thiourea and Schizophrenia

Disruption of oxidant/anti-oxidant ratio as well as endoplasmic reticulum (ER) stress are thought to be involved in the pathophysiology of schizophrenia. These stresses can lead to impairments in brain functions progressively leading to neuronal inflammation followed by neuronal cell death. Moreover, the cellular stresses are interlinked leading us to the conclusion that protein misfolding, oxidative stress and apoptosis are intricately intertwined events requiring further research into their mechanistic and physiological pathways. These pathways can be targeted by using different therapeutic interventions like anti-oxidants, sigma-1 receptor agonists and gene therapy to treat the neurodegenerative course of schizophrenia. We have also put empahsis on use of synthetic and natural ER stress inhibitors like 4-phenylbutyrate or salubrinal for the treatment of this disorder. This would provide an opportunity to create new therapeutic benchmarks in the field of neuropsychiatric disorders like schizophrenia, dissociative identity disorder and obsessive compulsive disorder.

Topics: Cinnamates; Endoplasmic Reticulum Stress; Humans; Molecular Chaperones; Oxidative Stress; Phenylbutyrates; Schizophrenia; Thiourea

Animal models based on N-methyl-d-aspartate receptor blockade have been extensively used for schizophrenia. Ketamine and MK-801 produce behaviors related to schizophrenia and exacerbated symptoms in patients with schizophrenia, which led to the use of PCP (phencyclidine)- and MK-801 (dizocilpine)-treated animals as models for schizophrenia.. The study investigated the effect of subchronic dosing (once daily, 7 days) of histamine H3 receptor (H3R) antagonists, ciproxifan (CPX) (3 mg/kg, i.p.), and clobenpropit (CBP) (15 mg/kg, i.p.) on MK-801 (0.2 mg/kg, i.p.)-induced locomotor activity and also measured dopamine and histamine levels in rat's brain homogenates. The study also included clozapine (CLZ) (3.0 mg/kg, i.p.) and chlorpromazine (CPZ) (3.0 mg/kg, i.p.), the atypical and typical antipsychotic, respectively.. Atypical and typical antipsychotic was used to serve as clinically relevant reference agents to compare the effects of the H3R antagonists. MK-801 significantly increased horizontal locomotor activity, which was reduced with CPX and CBP. MK-801-induced locomotor hyperactivity attenuated by CPX and CBP was comparable to CLZ and CPZ. MK-801 raised striatal dopamine level, which was reduced in rats pretreated with CPX and CBP. CPZ also significantly lowered striatal dopamine levels, although the decrease was less robust compared to CLZ, CPX, and CBP. MK-801 increased histamine content although to a lesser degree. Subchronic treatment with CPX and CBP exhibited further increased histamine levels in the hypothalamus compared to MK-801 treatment alone. Histamine H3 receptor agonist, R-α methylhistamine (10 mg/kg, i.p.), counteracted the effect of CPX and CBP.. The present study shows the positive effects of CPX and CBP on MK-801-induced schizophrenia-like behaviors in rodents.

Topics: Animals; Antipsychotic Agents; Behavior, Animal; Disease Models, Animal; Dizocilpine Maleate; Histamine; Histamine H3 Antagonists; Imidazoles; Methylhistamines; Motor Activity; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Schizophrenia; Thiourea

Schizophrenia (SCZ) afflicts around 1% of the world's population with characteristic symptoms such as hallucinations, delusions, and cognitive disorders. Several experimental studies in the past have indicted brain histaminergic neuronal system involvement in the pathogenesis of psychotic disorders including SCZ. Present study investigates anti-schizophrenic activity using two histamine H(3)-receptor (H(3)R)-antagonists/inverse agonists, ciproxifan (3.0 mg/kg, i.p.) and clobenpropit (15 mg/kg, i.p.), on some of the established animal model of schizophrenia, for example, amphetamine (AMPH) and dizocilpine (MK-801)-induced hyperactivity, apomorphine (APO)-induced climbing behavior, scopolamine and MK-801-induced learning and memory deficits and haloperidol-induced catalepsy including determination of acetylcholinesterase (AChE) activity. Results of the present study demonstrate that ciproxifan and clobenpropitwere able to control AMPH and MK-801-induced hyperlocomotor activities demonstrated as reduced horizontal activity and reduced number of movements made by rats. Further, there was overall reduction in APO-induced climbing behavior. Learning and memory deficits, as evaluated on elevated plus maze, followed by estimation of brain AChE activity demonstrated positive results with these protypical imidazole H(3)R-antagonists/inverse agonists.

Topics: Acetylcholinesterase; Animals; Behavior, Animal; Brain; Catalepsy; Female; Histamine Antagonists; Imidazoles; Learning Disabilities; Ligands; Male; Memory Disorders; Mice; Motor Activity; Rats; Rats, Wistar; Receptors, Histamine H3; Schizophrenia; Thiourea

The role of histamine neurons in schizophrenia and psychostimulant abuse remains unclear. Behavioural sensitization to psychostimulants is a cardinal feature of these disorders. Here, we have explored the ability of imetit and ciproxifan (CPX), a reference H₃-receptor agonist and inverse agonist, respectively, to modulate locomotor sensitization induced in mice by methamphetamine (MET). Mice received saline, CPX (3 mg/kg) or imetit (3 mg/kg) 2 h before MET (2 mg/kg), once daily for 12 days, and were killed after a 2-day wash out. Imetit had no effect, but CPX induced a decrease of MET-induced locomotor activity, which became significant at Day 5, and even more at Day 10. Quantitative polymerase chain reaction was used in the sensitized mice to quantify brain-derived neurotrophic factor (BDNF) and N-methyl-D-aspartate (NMDA)-receptor subunit 1 (NR1) mRNAs, two factors that are altered in both schizophrenia and drug abuse. Imetit and CPX used alone had no effect on any marker. Sensitization by MET decreased BDNF mRNAs by 40% in the hippocampus. This decrease was reversed by CPX. Sensitization by MET also induced strong decreases of NR1 mRNAs in the cerebral cortex, hippocampus and striatum, but not hypothalamus. These decreases were also reversed by CPX. The strong modulator effect of CPX in mice sensitized to MET may result from its modulator effect on NR1 mRNAs in the cerebral cortex and striatum. The reversal by CPX of BDNF and NR1 mRNAs in the hippocampus of sensitized animals further strengthens the interest of H₃-receptor inverse agonists for the long-term treatment of cognitive deficits of patients with schizophrenia.

Topics: Animals; Behavior, Animal; Brain; Brain-Derived Neurotrophic Factor; Central Nervous System Stimulants; Histamine Agonists; Histamine H3 Antagonists; Humans; Imidazoles; Male; Methamphetamine; Mice; Motor Activity; Receptors, N-Methyl-D-Aspartate; Schizophrenia; Thiourea