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PT-31, a putative α2-adrenoceptor agonist, is effective in schizophrenia cognitive symptoms in mice

Betti, Andresa Heemanna; Antonio, Camila Boquea; Herzfeldt, Viviana; Pitta, Marina Galdino da Rochab; da Rocha Pitta, Ivanb; do Rego, Jean-Lucd,,e; do Rego, Jean-Clauded,,e; Vaudry, Davidc; Rates, Stela Maris Kuzea

doi: 10.1097/FBP.0000000000000494
Research Reports
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Evidence of changes in central noradrenergic activity has been reported in schizophrenic patients and studies indicate that activation of the α2-adrenoceptor improves memory and neuroprotection. In this study, a new imidazolidine derivative 3-(2-chloro-6-fluorobenzyl)-imidazolidine-2,4-dione, PT-31, a putative α2A-adrenoceptor agonist, was evaluated in mouse models predictive of efficacy in the treatment of positive and cognitive symptoms of schizophrenia, as well as its ability to promote cerebellar granule cell survival in vitro, in the presence or absence of glutamate (100 µmol/l). PT-31 prevented apomorphine-induced climbing and the ketamine-induced hyperlocomotion, without inducing catalepsy or motor impairment. PT-31 protected against the impairment of prepulse inhibition induced by apomorphine, (±)-DOI, and ketamine. The molecule did not affect mouse short nor long-term memory per se, but it protected against ketamine-induced memory impairment when administered at different stages of the memory process (acquisition, consolidation, and retrieval) in the novel object recognition task. When added to cultured cerebellar granule neurons, PT-31 was not toxic per se and protected neurons from glutamate-induced apoptosis. In conclusion, PT-31 displayed a preclinical pharmacology predictive of neuroprotective effects and efficacy in relieving schizophrenia symptoms, without inducing motor side effects, suggesting that it could represent a molecular scaffold for antipsychotic drug development.

aDepartment of Raw Material Production, Federal University of Rio Grande do Sul, Porto Alegre

bLaboratory of Planning and Synthesis of Drugs, NUPIT-SG, Federal University of Pernambuco, Recife

cInstitute for Biomedical Research and Innovation, Normandie University, Regional Cell Imaging Platform of Normandy (PRIMACEN)

dInstitute for Research and Innovation in Biomedicine, Normandie University, Union Nationale Inter-Universitaire Rouen, Rouen

eBehavioural Analysis Platform (Service Commun d’Analyse Comportementale), Institute for Research and Innovation in Biomedicine, University of Rouen-Normandy, Normandy, France

Received 9 July 2018 Accepted as revised 23 April 2019

Correspondence to Andresa Heemann Betti, PhD, Universidade Feevale, Campus II, RS 239, 2755, CEP 93525-075 Novo Hamburgo, RS, Brazil E-mail: ahbetti@gmail.com

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