: Stem cells and their derivatives have emerged as a promising tool for cell‐based drug delivery because of (a) their unique ability to differentiate into various somatic cell types, (b) the virtually unlimited donor source for transplantation, and (c) the advantage of being amenable to a wide spectrum of genetic manipulations. Previously, adenosine‐releasing embryonic stem (ES) cells have been generated by disruption of both alleles of adenosine kinase (Adk−/‐). Lack of ADK did not compromise the cells differentiation potential into embryoid bodies or glial precursor cells. The aim of the present study was to investigate the potential of differentiated Adk−/‐ ES cell progeny for seizure suppression by paracrine adenosine release.

Seizure suppression by adenosine-releasing cells is independent of seizure frequency

Summary: u2002Purpose: Intraventricular cellular delivery of adenosine was recently shown to be transiently efficient in the suppression of seizure activity in the rat kindling model of epilepsy. We tested whether the suppression of seizures by adenosine‐releasing grafts was independent of seizure frequency.

Adenosine-Based Cell Therapy Approaches for Pharmacoresistant Epilepsies

Despite recent medical advances pharmacoresistant epilepsy continues to be a major health problem. The knowledge of endogenous protective mechanisms of the brain may lead to the development of rational therapies tailored to a patient’s needs. Adenosine has been identified as an endogenous neuromodulator with antiepileptic and neuroprotective properties. However, the therapeutic use of adenosine or its receptor agonists is largely precluded by strong peripheral and central side effects. Thus, local delivery of adenosine to a critical site of the brain may provide a solution for the therapeutic use of adenosine. The following rationale for the local augmentation of the adenosine system as a novel therapeutic principle in the treatment of epilepsy has been established: (1) Deficits in the adenosinergic system are associated with epileptogenesis and these deficits promote seizures. Thus, reconstitution of an inhibitory adenosinergic tone is a rational therapeutic approach. (2) The focal paracrine delivery of adenosine from encapsulated cells suppresses seizures in kindled rats without overt side effects. (3) The anticonvulsant activity of locally released adenosine is maintained in models of epilepsy which are resistant to major antiepileptic drugs. This review summarizes the rationale and recent approaches for adenosine-based cell therapies for pharmacoresistant epilepsies.

MicroRNA Technology and Small-Molecule Delivery

Abstract Homeostasis of the body’s small molecules is significant in health and disease. Homeostatic functions are in part regulated by microRNAs (miRNAs). In regenerative medicine, therapeutic miRNAs may be ideally suited to restoring the network homeostasis of small molecules, such as adenosine or glucose, in this way affecting entire regulatory networks on a more holistic level. Therapeutic miRNAs can be introduced via ex vivo gene therapies, as illustrated here for adenosine, or directly via in vivo gene therapies, an interesting area that should be explored in future applications. This chapter discusses miRNA-based experimental approaches to harness the therapeutic potential of small molecules.