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.

Hydroalcohol extract of Trigonella foenum-graecum seed attenuates markers of inflammation and oxidative stress while improving exocrine function in diabetic rats.

CONTEXT AND OBJECTIVE: The herb fenugreek, Trigonella foenum-graecum Linn (Fabaceae), seeds have been traditionally used in the treatment of diabetes but its effect on oxidative stress and pro-inflammatory cytokines in the improvement of exocrine function of diabetes has not been studied. The effect of hydroalcoholic extract of Trigonella foenum-graecum seeds (HEF) on alloxan-induced type-II diabetic rat model was investigated. MATERIALS AND METHODS: Effect of HEF (500, 1000, and 2000 mg/kg), glimepiride (4 mg/kg), and combination of HEF (500 mg/kg) + glimepiride (2 mg/kg), on alloxan-induced diabetic rats was evaluated by assaying (blood glucose, serum protein, glycosylated hemoglobin, muscle and liver glycogen, glucose uptake by diaphragm, liver glucose transport, serum pancreatic enzymes (α-amylase, lipase), pro-inflammatory cytokines (TNF-α, IL-6), antioxidant enzymes [glutathione (GSH), superoxide dismutase (SOD)], lipid peroxides (liver and pancreas), and histoarchitecture (liver, pancreas). RESULTS: Treatment with HEF (at different doses), glimepiride, and HEF + glimepiride increased body weight and glucose uptake, reduced plasma glucose, glycosylated hemoglobin, liver glucose transport, pro-inflammatory cytokines, pancreatic enzymes and restored depleted glycogen (muscle, liver) and total protein significantly (p < 0.01) and dose dependently, including prevention of lipid peroxidation and restoration of GSH and SOD (liver and pancreas). Treatment with HEF + glimepiride potentiated hypoglycemic activity of glimepiride. Histoarchitecture of liver and pancreas showed marked improvement. CONCLUSION: Present experimental findings suggest that HEF possesses promising hypoglycemic activity, presumably by amelioration of oxidative stress and pro-inflammatory cytokines. HEF may be useful as an adjuvant with clinically effective antidiabetic drugs in the management of type-II diabetes.

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.

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.

Probing in vivo trafficking of polymer/DNA micellar nanoparticles using SPECT/CT imaging.

Successful translation of nonviral gene delivery to therapeutic applications requires detailed understanding of in vivo trafficking of the vehicles. This report compares the pharmacokinetic and biodistribution profiles of polyethylene glycol-b-polyphosphoramidate (PEG-b-PPA)/DNA micellar nanoparticles after administration through intravenous infusion, intrabiliary infusion, and hydrodynamic injection using single photon emission computed tomography/computed tomography (SPECT/CT) imaging. Nanoparticles were labeled with (111)In using an optimized protocol to retain their favorable physicochemical properties. Quantitative imaging analysis revealed different in vivo trafficking kinetics for PEG-b-PPA/DNA nanoparticles after different routes of administration. The intrabiliary infusion resulted in the highest liver uptake of micelles compared with the other two routes. Analysis of intrabiliary infusion by the two-compartment pharmacokinetic modeling revealed efficient retention of micelles in the liver and minimal micelle leakage from the liver to the blood stream. This study demonstrates the utility of SPECT/CT as an effective noninvasive imaging modality for the characterization of nanoparticle trafficking in vivo and confirms that intrabiliary infusion is an effective route for liver-targeted delivery of DNA-containing nanoparticles.

Particle shape: a new design parameter for passive targeting in splenotropic drug delivery.

The role of particle size and surface modification on biodistribution of nanocarriers is widely reported. We report for the first time the role of nanoparticle shape on biodistribution. Our study demonstrates that irregular shaped polymer lipid nanoparticles (LIPOMER) evade kupffer cells and localize in the spleen. We also demonstrate the macrophage-evading characteristic of the irregular-shaped LIPOMER. Our results suggest particle shape as an important tool for passive targeting of nanocarriers in splenotropic drug delivery.

Engineered nanocarriers of doxorubicin: a current update.

Doxorubicin remains the first line of treatment for various cancers ever since its discovery in 1971. Cardiotoxicity and nephrotoxicity associated with unformulated doxorubicin triggered the development of doxorubicin nanocarriers. Although the therapeutic profile of doxorubicin is appreciably improved by entrapping in nanocarriers, they are largely taken up by organs of the reticuloendothelial system. Engineered nanocarriers of doxorubicin refer to carriers modified to escape recognition by reticuloendothelial system and/or functionalized with target specific ligands for selective accumulation at the target site. The first developments in engineered nanocarriers were the stealth carriers. These effectively bypassed the reticuloendothelial system and enhanced the therapeutic profile of doxorubicin by enabling passive accumulation in tumors. Stealth nanocarriers of doxorubicin revealed significant decrease in cardiotoxicity and nephrotoxicity, which led to the approval of liposomal doxorubicin for clinical applications. Success of liposomal doxorubicin was soon dulled by the appearance of newer toxicities like palmar-plantar erythrodysesthesia commonly referred as hand foot syndrome. The search for the magic bullet of doxorubicin has further intensified and resulted in design of engineered nanocarriers with high specificity for cancer cells. This review charts the progress from nanocarriers to engineered nanocarriers of doxorubicin, and highlights the current status of engineered nanocarriers of doxorubicin in clinical trials.