Archana R. Juvekar

Agmatine ameliorates lipopolysaccharide induced depressive-like behaviour in mice by targeting the underlying inflammatory and oxido-nitrosative mediators

Experimental and clinical evidence indicates that pro-inflammatory cytokines, oxidative stress and brain-derived neurotrophic factor (BDNF) signalling mechanisms play a role in the pathophysiology of depression. Agmatine is a neurotransmitter and/or neuromodulator that has emerged as a potential agent to manage diverse central nervous system disorders. Agmatine has been shown to exert antidepressant-like effect. The present study investigated ability of agmatine to abolish the depressive-like behaviour induced by the administration of the lipopolysaccharide (LPS) in mice. Agmatine (20 and 40mg/kg) was administered daily for 7days, then the mice were challenged with saline or LPS (0.83mg/kg; i.p.) on the 7th day. After 24h of LPS administration we tested mice for depressive-like behaviour. LPS treated animals presented an increase in immobility time in the forced-swim test (FST), tail suspension test (TST) which was reversed by agmatine pre-treatment (20 and 40mg/kg). Oxidative/nitrosative stress evoked by LPS was ameliorated by both doses of agmatine in hippocampus (HC) and prefrontal cortex (PFC). Administration of LPS caused an increase in interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), whereas BDNF was down regulated in the HC. Agmatine pre-treatment at 40mg/kg ameliorated LPS-induced neuroinflammation by attenuating brain IL-1β and TNF-α level. In addition, agmatine pre-treatment also up-regulated the BDNF level in the HC. The present study shows that pre-treatment of agmatine is able to abolish the behavioural responses in the FST and TST elicited by the LPS-induced model of depression that may depend on the inhibition of pro-inflammatory mediators, reduction of oxidative stress as well as activation neuroplasticity-related signalling in mice, suggesting that agmatine may constitute an monotherapy/adjuvant for the management of depression associated with inflammation.

An evaluation of the antidiabetic effects of Elaeocarpus ganitrus in experimental animals

Objective: To evaluate the antidiabetic effects of the aqueous extract of Elaeocarpus ganitrus (EAG) in experimental animals. Materials and Methods: The hypoglycemic activity of the EGA was evaluated in normoglycemic rats by single dose at three graded dose levels, viz. 250, 500 and 1000 mg/kg of body weight. Antihyperglycemic activity of the extract was also evaluated at the same dose levels in streptozotocin (STZ) (60 mg/kg, i.p.)-induced diabetic rats during a 30-day treatment period. Metformin (500 mg/kg) was used as the reference drug. Fasting blood glucose and lipid parameters, viz. triglycerides, total cholesterol, high-density lipoprotein and low-density lipoprotein levels were measured. Acute oral toxicity of the EGA extract was carried out in Swiss albino mice. Results: In normoglycemic rats, EGA showed a significant (P < 0.01) hypoglycemic effect at 2 h. In STZ-induced diabetic rats, the EGA treatment significantly (P < 0.05) decreased the blood glucose level in a dose-dependent manner during the 30 days of treatment period. EGA modulated lipid profile changes in STZ-diabetic rats in a dose-dependant manner. In the acute oral toxicity study, EGA showed no mortality till the 5 g/kg dose in mice. Conclusion: The present investigation shows that EAG seeds has potential antidiabetic effects.

Neuroprotective effect of curcumin as evinced by abrogation of rotenone-induced motor deficits, oxidative and mitochondrial dysfunctions in mouse model of Parkinson's disease.

Curcumin, a natural polyphenolic compound extracted from rhizomes of Curcuma longa (turmeric), a plant in the ginger family (Zingiberaceae) has been used worldwide and extensively in Southeast Asia. Curcumin exhibited numerous biological and pharmacological activities including potent antioxidant, cardiovascular disease, anticancer, anti-inflammatory effects and neurodegenerative disorders in cell cultures and animal models. Hence, the present study was designed in order to explore the possible neuroprotective role of curcumin against rotenone induced cognitive impairment, oxidative and mitochondrial dysfunction in mice. Chronic administration of rotenone (1mg/kg i.p.) for a period of three weeks significantly impaired cognitive function (actophotometer, rotarod and open field test), oxidative defense (increased lipid peroxidation, nitrite concentration and decreased activity of superoxide dismutase, catalase and reduced glutathione level) and mitochondrial complex (II and III) enzymes activities as compared to normal control group. Three weeks of curcumin (50, 100 and 200mg/kg, p.o.) treatment significantly improved behavioral alterations, oxidative damage and mitochondrial enzyme complex activities as compared to negative control (rotenone treated) group. Curcumin treated mice also mitigated enhanced acetylcholine esterase enzyme level as compared to negative control group. We found that curcumin restored motor deficits and enhanced the activities of antioxidant enzymes suggesting its antioxidant potential in vivo. The findings of the present study conclude neuroprotective role of curcumin against rotenone induced Parkinsons in mice and offer strong justification for the therapeutic prospective of this compound in the management of PD.

Agmatine attenuates chronic unpredictable mild stress-induced anxiety, depression-like behaviours and cognitive impairment by modulating nitrergic signalling pathway

Agmatine, a neurotransmitter/neuromodulator, has shown to exert numerous effects on the CNS. Chronic stress is a risk factor for development of depression, anxiety and deterioration of cognitive performance. Compelling evidences indicate an involvement of nitric oxide (NO) pathway in these disorders. Hence, investigation of the beneficial effects of agmatine on chronic unpredictable mild stress (CUMS)-induced depression, anxiety and cognitive performance with the involvement of nitrergic pathway was undertaken. Mice were subjected to a battery of stressors for 28days. Agmatine (20 and 40mg/kg, i.p.) alone and in combination with NO modulators like L-NAME (15mg/kg, i.p.) and l-arginine (400mg/kg i.p.) were administered daily. The results showed that 4-weeks CUMS produces significant depression and anxiety-like behaviour. Stressed mice have also shown a significant high serum corticosterone (CORT) and low BDNF level. Chronic treatment with agmatine produced significant antidepressant-like behaviour in forced swim test (FST) and sucrose preference test, whereas, anxiolytic-like behaviour in elevated plus maze (EPM) and open field test (OFT) with improved cognitive impairment in Morris water maze (MWM). Furthermore, agmatine administration reduced the levels of acetylcholinesterase and oxidative stress markers. In addition, agmatine treatment significantly increased the BDNF level and inhibited serum CORT level in stressed mice. Treatment with L-NAME (15mg/kg) potentiated the effect of agmatine whereas l-arginine abolished the anxiolytic, antidepressant and neuroprotective effects of agmatine. Agmatine showed marked effect on depression and anxiety-like behaviour in mice through nitrergic pathway, which may be related to modulation of oxidative-nitrergic stress, CORT and BDNF levels.

In vitro and in vivo immunostimulatory activity of Woodfordia fruticosa flowers on non-specific immunity

Context: Woodfordia fruticosa Kurz. (Lythraceae), a non-rasayana immunomodulatory Indian medicinal plant, used traditionally as an anthelmintic, in dysentery, leprosy, blood diseases, leucorrhea, and menorrhagia. Objective: To investigate the effect of ethanol extract of W. fruticosa flowers on non-specific immune responses in mice. Materials and methods: In vitro immunomodulatory activity of the extract was examined on murine peritoneal macrophage phagocytosis (nitroblue tetrazolium (NBT) dye reduction, lysosomal enzyme activity, nitric oxide and myeloperoxidase) and on proliferation of bone marrow cells by sulforhodamine B (SRB) assay, while the in vivo potential on macrophages and bone marrow cells was evaluated by using carbon clearance test and cyclophosphamide-induced myelosuppression, respectively. Results: Significant increase in the release of myeloperoxidase, nitric oxide lysosomal enzyme and superoxide from macrophages along with significant increase in phagocytic index in carbon clearance test indicate stimulatory activity of the extract on macrophages. The extract also demonstrated 60% increase in bone marrow cell proliferation and offer protection towards cyclophosphamide-induced myelosuppression which represents the stimulation of bone marrow activity. Discussion: Significant increase in mediators released from macrophages and phagocytic index in carbon clearance test suggests the release of cytokines from macrophages and stimulation of reticulo-endothelial system. Proliferation of bone marrow cells indicates the plausible release of colony stimulating factors, which further stimulates the immune system through generation of immune cells. Conclusion: The result described here indicates the immunostimulatory activity of ethanol extract of W. fruticosa flowers by stimulating non-specific immune responses, macrophages and bone marrow cells.

Attenuation of diabetic nephropathy in streptozotocin-induced diabetic rats by Punica granatum Linn. leaves extract

With an objective to develop Complementary and Alternative Medicine for the treatment of diabetic nephropathy, the present study investigated the protective effects of methanolic extract of Punica granatum leaves (MPGL) in streptozotocin-induced diabetic nephropathy. Diabetic nephropathy has become a leading cause of end stage renal failure worldwide. P. granatum, due to its anti-diabetic, anti-inflammatory and antioxidant activities may retard the progression of diabetic nephropathy. In this study, diabetes was induced by a single injection of streptozotocin (STZ, 45 mg/kg, i.p.) in rats. STZ-diabetic rats were treated with oral doses of MPGL (100, 200 and 400 mg/kg) for 8 weeks. At the end of the experimental period, body and kidney weight and blood glucose levels were determined. Serum and urine parameters were investigated. Antioxidant enzymes and lipid peroxide levels were determined in the kidney along with histopathological examination of the same. MPGL significantly increased body weight, lowered blood glucose levels and ameliorated kidney hypertrophy index in the STZ-diabetic rats. The extract also decreased the levels of creatinine, blood urea nitrogen, total cholesterol, triglycerides, advanced glycation end products and albumin in serum and urine, respectively. MPGL significantly increased the antioxidant parameters in the kidney. Histological evaluation revealed that MPGL treated STZ-diabetic rats demonstrated reduced vacuolar degeneration of tubules; periodic acid Schiff base (PAS) positivity staining intensity in glomeruli and basement membrane thickening. Present findings provide experimental evidence that MPGL has potential antioxidant, antihyperglycemic and anti-glycation activities which might be helpful in slowing the progression of diabetic nephropathy.

Involvement of nitric oxide in anticompulsive-like effect of agmatine on marble-burying behaviour in mice.

In view of the reports that nitric oxide modulates the neurotransmitters implicated in obsessive-compulsive disorder (OCD), patients with OCD exhibit higher plasma nitrate levels, and drugs useful in OCD influence nitric oxide. Agmatine is a polyamine and widely distributed in mammalian brain which interacts with nitrergic systems. Hence, the present study was carried out to understand the involvement of nitrergic systems in the anticompulsive-like effect of agmatine. We used marble-burying behaviour (MBB) of mice as the animal model of OCD, and nitric oxide levels in hippocampus (HC) and cortex homogenate were measured. Results revealed that, agmatine (20 and 40mg/kg, i.p) significantly inhibited the MBB. Intraperitoneal administration of nitric oxide enhancers viz. nitric oxide precursor - l-arginine (l-ARG) (400mg/kg and 800mg/kg) increased MBB as well as brain nitrites levels, whereas treatment with N(G)-nitro-l-arginine methyl ester (l-NAME) neuronal nitric oxide synthase inhibitor (30mg/kg and 50mg/kg, i.p.) and 7-nitroindazole (7-NI) (20mg/kg and 40mg/kg) attenuated MBB and nitrites levels in brain. Further, in combination studies, the anticompulsive-like effect of agmatine (20mg/kg, ip) was exacerbated by prior administration of l-ARG (400mg/kg) and conversely l-NAME (15mg/kg) or 7-NI (10.0mg/kg) attenuated OCD-like behaviour with HC and cortex changes in the levels of NO. None of the above treatment had any significant influence on locomotor activity. In conclusion, Agmatine is effective in ameliorating the compulsive-like behaviour in mice which appears to be related to nitric oxide in brain.

Evaluation of anti-inflammatory activity of Typha angustifolia pollen grains extracts in experimental animals

Objective: This study was designed to evaluate the anti-inflammatory activity of aqueous and 70% methanolic extracts of pollen grains of Typha angustifolia. Materials and Methods: Female Sprague Dawley rats were used for the study. The acute anti-inflammatory activity of pollen grains of T. angustifolia was studied using the carrageenan as phlogistic agent, whereas its chronic anti-inflammatory effect was investigated by the percentage inhibition of cotton pellet-induced granuloma. Results: Both aqueous and 70% methanolic extracts of pollen grains of T. angustifolia showed significant dose-dependent inhibition of carrageenan-induced paw edema as compared to the control (P<0.001). It was observed that both the extracts at dose of 125 mg/kg inhibited the granuloma formation by 44.30% which is higher than at dose of 500, 250 mg/kg, thus causing a significant (P<0.001) non-dose-related inhibition of granuloma formation. Conclusion: The results of this study indicate that extracts of pollen grains of T. angustifolia are effective in the treatment of both acute and chronic inflammatory conditions and thus support its traditional utilization.

Imperatorin ameliorates lipopolysaccharide induced memory deficit by mitigating proinflammatory cytokines, oxidative stress and modulating brain-derived neurotropic factor

Graphical abstract Figure. No Caption available. HighlightsIMP reversed the LPS induced memory deficit in MWM and Y‐maze.IMP attenuated oxidative stress and diminished acetylcholinesterase activity.IMP restored the BDNF levels and reversed the increase in TNF‐&agr; and IL‐6.IMP demonstrated neuroprotective potential in LPS induced memory deficit. Background: Lipopolysaccharide (LPS), an endotoxin from the outer membrane of Gram negative bacteria has been reported to cause neuroinflammation and learning and memory deficits. There are reports describing the beneficial effects of Imperatorin (IMP), a naturally occurring furanocoumarin in central nervous system (CNS) disorders such as anxiety and epilepsy. Objective: In the current study, we investigated whether IMP protects against LPS mediated memory deficits and neuroinflammation. Methods: Mice pretreated with IMP (5, 10 mg/kg po) were administered LPS (250 &mgr;g/kg ip) for 7 days. Memory was evaluated in the Morris water maze (MWM) and Y maze. The mice were euthanised and different biochemical assessments were carried out to measure oxidative stress and acetyl choline esterase (AChE). Further, evaluation of proinflammatory cytokines such as tumor necrosis factor (TNF‐&agr;) and interleukin‐6 (IL‐6) levels and brain derived neurotrophic factor (BDNF) in hippocampus and cortex of brain were performed. Results: LPS administration caused poor memory retention in both, MWM and Y maze, and caused distinct oxidative stress since decrease in superoxide dismutase (SOD), reduced glutathione (GSH) levels and increased lipid peroxidation were observed. Also, a significant rise was observed in the levels of AChE. Moreover, a rise in TNF‐&agr; and IL‐6 levels and depleted levels of BDNF were noted. IMP pretreatment reversed LPS induced behavioral and memory disturbances and significantly decreased the oxidative stress and AChE levels. It also reduced TNF‐&agr; and IL‐6 levels and caused a significant upregulation of BDNF levels. Conclusion: Present study highlights the potential neuroprotective role of IMP against LPS mediated cognitive impairment and neuroinflammation.

In vitro antiglycating effect and in vivo neuroprotective activity of Trigonelline in d-galactose induced cognitive impairment

BACKGROUND Alzheimers disease (AD) is characterized by amyloid beta (Aβ) plaques, neurofibrillary tangles (NFTs) and cognitive impairment. Literature cites the role of advanced glycation end products (AGEs) in AD due to increased cytotoxicity via oxidative stress. d-galactose (d-gal) induced amnesia stimulates Aβ overproduction via increased oxidative stress and AGEs. Trigonelline (TRG), a naturally occurring alkaloid has been reported to have neuroprotective and antidiabetic properties. METHODS Present study assessed the protective effect of TRG against in vitro AGEs formation. Since chronic administration of d-gal increases AGEs, we subsequently investigated the neuroprotective role of TRG (50 and 100 mg/kg as per body weight) against d-gal induced amnesia. Mice were subcutaneously (sc) injected with d-gal (150 mg/kg) for 6 weeks. Behavioral assessments in Morris water maze (MWM) and Y-maze were performed, followed by biochemical estimations to deduce the probable mechanism of action. RESULTS In vitro experiments demonstrated that TRG stalled early and late AGEs formation. Chronic d-gal administration significantly impaired cognitive performance in MWM and Y maze, caused marked oxidative damage, elevated the AGEs levels and significantly increased the acetylcholinesterase levels as compared to sham group. TRG (50 and 100 mg/kg) treatment significantly ameliorated cognitive performance, reversed the oxidative damage, decreased AGE levels and caused significant decline in acetylcholine esterase levels as compared to d-gal group. CONCLUSION Present study highlights the neuroprotective role of TRG against d-gal induced amnesia due to the antioxidant, antiglycative and anticholinesterase properties.