Targeting of α7 Nicotinic Acetylcholine Receptors in the Treatment of Schizophrenia and the Use of Auditory Sensory Gating as a Translational Biomarker.

Abstract

Accumulating evidence suggests that the α7 subtype of nicotinic acetylcholine receptors (nAChRs) plays a key role in inflammatory processes, thought to be involved in the pathophysiology of neuropsychiatric diseases, such as schizophrenia and Alzheimer’s disease. Preclinical and clinical studies showed that the diminished suppression of P50 auditory evoked potentials in patients with schizophrenia may be associated with a decreased density of α7 nAChRs in the brain. This points to a role for auditory sensory gating (P50) as a translational biomarker. A number of agonists and positive allosteric modulators (PAMs) for α7 nAChR promoted beneficial effects in animal models with sensory gating and cognitive deficits. Additionally, several clinical studies showed that α7 nAChR agonists could improve suppression in auditory P50 evoked potentials, as well as cognitive deficits, and negative symptoms in patients with schizophrenia. Taken together, α7 nAChR presents as an extremely attractive therapeutic target for schizophrenia. In this article, the author discusses recent findings on α7 nAChR agonists such as DMXB-A, RG3487, TC-5619, tropisetron, EVP-6124 (encenicline), ABT-126, AQW051 and α7 nAChR PAMs such as JNJ-39393406, PNU-120596 and AVL-3288 (also known as UCI-4083), and their potential as therapeutic drugs for neuropsychiatric diseases, such as schizophrenia.