Evaluation of the potential toxicity of haloperidol, clozapine and a new putative antipsychotic molecule, PT-31, in an alternative toxicity model, C. elegans

Schizophrenia is a disabling mental illness that affects approximately 1% of the world population. The treatment of this disorder is based on two generations of substances, typical antipsychotics, such as haloperidol, and atypical antipsychotics, such as clozapine, which can cause severe adverse effects. Therefore, the development of novel molecules that are safe and efficacious to treat the disease is crucial. PT-31 is a putative α2-adrenoceptor agonist effective against schizophrenia positive and cognitive symptoms in mice. C. elegans is an alternative model that has been successfully used to investigate the toxicity of a variety of substances. The present study aimed to evaluate the potential toxicity of the new molecule PT-31 and the antipsychotics haloperidol and clozapine in C. elegans. The evaluation was carried out based on toxicity endpoint tests, survival, developmental and behavioral assays. The antipsychotics haloperidol and clozapine decreased nematode survival by 30 and 40%, respectively, exposing the potential toxicity of these substances whereas PT-31 was safer based on this parameter. Similar results were obtained in the nematode developmental assay: haloperidol and clozapine significantly reduced nematode body length and area, whereas PT-31 preserved the normal development of the nematodes. The behavioral assessment was based on the frequency of body bends; none of the antipsychotics affected the locomotion rate of the nematodes, and PT-31 also did not compromise this parameter, demonstrating the safety of this new compound and reinforcing the recognized toxicity of antipsychotics