Manoj G Tyagi

Evaluation of Seizure Activity After Phospho-diesterase Inhibition (BRL 50481) with Guanylate Cyclase Activation (A-350619) and Inhibition (Methylene blue) in Animal Models of Epilepsy

The role of soluble guanylate cyclase (GC) activator (A-350619) and inhibitor (methylene blue) was evaluated in the presence of phosphodiesterase-7 (PDE-7) inhibitor such as BRL-50481, in animal models of epilepsy. Seizures were induced in the animals by subjecting them to an injection of chemical convulsant, pentylenetetrazole (PTZ) and maximal electroshock (MES). The study mainly comprises the onset of seizures, mortality/recovery, percentage of prevention of seizures (anti-convulsant) and total duration of convulsive time. The combination of GC inhibitor, methylene blue with BRL 50481 showed a delay onset (P<0.001) in incidence of seizures, compared to A-350619 and BRL 50481 alone treated group. The total convulsive time was prolonged significantly (P<0.01) in methylene blue alone treated (69.2%) groups, compared to DMSO received group (100%). The study also demonstrates that methylene blue alone and methylene blue with BRL 50481 greatly increased the anti-convulsant activity (P<0.01 and P<0.05) along with higher protection 83.3% and 66.7% range respectively in PTZ model. Methylene blue with BRL 50481 effectively (P<0.01) decreased the MES (150 mA, 0.2 sec) induced convulsion, compared to DMSO. The data shows that methylene blue alone, methylene blue with BRL 50481 greatly increased the anti-convulsant activity (P<0.01 and P<0.01) along with higher protection 83.3% range in animals treated with MES. The present result suggested of the possible involvement of methylene blue alone and with presence of BRL 50481, delays the onset of seizure activity as well as prolongs the total duration of convulsive time in both models.

Indispensable chemical genomic approaches in novel systemic targeted drug discovery

Chemogenomics is a new emerging area in the field of drug discovery and development. It describes the development of target specific chemical ligands and the use of such specific chemical ligands to globally study the gene level and protein level functions. The human genome contains around 100,000 genes and 30,000 proteins which are encoded by it. Primarily the novel, systemic, very small molecular sized, cell permeable and target specific chemical ligands are particularly useful in systematic genomic approaches to study the normal and abnormal biological functions. The complete genomic sequence information with structural and comparative genomics when combined with all the features in synthetic chemistry, ligand screening and identification provides target or functions specific chemical ligands and drugs. Currently, the in-silico approaches are in vogue in novel target prediction and systemic drug discovery. It is prediction of biological targets of small molecules via data mining in target annotated chemical databases. This review will focus on the chemogenomics, its approaches for rational drug design and the recent in-silico approaches in novel target prediction.