Apocynin-tandospirone derivatives demonstrate antioxidant properties in the animal model of schizophrenia

Antipsychotic medications based on the dopamine hypothesis possess limited effects for negative symptoms and cognitive impairments of schizophrenia. Growing body of evidence suggests that redox dysregulation contributes to the pathophysiology of the illness. We synthesized new chemicals using apocynin and tandospirone as leading compounds, and tested their antioxidant properties. The new compounds (A-1, A-2, A-3, and A-4), olanzapine (OLA), and clozapine (CLZ) were examined in terms of the ⋅OH radical decreasing activity and the effects on intracellular reactive oxygen species (ROS) formation induced by X-irradiation in human lymphoma U937 cells. The effects of these drugs, given around the period of puberty (postnatal days; PD 49 to 62), on glutathione (GSH) levels, as well as the number of parvalbumin (PV)-positive γ-aminobutyric acid (GABA) interneurons were evaluated in the medial prefrontal cortex (mPFC) of rats transiently exposed to MK-801 in the neonatal period. A-2, A-3, A-4, OLA, and CLZ decreased intracellular ⋅OH and OCl−. The novel compounds reversed the decrease in GSH concentrations and reduction of PV-positive neurons in the mPFC in the model rats. CLZ only decreased GSH levels while OLA did not show a significant effect on either measure. These findings suggest that the new compounds derived from apocynin and tandospirone elicit antioxidant properties, and may provide a novel therapeutic approach for the treatment of schizophrenia and its spectrum disorders.