Supplementation of probiotic Bifidobacterium breve Bif11 reverses neurobehavioural deficits, inflammatory changes and oxidative stress in Parkinson's disease model.

Human gut microbiota are thought to affect different physiological processes in the body, including brain functions. Gut dysbiosis has been linked to the progression of Parkinson's disease (PD) and thus, restoring the healthy gut microbiota with supplementation of putative probiotic strains can confer some benefits in PD. In the current study, we explored the neuroprotective potential of Bifidobacterium breve Bif11 supplementation in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP) treated female Sprague Dawley rats. This study investigated the behavioural, molecular and biochemical parameters in the MPTP rat model. A pharmacological intervention of Bif11 at doses of 1 × 1010 CFU and 2 × 1010 CFU for 21 days was found to attenuate the cognitive and motor changes in the MPTP rat model. Furthermore, it also increased the tyrosine hydroxylase levels, reduced pro-inflammatory markers and decreased oxidative and nitrosative stress in the mid brain of MPTP-lesioned rats. Bif11 supplementation even restored the levels of short-chain fatty acids and decreased intestinal epithelial permeability in MPTP-induced PD model rats. In summary, these findings demonstrate that B. breve Bif11 has the potential to ameliorate symptoms of PD. However, this therapy needs to be further investigated with in-depth mechanistic insights in the future for the treatment of PD.

Bifidobacterium breve Bif11 supplementation improves depression-related neurobehavioural and neuroinflammatory changes in the mouse.

Gut dysbiosis has been closely linked to the onset and progression of several brain-related disorders such as depression. The administration of microbiota-based formulations such as probiotics helps restore healthy gut flora and plays a role in preventing and treating depression-like behavior. Therefore, we evaluated the efficacy of probiotic supplementation using our recently isolated putative probiotic Bifidobacterium breve Bif11 in ameliorating lipopolysaccharide (LPS)-induced depression-like behavior in male Swiss albino mice. Mice were fed orally with B. breve Bif11 (1 × 1010 CFU and 2 × 1010 CFU) for 21 days before being challenged with a single intraperitoneal LPS injection (0.83 mg/kg). Behavioral, biochemical, histological and molecular analysis were done with an emphasis on inflammatory pathways linked to depression-like behavior. Daily supplementation with B. breve Bif11 for 21 days prevented the onset of depression-like behavior induced by LPS injection, besides reducing the levels of inflammatory cytokines such as matrix metalloproteinase-2, c-reactive protein, interleukin-6, tumor necrosis factor-alpha and nuclear factor kappa-light-chain-enhancer of activated B cells. It also prevented the decrease of the brain-derived neurotrophic factor levels and neuronal cell viability in the prefrontal cortex of LPS-treated mice. Furthermore, we observed that gut permeability was reduced, there was an improved short-chain fatty acid profile and reduced gut dysbiosis in the LPS mice fed with B. breve Bif11. Similarly, we observed a decrease in behavioural deficits and restoration of gut permeability in chronic mild stress. Together, these results would help in deciphering the role of probiotics in the management of neurological disorders where depression, anxiety and inflammation are prominent clinical features.

Parthenolide, an NF-κB Inhibitor Ameliorates Diabetes-Induced Behavioural Deficit, Neurotransmitter Imbalance and Neuroinflammation in Type 2 Diabetes Rat Model.

Diabetes is associated with behavioural and neurochemical alterations. In this manuscript, we are reporting the beneficial effects of parthenolide, an NF-κB inhibitor on behavioural and neurochemical deficits in type 2 diabetic rat model. Diabetes was induced by high-fat diet followed by low dose of streptozotocin (35 mg/kg). Elevated plus maze, open-field, MWM and passive avoidance test paradigm were used to assess behavioural and cognitive deficits. Three-week treatment of parthenolide (0.25 and 0.50 mg/kg; i.p.) attenuated diabetes-induced alteration in cognitive function in Morris water maze and passive avoidance test. Anxiety-like behaviour was also reduced by parthenolide treatment. Moreover, TNF-α and IL-6 levels were significantly decreased in cortex and hippocampus of parthenolide-treated rats. Three-week parthenolide treatment also toned down the alteration of GABA and glutamate homoeostasis. Results of this study corroborate the involvement of neuroinflammation in the development of behavioural and neurochemical deficits in diabetic animals and point towards the therapeutic potential of parthenolide in diabetes-induced alteration of learning, memory and anxiety behaviour.

Reversal of diabetes-induced behavioral and neurochemical deficits by cinnamaldehyde.

BACKGROUND: Chronic hyperglycemia during diabetes is associated with altered cognitive function. Cinnamaldehyde showed to have many pharmacological activities indicating anti-diabetic, cognitive enhancer, antiinflammatory etc. In the present study, we have investigated the effects of cinnamaldehyde (CA) on diabetes-induced cognitive deficits. METHODS: Diabetes was induced in Sprague Dawley rats using high fat diet followed by streptozotocin (35mg/kg, i.p.). High fat diet feeding was continued for 18 week after STZ administration. CA was administered daily during the last 3 weeks (week 16-18) at a doses of 10, 20 and 40mg/kg (p.o.). Animals were subjected to behavioral tests during 18th week. Neurotransmitter levels (glutamate and GABA), acetylcholine esterase (AChE) activity and inflammatory markers (TNF-α and IL-6) were assessed in the hippocampus and cortex. RESULTS: Vehicle-treated diabetic rats showed impaired behavior in open field, elevated plus maze and water maze test compared to age-matched control rats. Cinnamaldehyde showed significant reduction in blood glucose levels at dose of 20 and 40mg/kg. Three weeks treatments of cinnamaldehyde showed significant amelioration of behavioral deficits in diabetic rats. Chronic treatment with cinnamaldehyde showed improvement in brain ChE activity, neurotransmitter levels and reduction in IL-6 and TNF-α levels. CONCLUSION: The present study demonstrates that treatment with cinnamaldehyde reverse neuroinflammation and changes in neurotransmitter levels, and consequently improves behavioral deficits in diabetic rats.

Cinnamaldehyde supplementation prevents fasting-induced hyperphagia, lipid accumulation, and inflammation in high-fat diet-fed mice.

Cinnamaldehyde, a bioactive component of cinnamon, is increasingly gaining interest for its preventive and therapeutic effects against metabolic complications like type-2 diabetes. This study is an attempt to understand the effect of cinnamaldehyde in high-fat diet (HFD)-associated increase in fasting-induced hyperphagia and related hormone levels, adipose tissue lipolysis and inflammation, and selected cecal microbial count in mice. Cinnamaldehyde, at 40 µM dose, prevented lipid accumulation and altered gene expression toward lipolytic phenotype in 3T3-L1 preadipocyte cell lines. In vivo, cinnamaldehyde coadministration prevented HFD-induced body weight gain, decreased fasting-induced hyperphagia, as well as circulating leptin and leptin/ghrelin ratio. In addition to that, cinnamaldehyde altered serum biochemical parameters related to lipolysis, that is, glycerol and free fatty acid levels. At transcriptional level, cinnamaldehyde increased anorectic gene expression in hypothalamus and lipolytic gene expression in visceral white adipose tissue. Furthermore, cinnamaldehyde also decreased serum IL-1ß and inflammatory gene expression in visceral white adipose tissue. However, cinnamaldehyde did not modulate the population of selected gut microbial (Lactobacillus, Bifidibaceria, and Roseburia) count in cecal content. In conclusion, cinnamaldehyde increased adipose tissue lipolysis, decreased fasting-induced hyperphagia, normalized circulating levels of leptin/ghrelin ratio, and reduced inflammation in HFD-fed mice, which augurs well for its antiobesity role.

Structure based virtual screening to identify selective phosphodiesterase 4B inhibitors.

Phosphodiesterase 4 (PDE4), is a hydrolytic enzyme, is proposed as a promising target in asthma and chronic obstructive pulmonary disease. PDE4B selective inhibitors are desirable to reduce the dose limiting adverse effect associated with non-selective PDE4B inhibitors. To achieve this goal, ligand based pharmacophore modeling and molecular docking approach is employed. Pharmacophore hypotheses for PDE4B and PDE4D are generated using HypoGen algorithm. The best PDE4B pharmacophore hypothesis (Hypo1_PDE4B) consist of one hydrogen-bond acceptor and two ring aromatic features, whereas PDE4D pharmacophore hypothesis (Hypo1_PDE4D) consist of one hydrogen-bond acceptor, one hydrophobic aliphatic, and two ring aromatic features. The validated pharmacophore hypotheses are used in virtual screening to identify selective PDE4B inhibitors. The hits were screened for their estimated activity, FitValue, and quantitative estimation of drug likeness. After molecular docking analysis, ten hits were purchased for in vitro analysis. Out of these, six hits have shown potent and selective inhibitory activity against PDE4B with IC50 values ranging from 2 to 378nM.

Emerging potential of citrus flavanones as an antioxidant in diabetes and its complications.

A proper balance between oxidants and antioxidants is necessary in maintaining health and longevity. Alterations in this balance may result in oxidative stress causing functional disorders and diseases. Oxidative stress is considered to play a vital role in the pathogenesis of diabetes and its complications. Flavanones and flavanones-rich botanical extracts have been a subject of great interest for scientific research. Citrus flavanones like naringin and hesperidin exert a variety of biological activities such as anti-oxidant, anti-inflammatory, antihyperglycemic, anti-apoptotic etc. Naringin and hesperidin along with their respective aglycones, naringenin and hesperetin have been shown to attenuate diabetes and its related complications. This review discusses the role of flavanones as a possible emerging treatment for diabetes and its complications along with the possible mechanistic explanations.

Biological evaluation and structural insights for design of subtype-selective peroxisome proliferator activated receptor-α (PPAR-α) agonists.

Peroxisome proliferator activated receptors-α (PPAR-α) control the expression of several genes involved in diseases like diabetes, hyperlipidaemia, and inflammatory disorders. Herein, we report the biological evaluation of recently identified hits from pharmacophore based virtual screening. The most potent hits, ZINC17167211, ZINC06472206 and ZINC08438472 showed EC50 values of 0.16, 1.1 and 12.1nM in PPAR-α agonist assay, respectively. Further, comparative docking and molecular dynamics analysis of selective PPAR-α agonists revealed that Thr279, Ala333, Lys358 and Met325 residues play an important role in the selective PPAR-α agonistic activity. The insights from docking and molecular dynamic studies will serve as a guideline for the development of potent and selective PPAR-α agonists.

Bioanalytical method development, pharmacokinetics, and toxicity studies of paromomycin and paromomycin loaded in albumin microspheres.

Intracellular location of leishmania parasite in macrophages protects them from both hosts defence system as well as from antibiotics like paromomycin (PM) acting against them, thus there is a need of a formulation targeting intracellular parasites. Considering this, PM-loaded albumin microspheres (PM-MS) were prepared to target PM to macrophages where leishmania parasites resides and evaluated for their safety profile. A new bioanalytical method for quantitative determination of PM in rat plasma was developed by pre-column derivatization with 9-fluorenylmethyl chloroformate. The developed bioanalytical method was validated and applied for pharmacokinetic studies of PM administered by intramuscular and intravenous routes as well as for developed PM-MS which were administered by intravenous route. Comparative acute and subacute toxicity studies were also carried out for these formulations. The developed method was found to be very sensitive with a quantification limit of 40 ng/ml. Pharmacokinetic studies demonstrated nearly 80% reduction in C(max) of PM when administered as PM-MS, compared to other formulations at equivalent dose. Toxicity studies indicated increased level of blood urea and blood urea nitrogen in PM intramuscular injection at 90 mg/kg dose, whereas at the same dose level PM-MS showed no symptoms of toxicity. Results obtained suggest that developed PM-MS formulation is a promising alternative to the presently marketed PM intramuscular injection for the treatment of visceral leishmaniasis.

Edaravone attenuates hydroxyl radical stress and augmented angiotensin II response in diabetic rats.

Reactive oxygen species (ROS) potentiate angiotensin II (Ang II) responses in diabetic vasculature. However, superoxide scavengers partially restore this effect, suggesting free radicals other than superoxide could be involved. Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) is an antioxidant, which primarily scavenges hydroxyl radicals and is approved for use in stroke patients. Hence, to evaluate the role of hydroxyl radical stress in diabetic vascular complications, we studied the effect of edaravone (3 mgkg(-1), i.p., b.i.d.) treatment on Ang II responses in thoracic aorta isolated from streptozotocin (60 mgkg(-1) i.p.) induced 8 weeks diabetic male Sprague-Dawley rats. Ang II (10(-10) to 10(-6)M), tert-butyl hydro peroxide (tBHP; 10(-6) to 10(-2)M) or hydrogen peroxide (H2O2; 10(-6) to 10(-3)M) induced contractile response was significantly enhanced in aortic strips from diabetic as compared to control rats. Lipid peroxidation was significantly enhanced while the superoxide dismutase (SOD) and catalase activity was significantly lower in aorta of diabetic rats as compared to control rats. Acute (in vitro) exposure of edaravone (10(-5)M) to aortic strips from diabetic rats in the organ bath restored the augmented Ang II but not tBHP or H2O2-induced contractile response. In vivo edaravone (3mgkg(-1), i.p., b.i.d.) treatment for 2 weeks selectively attenuated the augmented Ang II- but not tBHP- or H2O2-induced contractile response. The enhanced systolic pressure, lipid peroxidation and the reduced SOD and catalase activity were restored to control values following 2 weeks edaravone treatment. From our results we infer that hydroxyl radical stress augments Ang II response in diabetic rat thoracic aorta and edaravone could be an ideal antioxidant adjuvant in the therapy of diabetic vascular complications.