437. Development of novel add-on treatment of cognitive dysfunction in schizophrenia

Abstract

Abstract Background Mental disorders and diseases, such as schizophrenia, are a major health problem that not only inflicts damage to the quality of life of individual patients but also a pose a huge burden of cost for society estimated to be $281 billion in the United States in 2020. Schizophrenia presents a broad range of symptoms often divided into positive (e.g. hallucinations) and negative symptoms (e.g. apathy) and cognitive dysfunction (e.g. memory impairment). Whilst the primary biological causative factors for schizophrenia remain to be determined it is generally recognized that a neurochemical imbalance and disrupted neurotransmission across multiple pathways, such as dopaminergic, glutamatergic, serotoninergic, GABAergic, and cholinergic, drives the development of the diverse range of symptoms observed in patients. Currently used antipsychotic drugs (APDs) for the treatment of schizophrenia are effective in the management of positive symptoms, although not in all patients, but are generally accepted to be ineffective towards the amelioration of primary negative and the cognitive symptoms. The treatment of latter symptom domains is thought to be critical for improvement in long term patient function and quality of life and thus represent areas of high unmet medical. Aims & Objectives The aim of this study was to characterise the effects of selective butyryl cholinesterase inhibitor (BuChEI), alone and in combination with APDs, in an in vitro model of relevance to cognitive dysfunction. Method We have used elctrophysiological recording of glutamate receptor-mediated field potentials in hippocampal slices from Sprague Dawley rats. Results We have investigated the effects of the butyryl cholinesterase inhibitor (BuChEI) GUK1811 on the field potential (fEPSP) recorded in rat hippocampal brain slices. Preliminary records of the field potentials 30 min post theta burst stimulation to induce long term potentiation, during exposure to vehicle or GUK1811, showed clearly that 10 μM GUK1811 had no effect while 100 μM of this compound facilitated the theta burst stimulation of the field potentials in the hippocampal slices. Previous work have shown that GUK1811 had no adverse in vitro effects on a cell viability in a variety of cells exposed to concentrations as high as 100μM and no acute in vivo adverse effects on motor coordination or sensorimotor functions in mice, even at 100 mg/kg or chronic adverse effects in dogs treated twice daily with 10 mg/kg for at least 6 months. Discussion & Conclusions Our preliminary data show that the butyryl cholinesterase inhibitor GUK1811 could modulate glutmatergic transmission in the hippocampus, and may, thus, have a potential to ameliorate cognitive dysfunction related to this brain region in schizophrenia.