Manavi Chatterjee

Discovery and synthesis of novel 3-phenylcoumarin derivatives as antidepressant agents

A series of 3-phenylcoumarins were synthesized and screened for potential antidepressant activity by tail suspension test (TST) in mice. Three compounds (6, 7 and 13) exhibited impressive antidepressant activity, measured in terms of percentage decrease in immobility duration (% DID). In addition, the active antidepressant compounds were subsequently studied at their most effective dose and activity of these compounds were confirmed in forced swimming test (FST) animal model, in which the compounds at a low dose of 0.5 mg/kg significantly decreased the immobility time and exhibited greater efficacy than the reference standards fluoxetine and imipramine. The potent compounds did not show any neurotoxicity in the rotarod test and the preliminary results are promising enough to warrant further studies around this scaffold.

Inhibitor of the Tyrosine Phosphatase STEP Reverses Cognitive Deficits in a Mouse Model of Alzheimer's Disease

This study identifies an unusual sulfur-based chemical as a novel and specific inhibitor of the tyrosine phosphatase STEP and shows that it can improve the cognitive function of a mouse model of Alzheimers disease.

Antidepressant and anxiolytic effects of amentoflavone isolated from Cnestis ferruginea in mice

The root decoction of Cnestis ferruginea (CF) Vahl DC (Connaraceae) is used in traditional African medicine in the management of psychiatric disorders. This study presents the antidepressant and anxiolytic effects of amentoflavone (CF-2) isolated from the root extract of C. ferruginea. The antidepressant effect was studied using the forced swimming (FST) and tail suspension tests (TST) while the hole-board, elevated plus maze (EPM) and light/dark tests were used to evaluate the anxiolytic effect. Acute treatment with CF extract and amentoflavone significantly (p<0.001) reduced the duration of immobility in FST and TST with peak effects observed at 100 and 50mg/kg respectively in comparison to control treated. Antidepressant effects of CF and amentoflavone were significantly higher (p<0.05) when compared to imipramine in FST but comparable to the fluoxetine treated group in TST. The pretreatment of mice with metergoline (4mg/kg, i.p., a 5-HT2 receptor antagonist), prazosin (62.5μg/kg, i.p., an α1-adrenoceptor antagonist), and yohimbine (1mg/kg, i.p., an α2-adrenoceptor antagonist), but not sulpiride (50mg/kg, i.p., a dopamine D2 receptor antagonist), cyproheptadine (3mg/kg, i.p., a 5-HT2 receptor antagonist), atropine (1mg/kg, i.p., a muscarinic receptor antagonist) 15mins before the administration of amentoflavone (50mg/kg; p.o.) significantly prevented its antiimmobility effect in the FST. CF extract and CF-2 significantly (p<0.05) attenuated anxiety by increasing the number of head-dips in the hole-board test, the time spent on the open arms in the EPM, and the exploration of the light chamber in the light/dark test. Pretreatment with flumazenil (3mg/kg, i.p., ionotropic GABA receptor antagonist) 15min before oral administration of amentoflavone (25mg/kg) significantly reduced the time spent in the open arms in EPM. It is concluded from the results obtained that amentoflavone produces its antidepressant effect through interaction with 5-HT2 receptor and α1-, and α2-adrenoceptors while the anxiolytic effect involved the ionotropic GABA receptor.

Sir-2.1 modulates ‘calorie-restriction-mediated’ prevention of neurodegeneration in Caenorhabditis elegans: Implications for Parkinson’s disease

The phenomenon of aging is known to modulate many disease conditions including neurodegenerative ailments like Parkinsons disease (PD) which is characterized by selective loss of dopaminergic neurons. Recent studies have reported on such effects, as calorie restriction, in modulating aging in living systems. We reason that PD, being an age-associated neurodegenerative disease might be modulated by interventions like calorie restriction. In the present study we employed the transgenic Caenorhabditis elegans model (P(dat-1)::GFP) expressing green fluorescence protein (GFP) specifically in eight dopaminergic (DA) neurons. Selective degeneration of dopaminergic neurons was induced by treatment of worms with 6-hydroxy dopamine (6-OHDA), a selective catecholaminergic neurotoxin, followed by studies on effect of calorie restriction on the neurodegeneration. Employing confocal microscopy of the dopaminergic neurons and HPLC analysis of dopamine levels in the nematodes, we found that calorie restriction has a preventive effect on dopaminergic neurodegeneration in the worm model. We further studied the role of sirtuin, sir-2.1, in modulating such an effect. Studies employing RNAi induced gene silencing of nematode sir-2.1, revealed that presence of Sir-2.1 is necessary for achieving the protective effect of calorie restriction on dopaminergic neurodegeneration. Our studies provide evidence that calorie restriction affords, an sir-2.1 mediated, protection against the dopaminergic neurodegeneration, that might have implications for neurodegenerative Parkinsons disease.

Comparative evaluation of forced swim test and tail suspension test as models of negative symptom of schizophrenia in rodents.

Previous studies have shown that the administration of NMDA antagonist can induce negative symptoms of schizophrenia which can be tested through the enhanced immobility observed in the forced swim test (FST). In the present study, we have compared the effects of acute as well as chronic administration of a noncompetitive NMDA receptor antagonist, ketamine on FST, and another behaviour despair model, tail suspension test (TST). Our observations suggest that chronic ketamine administration induced a state of enhanced immobility in FST, but such findings were not replicated in the TST model. Further, in FST, treatment with clozapine reverses the ketamine-induced immobility in mice, whereas it enhances the immobility duration in the TST model. However, haloperidol showed no protective effects in both models. The data suggests that although both of these tests show common behavioural measure of feeling despair, however, the underlying pathophysiology seems to be different. Hence, forced swim test but not tail suspension test can be used as a model of negative symptom of psychosis in mice.

Evaluation of ethanol leaf extract of Ocimum sanctum in experimental models of anxiety and depression.

Context: Recent studies reveal the co-occurrence of both anxiety and depressive disorders in many clinical conditions, which has introduced the concept of mixed anxiety and depressive disorders (MADD). Objective: The study evaluated the ethanol leaf extract of Ocimum sanctum (OS) Linn. (Labiatae), a prominent medicinal plant, against both anxiety and depressive disorder, to evaluate its potency in combating MADD. Materials and methods: Swiss albino mice weighing 20–25 g were used. Gross behavior was observed through Digiscan animal activity monitor. Depression was studied through tail suspension test (TST) and forced swim test (FST). Anxiety experiments included light dark test, elevated plus maze test, and holeboard test. Further, rotarod test was also used to study any defects in motor coordination. Discussion and conclusion: OS at 200 mg/kg showed motor-depressant activity as evaluated with locomotor activity and stereotypy measures. OS at 50 mg/kg shortened the immobility time in the TST and FST, respectively, indicating a possible antidepressant activity. Further, a diminution in the anxiety response at a dose of 50 mg/kg, p.o. body weight was also observed against light dark, elevated plus maze, and holeboard tests, which signifies its antianxiety activity. No defects were observed in the motor coordination of the mice in the rotarod test. Thus, the OS extract shows antianxiety and antidepressant properties at the same dose and can be a potential therapeutic agent against mixed anxiety and depressive syndrome.

Substrate-Based Fragment Identification for the Development of Selective, Nonpeptidic Inhibitors of Striatal-Enriched Protein Tyrosine Phosphatase

High levels of striatal-enriched protein tyrosine phosphatase (STEP) activity are observed in a number of neuropsychiatric disorders such as Alzheimers disease. Overexpression of STEP results in the dephosphorylation and inactivation of many key neuronal signaling molecules, including ionotropic glutamate receptors. Moreover, genetically reducing STEP levels in AD mouse models significantly reversed cognitive deficits and decreased glutamate receptor internalization. These results support STEP as a potential target for drug discovery for the treatment of Alzheimers disease. Herein, a substrate-based approach for the discovery and optimization of fragments called substrate activity screening (SAS) has been applied to the development of low molecular weight (<450 Da) and nonpeptidic, single-digit micromolar mechanism-based STEP inhibitors with greater than 20-fold selectivity across multiple tyrosine and dual specificity phosphatases. Significant levels of STEP inhibition in rat cortical neurons are also observed.

Aspm knockout ferret reveals an evolutionary mechanism governing cerebral cortical size

The human cerebral cortex is distinguished by its large size and abundant gyrification, or folding. However, the evolutionary mechanisms that drive cortical size and structure are unknown. Although genes that are essential for cortical developmental expansion have been identified from the genetics of human primary microcephaly (a disorder associated with reduced brain size and intellectual disability)1, studies of these genes in mice, which have a smooth cortex that is one thousand times smaller than the cortex of humans, have provided limited insight. Mutations in abnormal spindle-like microcephaly-associated (ASPM), the most common recessive microcephaly gene, reduce cortical volume by at least 50% in humans2–4, but have little effect on the brains of mice5–9; this probably reflects evolutionarily divergent functions of ASPM10,11. Here we used genome editing to create a germline knockout of Aspm in the ferret (Mustela putorius furo), a species with a larger, gyrified cortex and greater neural progenitor cell diversity12–14 than mice, and closer protein sequence homology to the human ASPM protein. Aspm knockout ferrets exhibit severe microcephaly (25–40% decreases in brain weight), reflecting reduced cortical surface area without significant change in cortical thickness, as has been found in human patients3,4, suggesting that loss of ‘cortical units’ has occurred. The cortex of fetal Aspm knockout ferrets displays a very large premature displacement of ventricular radial glial cells to the outer subventricular zone, where many resemble outer radial glia, a subtype of neural progenitor cells that are essentially absent in mice and have been implicated in cerebral cortical expansion in primates12–16. These data suggest an evolutionary mechanism by which ASPM regulates cortical expansion by controlling the affinity of ventricular radial glial cells for the ventricular surface, thus modulating the ratio of ventricular radial glial cells, the most undifferentiated cell type, to outer radial glia, a more differentiated progenitor.In a ferret model, the microcephaly-associated gene Aspm regulates cortical expansion by controlling the transition of ventricular radial glial cells to more differentiated cell types.

Antipsychotic activity of standardized Bacopa extract against ketamine-induced experimental psychosis in mice: Evidence for the involvement of dopaminergic, serotonergic, and cholinergic systems

Abstract Context: Schizophrenia is a chronic disabling psychiatric disorder affecting 1% of the population worldwide. Due to the adverse effects of available antipsychotic medications, recent investigations have focused on the search for well-tolerated, safe molecules from natural resources to control the severity and progression of schizophrenia. Objective: To screen the standardized extract of Bacopa monniera Linn. (Scrophulariaceae) (BM) for its antipsychotic potential in the ketamine-induced psychosis model with mice. Materials and methods: Graded dose of BM (40, 80, and 120 mg/kg, p.o.) were given to the mice 1 h prior to ketamine administration and tested for positive symptoms and cognitive deficits. A chronic ketamine treatment regimen was used to study the effect of BM on negative symptoms such as immobility enhancement. Each mouse was used once for the behavioral studies. Results: BM reduced ketamine-induced hyperactivity with an EC50 value of 76.60 mg/kg. The 80 mg/kg dose was used for all other behavior analysis. Pretreatment with BM at 80 mg/kg showed two-fold increases in transfer latency time (TLT) in passive avoidance task. Chronic BM pretreatment (80 mg/kg p.o. daily × 10 d) ameliorated the ketamine-induced enhanced immobility effect by 21% in the forced swim test. BM treatment reversed ketamine-induced increase in monoamine oxidase activity in both cortex and striatum and normalized the acetylcholinesterase activity and the glutamate levels in the hippocampus. Discussion and conclusion: Overall our findings suggest that BM possesses antipsychotic properties which might be due to its modulatory action on dopamine, serotonin, and glutamate neurotransmission.

STEP inhibition reverses behavioral, electrophysiologic, and synaptic abnormalities in Fmr1 KO mice

ABSTRACT Fragile X syndrome (FXS) is the leading cause of inherited intellectual disability, with additional symptoms including attention deficit and hyperactivity, anxiety, impulsivity, and repetitive movements or actions. The majority of FXS cases are attributed to a CGG expansion that leads to transcriptional silencing and diminished expression of fragile X mental retardation protein (FMRP). FMRP, an RNA binding protein, regulates the synthesis of dendritically‐translated mRNAs by stalling ribosomal translation. Loss of FMRP leads to increased translation of some of these mRNAs, including the CNS‐specific tyrosine phosphatase STEP (STriatal‐Enriched protein tyrosine Phosphatase). Genetic reduction of STEP in Fmr1 KO mice have diminished audiogenic seizures and a reversal of social and non‐social anxiety‐related abnormalities. This study investigates whether a newly discovered STEP inhibitor (TC‐2153) could attenuate the behavioral and synaptic abnormalities in Fmr1 KO mice. TC‐2153 reversed audiogenic seizure incidences, reduced hyperactivity, normalized anxiety states, and increased sociability in Fmr1 KO mice. Moreover, TC‐2153 reduced dendritic spine density and improved synaptic aberrations in Fmr1 KO neuronal cultures as well as in vivo. TC‐2153 also reversed the mGluR‐mediated exaggerated LTD in brain slices derived from Fmr1 KO mice. These studies suggest that STEP inhibition may have therapeutic benefit in FXS. HIGHLIGHTSSTEP inhibitor, TC‐2153 rescues the core behavioral symptoms in FXS.STEP inhibition rescues the abnormalities in dendritic spines in FXS.STEP is involved in mGluR mediated exaggerated LTD in FXS.