Effect of scopoletin on monoamine oxidases and brain amines.

Naturally, occurring compounds with MAO inhibitory property may provide promising lead molecules against neurodegenerative disorders. We report MAO inhibitory activity of a naturally occurring coumarin (validated chemical scaffold as MAO inhibitors), scopoletin. It selectively (and reversibly) inhibits human (Ki = 20.7 µM) and mouse (Ki = 22 µM) MAO-B, ∼3.5 times more selective towards MAO-B than MAO-A. Docking studies revealed its molecular recognition and explained the selectivity mechanism towards MAO isoforms. Scopoletin occupied the hydrophobic aromatic pockets showing favorable interactions for MAO-B; experimental Ki agreed with the predicted Ki. In vivo, scopoletin (80 mg/kg, i.p.) treatment significantly increases dopamine level and decreases its metabolite DOPAC in striatum. Overall, scopoletin is a partially selective MAO-B inhibitor that increases brain dopamine level.

Memory enhancement by Tamoxifen on amyloidosis mouse model.

Tamoxifen (TMX) is a selective estrogen receptor modulator (SERM) used in the treatment of breast cancer. Earlier studies show its neuroprotection via regulating apoptosis, microglial functions, and synaptic plasticity. TMX also showed memory enhancement in ovariectomized mice, and protection from amyloid induced damage in hippocampal cell line. These reports encouraged us to explore the role of TMX in relevance to Alzheimer's disease (AD). We report here, the effect of TMX treatment a) on memory, and b) levels of neurotransmitters (acetylcholine (ACh) and dopamine (DA)) in breeding-retired-female mice injected with beta amyloid1-42 (Aß1-42). Mice were treated with TMX (10mg/kg, i.p.) for 15 days. In Morris water maze test, the TMX treated mice escape latency decreased during training trials. They also spent longer time in the platform quadrant on probe trial, compared to controls. In Passive avoidance test, TMX treated mice avoided stepping on the shock chamber. This suggests that TMX protects memory from Aß induced toxicity. In frontal cortex, ACh was moderately increased, with TMX treatment. In striatum, dopamine was significantly increased, 3,4-dihydroxyphenylacetic acid (DOPAC) level and DOPAC/DA ratio was decreased post TMX treatment. Therefore, TMX enhances spatial and contextual memory by reducing dopamine metabolism and increasing ACh level in Aß1-42 injected-breeding-retired-female mice.

Anticonvulsant activity of Benkara malabarica (Linn.) root extract: In vitro and in vivo investigation.

AIM OF THE STUDY: To systematically investigate the anticonvulsant activity of methanol extract of Benkara malabarica roots and to provide a biochemical basis elucidating its mode of action. METHODS: The median lethal dose (LD(50)) of Benkara malabarica extract was determined. The anticonvulsant activity of the extract was assessed in strychnine-induced and isoniazide-induced convulsion models; phenytoin (20mg/kg) and diazepam (1mg/kg) were used as standards, respectively. Percentage protection provided by the drug was accounted as decrease in the number of convulsions within 8h of observation. Mechanism of action was studied by performing GABA transaminase (GABA-T) assay, isolated from rat brain. Active constituent was isolated and characterized from the plant extract. RESULTS: The median lethal dose (LD50) of Benkara malabarica was found to be more than 500 mg/kg. It demonstrated 30% and 35% protection against strychnine-induced convulsions and 60% and 80% protection against isoniazide-induced convulsions, at doses of 25mg/kg and 50mg/kg, respectively. Enzyme assay results revealed that Benkara malabarica extract possesses GABA-T inhibitory activity (IC50=0.721 mg/ml). Scopoletin which was identified as the major constituent of the extract was found to be an inhibitor of GABA-T (IC50=10.57 microM). CONCLUSIONS: The anticonvulsant activity of the plant extract is predominantly GABA mediated and may be due to the action of scopoletin alone or is a result of synergy of different compounds in the extract in which scopoletin is the major constituent.

Structure based virtual screening of GSK-3beta: importance of protein flexibility and induced fit.

GSK-3beta, one of the vital enzymes responsible for various phosphorylation catalysis. Induced fit mechanism and the presence of conserved water molecule(s) in the active site poses complexity during the process of virtual screening. The present investigation reveals the practical strategy to handle the induced fit mechanism of GSK-3beta though flexible docking protocol. This protocol provides an enrichment of 70% in top 1% of the dataset with a rank correlation of >0.9 and found better in comparison to earlier reported protocols.

Dosimetry and treatment planning of Occu-Prosta I-125 seeds for intraocular lesions.

Intraocular malignant lesions are frequently encountered in clinical practice. Plaque brachytherapy represents an effective means of treatment for intraocular lesions. Recently Radiopharmaceutical Division, BARC, Mumbai, has indigenously fabricated reasonable-cost I-125 sources. Here we are presenting the preliminary experience of dosimetry of sources, configuration of treatment planning system (TPS) and quality assurance (QA) for eye plaque therapy with Occu-Prosta I-125 seeds, treated in our hospital, for a patient with ocular lesions. I-125 seeds were calibrated using well-type chamber. BrachyVision TPS was configured with Monte Carlo computed radial dose functions and anisotropy functions for I-125 sources. Dose calculated by TPS at different points in central axis and off axis was compared with manually calculated dose. Eye plaque was fabricated of 17 karat pure gold, locally. The seeds were arranged in an outer ring near the edge of the plaque and in concentric rings throughout the plaque. The sources were manually digitized on the TPS, and dose distribution was calculated in three dimensions. Measured activity using cross-calibrated well-type chamber was within +/-10% of the activity specified by the supplier. Difference in TPS-calculated dose and manually calculated dose was within 5%. Treatment time calculated by TPS was in concordance with published data for similar plaque arrangement.