Neurotoxic/Neuroprotective Effects of Clozapine and the Positive Allosteric Modulator of mGluR2 JNJ-46356479 in Human Neuroblastoma Cell Cultures

Author:

Gassó PatriciaORCID,Martínez-Pinteño AlbertORCID,Rodríguez NataliaORCID,Madero Santiago,Gómez Marta,Segura Alex G.,García-Rizo Clemente,Morén ConstanzaORCID,Mas Sergi,Parellada Eduard

Abstract

Current antipsychotics (APs) effectively control positive psychotic symptoms, mainly by blocking dopamine (DA) D2 receptors, but have little effect on negative and cognitive symptoms. Increased glutamate (GLU) release would trigger neurotoxicity, leading to apoptosis and synaptic pruning, which is involved in the pathophysiology of schizophrenia. New pharmacological strategies are being developed such as positive allosteric modulators (PAMs) of the metabotropic GLU receptor 2 (mGluR2) that inhibit the presynaptic release of GLU. We previously reported that treatment of adult mice with JNJ-46356479 (JNJ), a recently developed mGluR2 PAM, partially improved neuropathological deficits and schizophrenia-like behavior in a postnatal ketamine mouse model. In the present study, we evaluated, for the first time, the putative neuroprotective and antiapoptotic activity of JNJ in a human neuroblastoma cell line and compared it with the effect of clozapine (CLZ) as a clinical AP with the highest efficacy and with apparent utility in managing negative symptoms. Specifically, we measured changes in cell viability, caspase 3 activity and apoptosis, as well as in the expression of key genes involved in survival and cell death, produced by CLZ and JNJ alone and in combination with a high DA or GLU concentration as apoptosis inducers. Our results suggest that JNJ is not neurotoxic and attenuates apoptosis, particularly by decreasing the caspase 3 activation induced by DA and GLU, as well as increasing and decreasing the number of viable and apoptotic cells, respectively, only when cultures were exposed to GLU. Its effects seem to be less neurotoxic and more neuroprotective than those observed with CLZ. Moreover, JNJ partially normalized altered expression levels of glycolytic genes, which could act as a protective factor and be related to its putative neuroprotective effect. More studies are needed to define the mechanisms of action of this GLU modulator and its potential to become a novel therapeutic agent for schizophrenia.

Funder

Instituto de Salud Carlos III

European Union

Catalan Pons Balmes

Government of Catalonia, Secretaria d′ Universitats i Recerca del Departament d′Economia I Coneixement

Publisher

MDPI AG

Subject

Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis

Cited by 1 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

1. Effects of the PAM of mGluR2, JNJ-46356479, on brain apoptotic protein levels in a mouse model of schizophrenia;Progress in Neuro-Psychopharmacology and Biological Psychiatry;2024-04

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