Protocatechuic acid attenuates chronic unpredictable mild stress induced-behavioral and biochemical alterations in mice.

Amelioration of oxidative stress via promoting the endogenous antioxidant system and enhancement of monoamines in brain were the important underlying antidepressant mechanism of protocatechuic acid (PCA). The aim of the present study is to explore the potential antidepressant mechanism(s) PCA in chronic unpredictable mild stress (CUMS) mice. Mice were subjected to CUMS protocol for 4 weeks, and administered with PCA (100 and 200 mg/kg) and fluoxetine (20 mg/kg) for 24 days (from day 8th to 31st). Behavioral (sucrose preference, immobility time, exploratory behavior), and biochemical alterations such as serum corticosterone, brain derived neurotrophic factor (BDNF), inflammatory cytokines, tumor necrosis factor- α (TNF-α), interleukin-6 (IL-6), and antioxidants parameters were investigated. Experimental findings revealed that CUMS subjected mice exhibited significant impairment in behavioral alterations, such as increased immobility time, impaired preference to the sucrose solution, BDNF levels and, serum corticosterone, cytokines, malondialdehyde (MDA) formation with impaired antioxidants in the hippocampus and cerebral cortex. Administration of PCA to CUMS mice attenuated the immobility time, serum corticosterone, cytokines TNF-α, and IL-6, MDA formation and improved sucrose preference, including restoration of BDNF level. Thus, the present findings demonstrated the antidepressant potential of PCA which is largely achieved probably through maintaining BDNF level, and by modulation of the oxidative stress response, cytokines systems, and antioxidant defense system in mice.

Protocatechuic acid attenuate depressive-like behavior in olfactory bulbectomized rat model: behavioral and neurobiochemical investigations.

The main objective of the present study is to investigate potential effects of PCA in OBX induced depressive-like behavior in rat model. PCA was administered at a dose of 100 mg/kg and 200 mg/kg, by per oral in OBX and sham operated rats. Behavioral (ambulatory and rearing activity and immobility time), neurochemical [serotonin (5-HT), dopamine (DA), norepinephrine (NE) and brain derived neurotrophic factor (BDNF) expression], biochemical (MDA formation, IL-6, TNF-α and antioxidants) changes in hippocampus and cerebral cortex along with serum corticosterone were investigated. Experimental findings reveals that OBX subjected rats showed alteration in behaviors like, increase in immobility time, ambulatory and rearing behaviors significantly, reduced BDNF level, 5-HT, DA,NE and antioxidant parameters along with increased serum corticosterone, MDA formation, IL-6, and TNF-α in hippocampus and cerebral cortex compared to sham operated rats. Administration of PCA significantly attenuated behavioral and neurobiochemical alterations, thus, its antidepressant-like activity is largely mediated through modulation of neurotransmitter, endocrine and immunologic systems, mainly by improvements of BDNF, 5-HT, DA, NE, reduced MDA, IL-6, and TNF-α in hippocampus and cerebral cortex.

Therapeutic potential of silymarin in chronic unpredictable mild stress induced depressive-like behavior in mice.

Silymarin, a plant-derived polyphenolic flavonoid of Silybum marianum, elicited significant antidepressant-like activity in an acute restraint stress model of depression. It improved monoamines, mainly 5-hydroxytryptamine (5-HT) levels in the cortex, dopamine (DA) and norepinephrine (NE) in the cerebellum in mice. The present study was undertaken to explore the antidepressant potential of silymarin in chronic unpredictable mild stress (CUMS) induced depressive-like behavior in mice, and to find out its probable mechanism(s) of action, mainly neurogenesis, neuroinflammation, and/or oxidative stress. The mice were subjected to CUMS for 28 days (4 weeks) and administered with silymarin (100 mg/kg and 200 mg/kg), or fluoxetine or vehicle from days 8 to 28 (3 weeks simultaneously). Animals were evaluated for behavioral changes, such as anhedonia by sucrose preference test, behavioral despair by forced swim test, and exploratory behaviors by an open field test. In addition, neurobiochemical alterations, mainly monoamines, 5-HT, NE, DA, neurotrophic factor BDNF, and cytokines, IL-6, TNF-α, oxidant-antioxidant parameters by determining the malondialdehyde formation (an index of lipid peroxidation process), superoxide dismutase (SOD) and catalase (CAT) activity in hippocampus and cerebral cortex along with serum corticosterone were investigated. Our findings reveal that mice subjected to CUMS exhibited lower sucrose preference, increase immobility time without affecting general locomotion of the animals, and reduce BDNF, 5-HT, NE, and DA level, increased serum corticosterone, IL-6 and TNF-α along with an oxidant-antioxidant imbalance in the hippocampus and cerebral cortex. Silymarin significantly reversed the CUMS-induced changes in the hippocampus and cerebral cortex in mice. Thus, the possible mechanism involved in the antidepressant-like activity of silymarin is correlated to the alleviation of monoaminergic, neurogenesis (enhancing 5-HT, NE, and BDNF levels), and attenuation of inflammatory cytokines system and oxidative stress by modulation of corticosterone response, restoration of antioxidant defense system in cerebral cortex and hippocampus.

Silymarin ameliorates experimentally induced depressive like behavior in rats: Involvement of hippocampal BDNF signaling, inflammatory cytokines and oxidative stress response.

Silymarin is a polyphenolic flavonoid of Silybum marianum, exhibited neuroprotection and antidepressant like activity in acute restraint stressed mice. The main objective of the present study is to investigate possible antidepressant like activity of silymarin in experimentally induced depressive behavior in rats. The depressive behaviors were induced in rats by olfactory bulbectomized (OBX) technique. Wistar rats were administered with silymarin at a dose of 100mg/kg and 200mg/kg, by per oral in OBX and sham operated rats. Behavioral (ambulatory and rearing activity and immobility time), neurochemical [serotonin (5-HT), dopamine (DA), norepinephrine (NE) and brain derived neurotrophic factor (BDNF) level], biochemical (MDA formation, IL-6, TNF-α and antioxidants) changes in hippocampus and cerebral cortex along with serum corticosterone were investigated. Rats subjected to OBX elicited significant increase in immobility time, ambulatory and rearing behaviors, reduced BDNF level, 5-HT, DA, NE and antioxidant parameters along with increased serum corticosterone, MDA formation, IL-6, and TNF-α in hippocampus and cerebral cortex compared to sham operated rats. Administration of with silymarin significantly attenuated immobility time, ambulatory and rearing behaviors, serum corticosterone and improved BDNF expression, 5-HT, DA, NE and antioxidant paradigms in cerebral cortex as well as hippocampus. In addition, silymarin attenuated IL-6, and TNF-α significantly in hippocampus and cerebral cortex in OBX rats. Thus, silymarin exhibits anti-depressant-like activity in OBX rats due to alterations in several neurotransmitters, endocrine and immunologic systems, including BDNF, 5-HT, DA, NE, MDA formation, IL-6, and TNF-α in hippocampus and cerebral cortex as well as serum corticosterone.

Attenuation of acute restraint stress-induced depressive like behavior and hippocampal alterations with protocatechuic acid treatment in mice.

Protocatechuic acid ethyl ester (PCA), a phenolic compound, exhibits neuroprotective effects through improving endogenous antioxidant enzymatic and nonezymatic system. Based on the role of oxidative stress in modulating depressive disorders and the relationship between neuroprotective and antioxidant potential of PCA, we studied if its antidepressant like effect is associated by modulation of cerebral cortex and hippocampal antioxidant alterations. Acute restraint stress (ARS) is known to induce depressive like behavior by neuronal oxidative damage in mice. Swiss albino mice subjected to ARS exhibited an increased immobility time in forced swim test, elevated serum corticosterone and produced oxidative stress dependent alterations in cerebral cortex and hippocampus mainly increased thiobarbituric acid reactive substances and reduced catalase (CAT), superoxide dismutase (SOD) activity. Treatment with PCA was able to prevent stress induced immobility time in forced swim test without altering locomotor activity in mice. Further, PCA treatment attenuated the elevation of serum corticosterone, lipid peroxidation and restored enzymatic antioxidants in cerebral cortex and hippocampus in ARS mice. Altogether, the experimental findings demonstrate the notion that PCA exhibit antidepressant like activity might be related, at least in part, to its capability of modulating antioxidant defense system and oxidative damage induced by ARS in cerebral cortex and hippocampus in mice and thus maintain the pro-/anti-oxidative homeostasis.

Potential antidepressant-like activity of silymarin in the acute restraint stress in mice: Modulation of corticosterone and oxidative stress response in cerebral cortex and hippocampus.

BACKGROUND: Silymarin is a polyphenolic flavanoid of Silybum marianum, elicited neuroprotection and antidepressant like activity in stressed model. It was found to increase 5-hydroxytryptamine (5-HT) levels in the cortex and dopamine (DA) and norepinephrine (NE) in the cerebellum in normal mice. The aim of the present study was to investigate the potential antidepressant-like activity of silymarin in the acute restraint stress (ARS) in mice. METHODS: The ARS was induced by immobilizing the mice for a period of 7h using rodent restraint device preventing them for any physical movement. One hour prior to ARS, silymarin was administered at doses of 100mg/kg and 200mg/kg per oral to non stressed and ARS mice. Various behavioral parameters like immobility time in force swim test, locomotor activity in open field test, and biochemical alterations, serum corticosterone, 5-HT, DA, NE level, malondialdehyde (MDA), and antioxidant enzymes (GSH, CAT and SOD) in hippocampus and cerebral cortex in non stressed and ARS subjected mice were investigated. RESULTS: Experimental findings reveals mice subjected to ARS exhibited significant increase immobility time, serum corticosterone, MDA formation and impaired SOD and CAT activities in hippocampus and cerebral cortex as compared to non stressed mice. Silymarin treatment (100mg/kg and 200mg/kg) significantly attenuated immobility time, corticosterone and restored the antioxidant enzymes after ARS. CONCLUSION: The present experimental findings indicate that silymarin exhibits antidepressant like activity probably either through alleviating oxidative stress by modulation of corticosterone response, and antioxidant defense system in hippocampus and cerebral cortex in ARS mice.

Preparation and Pharmacological Evaluation of Novel Orally Active Ester Prodrugs of Ketoprofen with Non-Ulcerogenic Property.

This study investigates anti-inflammatory activity with improved pharmacokinetic and non-ulcerogenic properties of various novel synthesized prodrugs of ketoprofen in experimental animals. Prodrugs 3a, 3f and 3k were found to possess significant anti-inflammatory activity with almost non-ulcerogenic potential than standard drug ketoprofen (1) in both normal and inflammation-induced rats. The experimental findings elicited higher AUC and plasma concentration at 1 and 2 h indicating improved oral bioavailability as compared to parent drug ketoprofen. These prodrugs are found to have no gastric ulceration with retained anti-inflammatory activity. Therefore, present experimental findings demonstrated significant improvement of various pharmacokinetic properties with non-ulcerogenic potential of ester prodrugs of ketoprofen.

Ameliorative effects of Tricholepis glaberrima in experimentally induced hepatic damage in rats: modulation of cytokines functions.

ETHNOPHARMACOLOGICAL RELEVANCE: Tricholepis glaberrima belonging to family Asteraceae is popularly known as "Brahmadandi" in Indian system of medicine and is claimed to be effective in the treatment of various ailments such as neurological disorders, hepatic disorders, sexual dysfunction, skin disease etc. The present study was undertaken to investigate the possible role of Tricholepis glaberrima in rifampicin and Bacillus Calmette-Guerin/lipopolysaccharides (BCG/LPS) induced hepatotoxicity in rats and its possible mechanism of actions. MATERIALS AND METHODS: Hepatotoxicity was induced in rats by administration of rifampicin for 30 days and in another experiment BCG on day 1 and LPS on day 11. In both the experiments, hepatotoxicity was assessed by alteration of serum marker enzymes (AST, ALT, and LDH), total proteins, MDA and NO formation, cytokines mainly IL-6 and TNF-α and histoarchitecture alterations. The IL-6 and TNF-α level in liver homogenates were determined by ELISA technique. RESULTS: Administration of both rifampicin and BCG-LPS elicited hepatic damage reflected in significantly (p<0.01) increased serum marker enzymes AST, ALT, ALP, GGT, LDH and decreased total proteins, increased MDA and NO formation in liver homogenate. Furthermore, IL-6 and TNF-α increased significantly in both the experimental conditions. Pretreatment with METg and silymarin attenuated significantly (p<0.01) marker enzymes, TP, MDA and NO formation as well as IL-6 and TNF-α production in liver homogenates. Prophylactic treatment with METg exhibits significant improvement in liver damage as compared to therapeutic treatment. CONCLUSION: The hepatoprotective activity of METg may be correlated with the amelioration of oxidative stress due to immunological insult, by improving antioxidant defense ability of hepatocytes and also by reducing the cytokines (TNF-α, IL-6 and NO) production.

Design, synthesis, characterization and in vitro and in vivo anti-inflammatory evaluation of novel pyrazole-based chalcones.

Abstract A series of novel pyrazole-based chalcones have been designed, synthesized from 1-methyl-5-(2,4,6-trimethoxyphenyl)-1H-pyrazole (6). The structures of regioisomers 6 and 7 were determined by 2D (1)H-(1)H COSY, (1)H-(13)C HSQC and (1)H-(13)C HMBC experiments. The newly synthesized compounds were tested for their inhibitory activity against COX-1 and COX-2 using an in vitro cyclooxygenase (COX) inhibition assay. Moreover, they were investigated in vivo for their anti-inflammatory activities using carrageenan-induced rat paw edema model for acute inflammation and cotton pellet-induced granuloma model for chronic inflammation. All the synthesized compounds showed potential to demonstrate anti-inflammatory activities, of particular interest compounds 10i, 10e, 10f, and 10h were found to be potent anti-inflammatory agents.

Potential targets for the development of novel antidepressants: future perspectives.

Depression is an affective disorder characterized by hallucination, delusion and increased social risk and is estimated to affect approximately 20 % of the population at some point during the lifetime. As per World Health Organization (WHO) it is predicted to be the leading cause of burden of disease by 2030. Effects of currently available antidepressants have explained the monoamine hypothesis of depression, which proposes that impaired release of serotonin, noradrenaline and dopamine, are thought to be responsible for the development of depressive symptoms. However, these drugs are not specific for their action, as they also inhibit other enzymes; this explains the side effects/drug interactions associated with these agents. The present review will familiarize the readers with novel targets being identified for depression which will be certainly beneficial for researcher, academician for the development of drugs for the management of depression and related behavior.

Some molecular targets for antihyperlipidemic drug research.

High levels of cholesterol and other lipid constituents are major risk factors in the development of atherosclerosis as well as diseases and disorders associated with it. Though, drugs of various categories acting through different mechanisms are available for antihyperlipidemic therapy, there are limitations associated with each of them, keeping the interest in discovery of newer and better antihyperlipidemic drugs alive. Identification and exploitation of novel molecular targets for discovery of new antihyperlipidemic drugs is an important area of research. Twenty such drug targets are elaborated herein, for their biochemical roles, structures, estimations, as well as, exploitation for new drug discovery research. Few recently discovered drugs are based on such molecular targets are also discussed.

Ameliorative effect of Luffa acutangula Roxb. on doxorubicin induced cardiac and nephrotoxicity in mice.

The present study reports protective effect of hydro-alcoholic extract of Luffa acutangula (HAELA) on doxorubicin (DXR) induced cardio and nephrotoxicity in mice by studying various serum biomarkers, antioxidants in target organs and histoarchitecture alterations. Pretreatment with HAELA reversed significantly the elevated serum biomarkers, alanine amino transferase, lactate dehydrogenase and creatinine phosphokinase in heart and kidney in DXR treated mice. In addition, HAELA treatment inhibited elevated malondialdehyde formation and restored the depleted glutathione, catalase, superoxide dismutase in heart and kidney tissue. The altered histoarchitecture of heart and kidney tissue due to DXR treatment were also improved with HAELA. The protective activity observed with HAELA on DXR induced cardio and nephrotoxicity in mice was found to be related to its antioxidant property which finally results in membrane stabilization.

Amelioration of cognitive, motor and endogenous defense functions with silymarin, piracetam and protocatechuic acid in the cerebral global ischemic rat model.

AIMS: The neuroprotective activities of silymarin, piracetam and protocatechuic acid ethyl ester (PCA) on cerebral global ischemic/reperfusion were evaluated in a rat model. MAIN METHODS: A midline ventral incision was made in the throat region. The right and left common carotid arteries were located and a bilateral common carotid artery occlusion (BCCAO) was performed for 30min using atraumatic clamps followed by a 24h period of reperfusion. Neurological/behavioral functions (cognitive and motor), endogenous defense systems (lipid peroxidation, glutathione, catalase, and superoxide dismutase), reduced water content and infarct size and histopathological alterations were then studied. KEY FINDINGS: Silymarin and PCA treatments significantly improved cognitive, motor and endogenous defense functions, histopathological alterations, and, reduced both water content and infarct size compared to the vehicle-treated ischemic control group. Piracetam treatment improved neurological and histopathological alterations, reduced water content and infarct size, but failed to restore/prevent the impaired endogenous defense functions significantly. SIGNIFICANCE: Silymarin showed better neuroprotection than piracetam and PCA in experimentally induced global ischemic/reperfusion and was able to facilitate mnemonic performance.

Therapeutic potential of curcumin in experimentally induced allergic rhinitis in guinea pigs.

In the present experiments, the possible role of curcumin in ovalbumin induced allergic rhinitis in guinea pig model was investigated. Various allergic rhinitis symptoms viz sneezing, rubbing frequencies, lacrimation and nasal congestion at various humidity conditions as well as on repeated sensitization were studied. The biochemical changes like serum IgE, IL-4 and nitric oxide (NO) in nasal lavage and eosinophil peroxidase activity in nasal homogenates were determined in allergic rhinitis. Curcumin treatment significantly reduced the symptoms (sneezing, rubbing frequencies, lacrimation and nasal congestion) and improved the histopathological alterations (reduction in inflammatory cells infiltration) of nasal mucosa in allergic rhinitis. Furthermore, curcumin treatment prevented significantly elevation of serum IgE, IL-4, NO in nasal lavage and eosinophil peroxidase in nasal homogenate. In the present experimental findings, we suggest that curcumin is a promising anti-allergic agent that may be useful in the clinical management of allergic rhinitis.

Design, synthesis, characterization and biological evaluation of novel pyrazole integrated benzophenones.

A series of novel pyrazole integrated benzophenones (9a-j) have been designed, synthesized from 1-methyl-5-(2,4,6-trimethoxy-phenyl)-1H-pyrazole 6. The structures of the regioisomers 6 and 7 were determined by 2D (1)H-(1)H COSY, (1)H-(13)C HSQC and (1)H-(13)C HMBC experiments. The newly synthesized compounds (9a-j) were evaluated for in vivo anti-inflammatory activity by carrageenan paw edema in rats and in vitro COX-1/COX-2 inhibition and antioxidant potential. Among the synthesized compounds, compounds 9b, 9d and 9f, were found to be active anti-inflammatory agents in addition to having potent antioxidant activity.

Design, synthesis, characterization and anti-inflammatory evaluation of novel pyrazole amalgamated flavones.

A series of novel pyrazole amalgamated flavones has been designed and synthesized from 1-methyl-5-(2,4,6-trimethoxy-phenyl)-1H-pyrazole 6. The structures of regioisomers 6 and 7 were resolved by 2D (1)H-(1)H COSY, (1)H-(13)C HSQC and (1)H-(13)C HMBC experiments. The newly synthesized compounds were tested for their in vitro COX inhibition and in vivo carrageenan induced hind paw edema in rats and acetic acid induced vascular permeability in mice. Although the compounds have inhibitory profile against both COX-1 and COX-2, some of the compounds are found to be selective against COX-2, supported by inhibition of paw edema and vascular permeability. Docking studies were also carried out to determine the structural features which sway the anti-inflammatory activity of the tested compounds. The keto and phenolic -OH are major factors that are prominently involved in interaction with COX-2 active site.

Silymarin improves the behavioural, biochemical and histoarchitecture alterations in focal ischemic rats: a comparative evaluation with piracetam and protocatachuic acid.

Comparative neuroprotective potential of silymarin, piracetam and protocatechuic acid ethyl ester (PCA) was evaluated in focal ischemic rats. Various pharmacological, biochemical (lipid peroxidation, reduced glutathione, catalase, nitrite content, brain water content) and behavioural (memory impairment, motor control, neurological score) including infarct size and histopathological alterations were evaluated. Silymarin (200mg/kg) and PCA treatment significantly improved behavioural, biochemical and histopathological changes, and reduced water content and infarct size. However, piracetam only improved behavioural and histopathological changes, reduced water content and infarct size. The findings indicate that silymarin exhibits neuroprotective activity better than PCA and piracetam in focal ischemia/reperfusion reflected by its better restoration of behavioural and antioxidant profile.

Study of immunological aspects of aspergillosis in mice and effect of polyene macrolide antibiotic (SJA-95) and IFN-γ: a possible role of IFN-γ as an adjunct in antifungal therapy.

New polyene macrolide antibiotic SJA-95 in free as well as liposomal (lip.) forms, with and without interferon-γ (IFN-γ) was studied in mice model of aspergillosis using biological and biochemical parameters viz. colony forming units (CFU) in liver, spleen, kidney, lung and brain, and serum IgG, and interleukin-4 (IL-4). Treatment with free and lip SJA-95 along with IFN-γ prolonged the survival time, reduced CFU in vital organs, decreased serum IgG and IL-4 levels. SJA-95 lip form showed greater antifungal activity as compared to free form. The combined treatment of lip SJA-95 with IFN-γ showed further enhancement in antifungal activity of SJA-95 (lip). The present experimental findings demonstrated IFN-γ might act as a potent modulator in immune reaction during fungal infection and can be a useful adjunctive in antifungal therapy in the management of deep seated systemic mycoses.

Protective effect of curcumin on experimentally induced inflammation, hepatotoxicity and cardiotoxicity in rats: evidence of its antioxidant property.

The present study investigates the protective effects of curcumin on experimentally induced inflammation, hepatotoxicity, and cardiotoxicity using various animal models with biochemical parameters like serum marker enzymes and antioxidants in target tissues. In addition, liver and cardiac histoarchitecture changes were also studied. Curcumin treatment inhibited carrageenin and albumin induced edema, cotton pellet granuloma formation. The increased relative weight of liver and heart in CCl(4) induced liver injury and isoproterenol induced cardiac necrosis were also reduced by curcumin treatment. Elevated serum marker enzymes, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) increased lipid peroxidation, decreased gluthione (GSH), glutathione peroxidase (GPx) and superoxide dismutase (SOD) in edematous, granulomatus, liver and heart tissues during inflammation, liver injury and cardiac necrosis, respectively. Curcumin treatment reversed all these above mentioned biochemical changes significantly in all animal models studied. Even histoarchitecture alterations observed in liver injury and cardiac necrosis observed were partially reversed (improved) by curcumin treatments. In in vitro experiments too curcumin inhibited iron catalyzed lipid peroxidation in liver homogenates, scavenged nitric oxide spontaneously generated from nitroprusside and inhibited heat induced hemolysis of rat erythrocytes. The present in vitro and in vivo experimental findings suggest the protective effect of curcumin on experimentally induced inflammation, hepatotoxicity, and cardiotoxicity in rats.

Stem bark extraction of Ficus bengalensis Linn for anti-inflammatory and analgesic activity in animal models.

In the present study, anti-inflammatory and analgesic effect of aqueous extract of Ficus bengalensis (AEFB) and methanolic extract of F. bengalensis (MEFB) was evaluated in animal models. Preliminary results indicated that MEFB treatment possesses significant anti-inflammatory potential as compared to AEFB. The anti-inflammatory activity of MEFB exhibited in both acute (carrageenan induced hind paw edema and acetic acid induced vascular permeability) and subchronic (cotton pellet-induced granuloma) models of inflammation was found to be significant. In addition, the extract also showed significant analgesic activity in acetic acid induced writhing. Pretreatment with MEFB during inflammatory condition (both acute and sub-chronic) prevented increase in malondialdehyde (MDA) formation and myeloperoxidase activity in edematous as well as granulomatous tissue. Further, serum marker enzymes (AST, ALT and ALP) increased in inflammatory conditions were also inhibited with MEFB treatment. Hence, the anti-inflammatory activity observed in the present study with MEFB could be attributed largely to its antioxidant and lysosomal membrane stabilizing effects.