Dilip Kumar Pandey

Depression-like and anxiety-like behavioural aftermaths of impact accelerated traumatic brain injury in rats: a model of comorbid depression and anxiety?

Depression and anxiety tend to be the most prevalent conditions among the multitude of neurobehavioural disorders which cause distress in the survivors of traumatic brain injury (TBI). The objective of the present investigation was to examine depression-like and anxiety-like behaviour of rats following diffuse TBI. Impact accelerated TBI was induced in anaesthetised rats by a modified weight drop method. TBI and sham-operated rats received either a chronic (14 days) regimen of escitalopram (5-20 mg/kg) or vehicle, following which they were subjected to a behavioural test battery. The results evince the depression-like behaviour of TBI rats in modified open field exploration, hyperemotionality, socio-sexual interaction and elevated plus-maze exploration paradigms. In addition, an anxiety-like behaviour was evident in social interaction and marble-burying tests. Chronic escitalopram (10 and 20 mg/kg) treatment significantly attenuated the TBI associated behavioural deficits. In conclusion, the aforesaid behavioural anomalies observed in TBI rats are analogous to comorbid anxiety and depression in humans. These findings substantiate the TBI rats as a candidate model of comorbid anxiety and depression.

A novel 5-HT2A receptor antagonist exhibits antidepressant-like effects in a battery of rodent behavioural assays: Approaching early-onset antidepressants

Collective evidence suggests that inhibition of neuronal 5-hydroxytryptamine type 2A (5-HT(2A)) receptors contributes to the assuagement of depression-like behaviour in rodents. The present study evaluated the antidepressant-like effect of the 5-((4-benzo [alpha] isothiazol-3-yl) piperazin-1-yl) methyl)-6-chloroindolin-2-one (BIP-1), a compound having affinity to 5-HT(2A) receptors, using a rodent behavioural test battery. Acute BIP-1 (0.25-4mg/kg) pretreatment reduced the quipazine-induced head twitches in mice and produced antidepressant-like effects in mouse forced swim and tail suspension tests. BIP-1 reversed the depressogenic-like effects of meta-chlorophenyl piperazine and augmented the antidepressant-like effects of amitryptiline and harmane. Chronic (14days) treatment with BIP-1 (1 and 2mg/kg) or amitriptyline (10mg/kg) alleviated the behavioural anomalies of olfactory bulbectomised rats in modified open field exploration, social interaction, hyperemotionality and sucrose preference paradigms. When BIP-1 treatment was combined with amitryptyline, a short duration regimen (7days) was sufficient to reverse the bulbectomy induced anomalies. This investigation revealed that 5-HT(2A) receptor antagonism is the principal mechanism behind the antidepressant-like effects of BIP-1. Finally, we propound the combination of 5-HT(2A) receptor antagonists and tricyclic antidepressants as a likely strategy to achieve an early-onset of antidepressant action.

1-(m-Chlorophenyl)piperazine induces depressogenic-like behaviour in rodents by stimulating the neuronal 5-HT2A receptors: Proposal of a modified rodent antidepressant assay

1-(m-Chlorophenyl)piperazine (mCPP) has a fairly complex neuropsychopharmacological profile owing to its affinity to multiple serotonergic receptors. This investigation was designed to establish the effect of mCPP on rodent depression-like behaviour. mCPP was screened in a rodent behavioural test battery comprising of validated antidepressant assays and interaction studies with conventional antidepressants and ligands were carried out in forced swim and tail suspension test (in mice). mCPP (1 mg/kg, i.p.) exhibited depressant-like effects in forced swim and tail suspension test (in mice), without influencing the locomotor status. Potentiation of 5-hydroxytryptophan/pargyline induced head twitches (in mice) and hyperthermic effects (in rats) were observed at the same dose level. Further, the behavioural anomalies of the olfactory bulbectomised (OBX) rats were augmented by chronic mCPP (1-2 mg/kg) treatment as observed from the modified open field, elevated plus maze and social interaction paradigms. Interaction studies revealed that the mCPP induced depressant-like effects were reversed by ketanserin, escitalopram, amitriptyline, ziprasidone, venlafaxine pretreatments but not by bupropion, harmane, ondansetron, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) and MK-801. In conclusion, this study provided ample evidence that the stimulation of 5-HT(2A) receptors underlies the depressogenic-like effect of mCPP. Finally, the mCPP induced depression-like behaviour in rodents is envisaged as a modified antidepressant assay to identify novel serotonergic antidepressants.

Depressant-like effects of parthenolide in a rodent behavioural antidepressant test battery.

The anti‐serotonergic effects of parthenolide (PTL) demonstrated in platelets inspired the present psychopharmacological investigation, which employs a battery of rodent behavioural assays of depression. In mice, PTL (0.5‐2 mg kg−1) exhibited dose‐dependent depressant‐like effects in a forced swim test and a tail suspension test, without affecting the baseline locomotor status. The doses (1 and 2 mg kg−1) that induced depressant‐like effects were found to significantly reduce 5‐hydroxytrypto‐phan‐induced head twitch response. Interaction studies revealed that the depressant‐like effects of PTL (1 mg kg−1) were reversed more efficiently by serotonergic antidepressants (venlafaxine, escitalopram, citalopram, fluoxetine) than by others (desipramine, bupropion) tested. Chronic treatment of PTL (1 and 2 mg kg−1) augmented the hyper‐emotionality of olfactory bulbectomized rats, when compared with sham rats, as observed in modified open field, elevated plus maze and social interaction paradigms. This study depicts the severe depressogenic potential of PTL (in its pure form) plausibly mediated by platelet/neuronal hypo‐serotonergic effects.

Antidepressant-like effect of etazolate, a cyclic nucleotide phosphodiesterase 4 inhibitor—an approach using rodent behavioral antidepressant tests battery

Etazolate, a pyrazolopyridine class derivative is selective inhibitor of type 4 phosphodiesterase (PDE4), an enzyme catalyzes the hydrolysis of cyclic nucleotide viz. cAMP & regulates cAMP signal transduction. Enhancing cAMP signal transduction by inhibition of PDE4 is known to be beneficial in depression disorders. Thus, the present study was designed to investigate thoroughly the antidepressant potential of etazolate using rodent behavioral models of depression. Acute treatment of etazolate (0.25-1 mg/kg, i.p.) exhibited antidepressant-like effects in forced swim test (FST) & tail suspension test (TST) in mice without influencing the baseline locomotion in actophotometer test. Interaction studies of etazolate sub-effective dose (0.12 mg/kg, i.p.), were carried out with sub-effective dose of conventional antidepressants like fluoxetine (5mg/kg, i.p.), venlafaxine (4 mg/kg, i.p.) & desipramine (5 mg/kg, i.p.) in FST. Etazolate at sub-effective dose produced synergistic antidepressant-like effect with conventional antidepressants in the mouse FST. In addition, combined treatment of etazolate & conventional antidepressants had no significant effect on baseline locomotion. Moreover, etazolate (0.5 and 1 mg/kg, i.p.) increased head twitch scores in mice & antagonized the reserpine-induced hypothermia in rats. Chronic treatment (14 days) with etazolate (0.5 and 1 mg/kg, p.o.) & fluoxetine (10 mg/kg, p.o.) significantly reversed the behavioral anomalies induced by bilateral olfactory bulbectomy in rats in modified open field exploration. In conclusion, taken together, our results suggested that etazolate exhibited antidepressant-like activity in acute & chronic rodent models of depression & deserves as a therapeutic tool that could help the conventional pharmacotherapy of depression.

Discovery of new anti-depressants from structurally novel 5-HT3 receptor antagonists: design, synthesis and pharmacological evaluation of 3-ethoxyquinoxalin-2-carboxamides.

A novel series of 3-ethoxyquinoxalin-2-carboxamides were designed as per the pharmacophoric requirements of 5-HT(3) receptor antagonist using ligand-based approach. The desired carboxamides were synthesized from the key intermediate, 3-ethoxyquinoxalin-2-carboxylic acid by coupling with appropriate amines in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC·HCl) and 1-hydroxybenzotriazole (HOBt). The 5-HT(3) receptor antagonism was evaluated in longitudinal muscle myenteric plexus preparation from guinea pig ileum against 5-HT(3) agonist, 2-methy-5-HT, which was expressed in the form of pA(2) values. Compound 6h (3-ethoxyquinoxalin-2-yl)(4-methylpiperazin-1-yl)methanone was found to be the most active compound, which expressed a pA(2) value of 7.7. In forced swim test, the compounds with higher pA(2) value exhibited good anti-depressant-like activity and compounds with lower pA(2) value failed to show activity as compared to the vehicle-treated group.

Evaluation of anti-depressant-like activity of linezolid, an oxazolidinone class derivative – An investigation using behavioral tests battery of depression

Linezolid, an oxazolidinone class derivative is a reversible and nonselective inhibitor of monoamine oxidase (MAO), predominantly for MAO-A type. MAO-A is a key enzyme regulating the catabolism of catecholamine neurotransmitters in the brain. It is well known that the catecholaminergic neuronal systems are associated with depression and inhibition of MAO-A level in the brain could be used to treat depression. Hence, the objective of this study was to evaluate the anti-depressant-like effect of linezolid, a MAO-A inhibitor in the animal models of depression. In the present study, linezolid (10 & 20mg/kg, i.p.), exhibited anti-depressant-like effects in forced swim test (FST) and tail suspension test (TST) in mice without influencing the baseline locomotion. Moreover, linezolid (10 & 20mg/kg, i.p.), potentiated the 5-hydroxytryptophan (5-HTP)-induced head twitch responses in mice and antagonized the reserpine-induced hypothermia in rats. In conclusion, the behavioral investigation revealed the anti-depressant-like effect of linezolid in rodents behavioral model.

Antidepressant Potential of 5-HT3 Receptor Antagonist, N-n- propyl-3-ethoxyquinoxaline-2-carboxamide (6n)

The present study was designed to evaluate the antidepressant potential of 5-HT3 receptor antagonist N-n-propyl-3-ethoxyquinoxaline-2-carboxamide ( 6n). The compound ′ 6n′ with optimum log P and pA 2 value identified from a series of compounds synthesized in our laboratory was subjected to forced Swim Test (FST) (1, 2, and 4 mg/kg, i.p) and Tail Suspension Test (TST) (1, 2, and 4 mg/kg, i.p.). The compound ′ 6n′ significantly reduced the duration of immobility in mice without affecting the baseline locomotion. Moreover, ′ 6n′ (2 mg/kg, i.p.) potentiated the 5-hydroxytryptophan (5-HTP)-induced head twitch responses in mice and ′ 6n′ at tested dose (1 and 2 mg/kg, i.p.) reversed the reserpine-induced hypothermia in rats. In interaction studies of ′ 6n′ with various standard drugs/ligands using FST, ′ 6n′ (1 mg/kg, i.p.) potentiated the antidepressant effect of venlafaxine (4 and 8 mg/kg, i.p.) and fluoxetine (10 and 20 mg/kg, i.p.). Additionally, ′ 6n′ (1 and 2 mg/kg, i.p.) influenced the effect of harmane (5 mg/ kg, i.p.) as well as reversed the effect of parthenolide (1 mg/kg, i.p.) by reducing the duration of immobility in FST. Furthermore, ′ 6n′ (1 mg/kg, i.p.) potentiated the effect of bupropion (10 and 20 mg/kg, i.p.) in TST. Chronic ′ 6n′ (1 and 2 mg/kg, i.p.) treatment attenuated the behavioral abnormalities in olfactory bulbectomized rats. In conclusion, these various findings reiterated the antidepressant-like effects of ′ 6n′ in behavioral models of depression.

Antidepressant-like activity of (4-phenylpiperazin-1-yl) (quinoxalin-2-yl) methanone (4a), a novel 5-HT(3) receptor antagonist: an investigation in behaviour-based rodent models of depression.

Aim: The present study was designed to investigate the antidepressant potential of (4-phenylpiperazin-1-yl) (quinoxalin-3-yl) methanone (4a), a novel 5-HT3 receptor antagonist, with an optimal log P (2.84) and pA2 value (7.3) greater than ondansetron (6.9) using rodent behavioural models of depression. Materials and Methods: Swiss albino mice were used in actophotometer test, forced swim test (FST) and 5-hydroxytryptophan (5-HTP) induced head twitch response. Reserpine induced hypothermia (RIH) and olfactory bulbectomy were performed in male Wistar rats. Statistical analysis was carried out by using one-way analysis of variance followed by Tukeys test. Results: Acute treatment of 4a (1-4 mg/kg, i.p.) in mice produced antidepressant-like effects in FST without affecting the baseline locomotion in actophotometer test. Further, 4a (2-4 mg/kg, i.p.) potentiated the 5-HTP induced head twitches response in mice and also antagonized RIH in rats. Furthermore, sub-chronic (14 days) treatment with 4a (2-4 mg/ kg, p.o.) significantly attenuated the behavioural anomalies induced by bilateral olfactory bulbectomy in rats in modified open field exploration. Conclusions: These preliminary investigations confirm that 4a exhibits antidepressant-like activity in behaviour based rodent models of depression.

Ligand-based design, synthesis, and pharmacological evaluation of 3-Methoxyquinoxalin-2-carboxamides as structurally novel serotonin type-3 receptor antagonists.

Employing a ligand‐based approach, 3‐methoxyquinoxalin‐2‐carboxamides were designed as serotonin type‐3 (5‐HT3) receptor antagonists and synthesized from the starting material o‐phenylenediamine in a sequence of reactions. The structures of the synthesized compounds were confirmed by spectral data. These carboxamides were investigated for their 5‐HT3 receptor antagonisms in longitudinal muscle myenteric plexus preparations from guinea‐pig ileum against a standard 5‐HT3 agonist, 2‐methy‐5‐HT, and their antagonism activities are expressed as pA2 values. Compounds 6a (pA2: 7.2), 6e (pA2: 7.0), 6f (pA2: 7.5), 6g (pA2: 7.5), 6n (pA2: 7.0), and 6o (pA2: 7.2) exhibited antagonism greater than that of the standard 5‐HT3 antagonist, ondansetron (pA2: 6.9).