Monu Yadav

Potential drug targets and treatment of schizophrenia

Schizophrenia is one of the most prevalent chronic psychiatric disorders that affect 1% of the world’s population. Despite its societal burden, pathophysiology of schizophrenia remains poorly understood. Currently available drugs predominantly control positive symptoms, and often have no or poor control on negative and related cognitive symptoms, which strongly affect functional outcome in schizophrenia. The present article is an attempt to provide a critical review of recent hypothesis to understand pathophysiology of schizophrenia and to highlight exploitable molecular drug targets other than dopaminergic systems to treat and manage schizophrenia effectively.

Evaluation of antipsychotic effect of methanolic extract of Ocimum sanctum leaves on laboratory animals

Ocimum sanctum (Lamiaceae) commonly known as tulsi, is well known for its excellent nutritional and medicinal values throughout the world. The present study was undertaken to test the effect of methanolic extract of Ocimum sanctum leaves (50, 100 and 200mg/kg, p.o) on psychosis employing Ketamine induced stereotypic behaviour in mice and Pole climbing avoidance in rats. Haloperidol (1mg/kg, i.p.) and Olanzapine (5mg/kg, i.p.) are established antipsychotic drugs used as standard drugs in the present study. Effect of methanolic extract of Ocimum sanctum leaves (OS), on brain dopamine levels was also estimated. Methanolic extract of Ocimum sanctum leaves (50, 100 and 200mg/kg, p.o), significantly reduced the Ketamine induced falling, weaving, head bobbing and turning behavior in mice. Furthermore, it significantly delayed the latency time taken by the rats to climb the pole. Haloperidol (1mg/kg; i.p.) and Olanzapine (5mg/kg, i.p.) significantly reduced the Ketamine induced stereotypic behavior in mice and condition avoidance behavior in rats. Interestingly, Brain dopamine level was significantly reduced by methanolic extract of Ocimum sanctum leaves. These findings, when taken together indicate that methanolic extract of Ocimum sanctum leaves possesses anti-psychotic like property.

Brain targeted oral delivery of doxycycline hydrochloride encapsulated Tween 80 coated chitosan nanoparticles against ketamine induced psychosis: behavioral, biochemical, neurochemical and histological alterations in mice

Abstract To develop statistically optimized brain targeted Tween 80 coated chitosan nanoparticulate formulation for oral delivery of doxycycline hydrochloride for the treatment of psychosis and to evaluate its protective effect on ketamine induced behavioral, biochemical, neurochemical and histological alterations in mice. 32 full factorial design was used to optimize the nanoparticulate formulation to minimize particle size and maximize entrapment efficiency, while independent variables chosen were concentration of chitosan and Tween 80. The optimized formulation was characterized by particle size, drug entrapment efficiency, Fourier transform infrared, Transmission electron microscopy analysis and drug release behavior. Pure doxycycline hydrochloride (25 and 50 mg/kg, p.o.) and optimized doxycycline hydrochloride encapsulated Tween 80 coated chitosan nanoparticles (DCNPopt) (equivalent to 25 mg/kg doxycycline hydrochloride, p.o.) were explored against ketamine induced psychosis in mice. The experimental studies for DCNPopt, with mean particle size 237 nm and entrapment efficiency 78.16%, elucidated that the formulation successfully passed through blood brain barrier and exhibited significant antipsychotic activity. The underlying mechanism of action was further confirmed by behavioral, biochemical, neurochemical estimations and histopathological study. Significantly enhanced GABA and GSH level and diminished MDA, TNF-α and dopamine levels were observed after administration of DCNPopt at just half the dose of pure doxycycline hydrochloride, showing better penetration of doxycyline hydrochloride in the form of Tween 80 coated nanoparticles through blood brain barrier. This study demonstrates the hydrophilic drug doxycycline hydrochloride, loaded in Tween 80 coated chitosan nanoparticles, can be effectively brain targeted through oral delivery and therefore represents a suitable approach for the treatment of psychotic symptoms.

Protective effects of stigmasterol against ketamine‐induced psychotic symptoms: Possible behavioral, biochemical and histopathological changes in mice

BACKGROUND Stigmasterol, a naturally occurring phytoestrogen has been reported to possess many pharmacological activities. The aim of the present study was to screen the effect of stigmasterol against ketamine-induced mice model of psychosis. METHODS The behavioural studies included an assessment of locomotor activity, stereotypic behaviours, immobility duration, step down latency and effects on catalepsy. Biochemical estimations involved the estimations of GABA, dopamine, GSH, MDA, TNF-α, total protein content and AChE activity. Histopathological changes and effect on androgenic parameters were also evaluated. RESULTS Stigmasterol treated animals showed significant decrease in locomotor activity, stereotypic behaviours, immobility duration and increased step down latency. Biochemical estimations revealed increased GABA, GSH levels and decreased dopamine, MDA, TNF-α levels and AChE activity. These findings were confirmed by histopathological changes in the cortex part of the brain. Further, stigmasterol was not found to cause catalepsy and any adverse effect on the reproductive system. CONCLUSION This study concluded that stigmasterol could ameliorate ketamine-induced behavioral, biochemical and histopathological alterations in mice showing its potential effects in the management of psychotic symptoms.

Potential effect of spermidine on GABA, dopamine, acetylcholinesterase, oxidative stress and proinflammatory cytokines to diminish ketamine-induced psychotic symptoms in rats

Ketamine, N-methyl-d-aspartate receptor antagonist has been implanted in such behavioural and biochemical alterations in animals similar to human psychosis. Spermidine, a biogenic polyamine, involved in various cellular functions in living organisms, on the contrary possess NMDA receptor agonistic effect. Therefore, we aimed to study the effect of spermidine (10 and 20 mg/kg, i.p.) in ketamine (50 mg/kg, i.p.) induced psychotic symptoms using various behavioural animal models. Biochemical assays were done to confirm the molecular pathways associated with spermidine and psychosis. Spermidine was significant to alleviate the ketamine-induced psychotic symptoms as indicated by decrease in locomotor activity in actophotometer, stereotypic behaviours, immobility duration in force swim test and latency to climb the pole in pole climb avoidance test. Interestingly, spermidine significantly decreased acetylcholinesterase (AChE) activity, serum tumor necrosis factor (TNF-α), dopamine and malondialdehyde (MDA) level while increased gamma-amino butyric acid and reduced glutathione (GSH) level in different regions of brain. Spermidine did not produce cataleptic effect on bar test at lower dose, but at the higher dose its cataleptic effect was similar to haloperidol. Based on behavioural and biochemical results, present study revealed spermidine as a promising antipsychotic biomolecule, however, its cataleptic effect at higher doses must be ruled out before use in clinical settings.

Protective effects of Spinacia oleracea seeds extract in an experimental model of schizophrenia: Possible behavior, biochemical, neurochemical and cellular alterations

Schizophrenia is one of the psychotic mental disorders characterized by symptoms of thought, behavior, and social problems. Newer biomedicine and pharmacotherapy has been investigated for the treatment of various neuropsychiatric disorders in the past few decades. Spinacia oleracea is one of these, reported to have beneficial effect against several neurodegenerative disorders. The present study was carried to explore the protective effects of Spinacia oleracea seed extract (SOEE) in an experimental model of ketamine-induced schizophrenia in mice. Ketamine (50 mg/kg, i.p.) was used to induce stereotyped psychotic behavioural symptoms in mice. Behavioral studies (locomotor activity, stereotype behaviors, immobility duration and memory retention) were carried out to investigate the protective of SOEE on ketamine-induced psychotic symptoms, followed by biochemical, neurochemical and cellular alterations in the brain. Treatment with SOEE for 15 consecutive days significantly attenuated stereotyped behavioral symptoms in mice. Biochemical estimations revealed that SOEE reduced lipid peroxidation and restored total brain proteins. Furthermore, SOEE remarkably reduced dopamine levels, AChE activity & inflammatory surge (serum TNF-α) and increased the levels of GABA and reduced glutathione in mice. The outcomes of the study suggested that SOEE could ameliorate ketamine-induced psychotic symptoms in mice, indicating a protective effect in the treatment of schizophrenia.

Standardisation and Validation of Acute and Chronic Administration Ketamine at Different Doses to Produce Psychosis Like Behavioural Changes in Mice

Psychosis is a complex mental illness, characterised by positive, negative and cognitive symptoms. NMDA receptor antagonists have been established to induce behavioural as well as biochemical changes in rodents similar to psychotic patients. The aim of the present study was to investigate the effective dose and treatment period of ketamine to induce some behavioural changes. The results suggest that acute treatment of ketamine (50 and 100 mg/kg, i.p.) induced hyperlocomotor activity and reduced step down latency time in passive avoidance test, whereas in effective in forced swim test. Further, with the chronic administration of ketamine (50 and 100 mg/kg, i.p.) effective to produced hyperlocomotor activity, reduced the step down latency time in passive avoidance test and enhanced the immobility duration in forced swim test. Moreover, these behavioural changes persisted for 7 days after the treatment period. Thus, our findings suggest that the chronic administration of Ketamine (50 and 100 mg/kg, i.p.) potential to produce behavioural changes, would serve as an effective tool to screen antipsychotic drugs.