Baldev Gautam

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.

Antidepressant-like activity of 2-(4-phenylpiperazin-1-yl)-1, 8-naphthyridine-3-carboxylic acid (7a), a 5-HT3 receptor antagonist in behaviour based rodent models: Evidence for the involvement of serotonergic system

The present study was designed to investigate the putative antidepressant-like activity of 7a, a 5-HT₃ receptor antagonist, (although indirect evidence of 5-HT3 antagonism) with an optimal log P (3.35) and pA₂ value (7.6) greater than ondansetron (pA₂--6.6) using behavioural tests battery of depression. Acute treatment of 7a (0.5-2 mg/kg, i.p.) in mice produced antidepressant-like effects in forced swim test (FST) and tail suspension test (TST) without affecting the baseline locomotion in actophotometer test in mice. Moreover, the combination of a sub-effective dose of 7a (0.25 mg/kg, i.p.) and fluoxetine (5 mg/kg, i.p.) produced an anti-immobility effect in mouse FST. Pretreatment of mice with p-chlorophenylalanine methyl ester (PCPA; 100 mg/kg, i.p., an inhibitor of serotonin (5-HT) synthesis, for 4 consecutive days) and 1-(m-Chlorophenyl)-biguanide (mCPBG, 10 mg/kg, i.p., a 5-HT₃ receptor agonist) prevented the anti-immobility effects of 7a (2 mg/kg, i.p.) in the mouse FST. In addition, 7a (0.5-2 mg/kg, i.p.) treatment also potentiated the 5-hydroxytryptophan (5-HTP) and pargyline induced head twitch response in mice. Furthermore, sub-chronic treatment (14 days) with 7a (0.5-2 mg/kg, i.p.) and paroxetine (10 mg/kg, i.p.) significantly attenuated the behavioural anomalies induced by bilateral olfactory bulbectomy in rats in a modified open field paradigm. These results suggest that the antidepressant-like action of 7a may be mediated by an interaction with the serotonergic system and this molecule should be further investigated as an alternative therapeutic approach for the treatment of depression.

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.

Effect of combination of ketanserin and escitalopram on behavioral anomalies after olfactory bulbectomy: Prediction of quick onset of antidepressant action

Objectives: Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed antidepressant drugs. The addition of low dose of 5-hydroxytryptamine type 2A enhances the therapeutic effect of SSRIs. The purpose of the present studies was to test the effects of combined treatment of a low dose of ketanserin (KET) and escitalopram (ESC) on behavioral anomalies occurring after olfactory bulbectomy (OBX). Materials and Methods: Chronic Depression was induced by OBX as shown in behavioral tests such as Open field, social interaction, and hyperemotionality tests. Acute and chronic treatment effect of KET, ESC, and combination was administered to the OBX rats. Results: Chronic (14 days) treatment with KET (1 mg/kg) or ESC (10 mg/kg) alleviated the behavioral anomalies of olfactory bulbectomized rats in modified open field exploration, social interaction, hyperemotionality. When KET treatment was combined with ESC, a short duration regimen (7 days) was sufficient to reverse the bulbectomy-induced anomalies. Conclusion: The combination therapy as a likely strategy to achieve an early-onset of antidepressant action.

Evaluation of anti‑diabetic activity of methanolic extract from the bark of Atalantia monophylla (Linn.) in alloxan‑induced diabetic mice

Objective: The objective of the present study was to evaluate the anti-diabetic activity of methanolic extract from the bark of Atalantia monophylla (Linn.) in alloxan-induced diabetic mice. Materials and Methods: Diabetes was induced in mice by injection of alloxan (200 mg/kg, i.p.). Diabetic mice were divided into different groups and methanolic bark extract of Atalantia monophylla (AMMt) was administered at dose ranges of 50–200 mg/kg, p.o for 14 days. Control group received normal saline (0.9%) for 14 days. Glibenclamide (4 mg/kg, p.o) was used as standard drug. Blood samples were collected from all the groups and analysed for serum glucose and lipid levels such as total cholesterol (TC), triglyceride (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL). AMMt was also tested for oral glucose tolerance test (OGTT) in normal fasted rats. Results: AMMt (100 and 200 mg/kg, p.o) showed a significant (P<0.05) reduction of serum glucose level in alloxan-induced diabetic mice as compared with diabetic control. AMMt (100 and 200 mg/kg) also showed a significant reduction in serum TC, TG, LDL and VLDL levels in alloxan-induced diabetic mice. In addition, AMMt (100 and 200 mg/kg, p.o) significantly increased serum HDL level as compared with diabetic mice. AMMt (100 and 200 mg/kg, p.o) significantly (P<0.05) increased the glucose tolerance in OGTT. Conclusion: The results obtained from the present study revealed the potential anti-diabetic activity of methanolic extract from the bark of A. monophylla. Key words: Alloxan, anti‑diabetic, anti‑hyperlipidaemic, Atalantia monophylla