Drug Discovery from Peruvian Medicinal Plants for the Treatment of Psychosis

Abstract

BackgroundSchizophrenia is a severe mental disorder that affects approximately 1% of the population. The main symptom is psychosis in which thought and emotions are impaired. Current pharmacological treatments for schizophrenia are partially effective and its long term intake causes side effects. In Peru, native communities since ancient times have considered the psychosis like “madness” and they have treated it using preparations from natural products. The Peruvian traditional medicine is a potential source of drugs because its effectiveness, possible low side effects and they could be acting on different molecular mechanisms compared to the current drugs on the market.AimIn this work, as a part of drug discovery process, we tested compounds‐containing fractions from four ethanolic extracts (EEs) on psychosis animal model, mammalian cells and receptors altered in mental diseases.MethodsWe carried out the separation of compounds‐containing fractions from EEs 1, 2, 3 and 4 based on solubility using medium pressure liquid chromatography. The selection of each fraction was based on thin layer chromatography profile. These fractions were tested in mice treated with MK‐801 (N‐methyl D‐aspartate receptor antagonist) to induce psychosis‐like symptoms. We used the open field test (OFT) to measure the hyperactivity over a period of time and prepulse inhibition (PPI) test to measure the startle response. Cytotoxicity assays were performed in mammalian cells to determine the IC50 using the sulforhodamine B method. Moreover, we determined for the EEs, functional and binding assays on a panel of receptors altered in mental diseases.ResultsFour compounds‐containing fractions (A, B, C and D) were obtained for each EE. In behavioural tests, the fraction A, C and D of EE1, the fraction A and B of EE2 suppressed psychosis‐like symptoms in OFT (p <0.001) and PPI test. Fraction C and D of EE3 only showed an effect on PPI test and all fractions of EE4 were not active neither in the OFT nor in the PPI test. The IC50 for each EE was >0. 01563mg/ml. Finally, functional and binding assays indicates that the four EEs have an effect on serotonin, dopamine, glutamate, adenosine receptors.ConclusionWe obtained potential antipsychotic compounds‐containing fractions as initial stage of drug discovery from four EE of medicinal plants used for the treatment psychotic‐like symptoms. The four EE has an effect on receptors altered in this disease suggesting an effect on signalling pathways altered in psychosis. Therefore, purification and structure elucidation of the active(s) molecule(s) will help us to better understanding of the molecular mechanism by which they are doing their antipsychotic effect.Support or Funding InformationNational Council of science of technology (CONCYTEC) through CIENCIACTIVA and Universidad Peruana Cayetano Heredia.