Homeostatic bioenergetic network regulation - a novel concept to avoid pharmacoresistance in epilepsy.

INTRODUCTION: Despite epilepsy being one of the most prevalent neurological disorders, one third of all patients with epilepsy cannot adequately be treated with available antiepileptic drugs. One of the significant causes for the failure of conventional pharmacotherapeutic treatment is the development of pharmacoresistance in many forms of epilepsy. The problem of pharmacoresistance has called for the development of new conceptual strategies that improve future drug development efforts. AREAS COVERED: A thorough review of the recent literature on pharmacoresistance in epilepsy was completed and select examples were chosen to highlight the mechanisms of pharmacoresistance in epilepsy and to demonstrate how those mechanistic findings might lead to improved treatment of pharmacoresistant epilepsy. The reader will gain a thorough understanding of pharmacoresistance in epilepsy and an appreciation of the limitations of conventional drug development strategies. EXPERT OPINION: Conventional drug development efforts aim to achieve specificity of symptom control by enhancing the selectivity of drugs acting on specific downstream targets; this conceptual strategy bears the undue risk of development of pharmacoresistance. Modulation of homeostatic bioenergetic network regulation is a novel conceptual strategy to affect whole neuronal networks synergistically by mobilizing multiple endogenous biochemical and receptor-dependent molecular pathways. In our expert opinion we conclude that homeostatic bioenergetic network regulation might thus be used as an innovative strategy for the control of pharmacoresistant seizures. Recent focal adenosine augmentation strategies support the feasibility of this strategy.

Modulation of sensorimotor gating in prepulse inhibition by conditional brain glycine transporter 1 deletion in mice.

Inhibition of glycine transporter 1 (GlyT1) augments N-methyl-D-aspartate receptor (NMDAR)-mediated transmission and represents a potential antipsychotic drug target according to the NMDAR hypofunction hypothesis of schizophrenia. Preclinical evaluation of GlyT1 inhibiting drugs using the prepulse inhibition (PPI) test, however, has yielded mixed outcomes. Here, we tested for the first time the impact of two conditional knockouts of GlyT1 on PPI expression. Complete deletion of GlyT1 in the cerebral cortices confers resistance to PPI disruption induced by the NMDAR blocker MK-801 (0.2mg/kg, i.p.) without affecting PPI expression in unchallenged conditions. In contrast, restricting GlyT1 deletion to neurons in forebrain including the striatum significantly attenuated PPI, and the animals remained sensitive to the PPI-disruptive effect of MK-801 at the same dose. These results demonstrate in mice that depending on the regional and/or cell-type specificity, deletion of the GlyT1 gene could yield divergent effects on PPI.

Adenosine as a modulator of brain activity.

The endogenous neuromodulator adenosine controls and integrates a wide range of brain functions. Consequently, dysfunction of the adenosine system is involved in pathologies ranging from epilepsy to neurodegenerative disorders and psychiatric conditions. The adenosine system has therefore been recognized as a prime target for the development of new therapeutics for neurological diseases. This review covers the upstream and downstream targets of adenosinergic neurotransmission and provides the neurochemical rationale for the development of adenosine receptor modulating drugs (downstream) and inhibitors of adenosine kinase, the key upstream regulator of ambient levels of adenosine. Due to the unique role of adenosine to integrate and fine-tune glutamatergic and dopaminergic neurotransmission, adenosine-regulating agents have the potential to modify a wide range of downstream effects. Thus, adenosine-based therapies are rapidly evolving in preclinical and clinical studies.