Punit Kumar Srivastava

Prostaglandin E2 synthase inhibition as a therapeutic target

Background: Most NSAIDs function by inhibiting biosynthesis of PGE2 by inhibition of COX-1 and/or COX-2. Since COX-1 has a protective function in the gastro-intestinal tract (GIT), non-selective inhibition of both cycloxy genases leads to moderate to severe gastro-intestinal intolerance. Attempts to identify selective inhibitors of COX-2, led to the identification of celecoxib and rofecoxib. However, long-term use of these drugs has serious adverse effects of sudden myocardial infarction and thrombosis. Drug-mediated imbalance in the levels of prostaglandin I2 (PGI2) and thromboxane A2 (TXA2) with a bias towards TXA2 may be the primary reason for these events. This resulted in the drugs being withdrawn from the market, leaving a need for an effective and safe anti-inflammatory drug. Methods: Recently, the focus of research has shifted to enzymes downstream of COX in the prosta glandin biosynthetic pathway such as prostaglandin E2 synthases. Microsomal prostaglandin E2 synthase-1 (mPGES-1) specifically isomerizes PGH2 to PGE2, under inflammatory conditions. In this review, we examine the biology of mPGES-1 and its role in disease. Progress in designing molecules that can selectively inhibit mPGES-1 is reviewed. Conclusion: mPGES-1 has the potential to be a target for anti-inflammatory therapy, devoid of adverse GIT and cardiac effects and warrants further investigation.

Chronic obstructive pulmonary disease: role of matrix metalloproteases and future challenges of drug therapy

COPD is a chronic disease of the lung that is characterised by decreased air flow and associated abnormal inflammatory responses of the lungs. A total of 80% of COPD incidences are observed in patients with history of smoking tobacco. The chronic condition of COPD is characterised by airway remodelling, which leads to emphysema and chronic bronchitis. Inflammatory cells of the immune system play a major role in pathophysiology of COPD. High levels of neutrophils, macrophages and CD8+ T cells have been found in bronchoalveolar lavage samples of COPD patients. Matrix metalloproteases (MMPs), which are secreted by these inflammatory cells, have the enzymatic capacity to cause morphological changes in the lungs and contribute significantly to the COPD state. Increased concentrations of MMP-1, -2, -9, -12 and so on have been found in bronchoalveolar lavage samples of COPD patients compared with non-COPD individuals. COPD is rated as among the top five diseases with high mortality rates and it is estimated that in the next 20 years, the healthcare cost alone for COPD will be US

Therapeutic potential of matrix metalloprotease inhibitors in neuropathic pain

800 million worldwide. The present drug therapies are neither very efficacious nor cost effective; hence, there is unmet medical need to discover small-molecule drugs for COPD. In this regard, synthetic MMP inhibitors show a great promise for COPD treatment.

Heterocyclic compounds as protein kinase inhibitors

Importance of the field: Millions of people suffer from neuropathic pain (NP), but the treatment is empirical and results in transient relief in only a few patients. This is primarily because of the poor understanding of the molecular mechanism underlying NP. Following nerve injury, there is a differential and temporal pattern of MMPs expression that coincides with changes in levels of pro-inflammatory cytokines, suggesting that MMPs not only act as mediators for neuroinflammation but might also be directly involved in pain associated with nerve damage. Areas covered in this review: The present review describes the different mechanisms of NP. The main focus of the review is to highlight the importance of MMPs in NP and their inhibition as a novel approach for treating NP. What the reader will gain: A comprehensive overview of the role of MMPs in the pathogenesis of NP and the potential of MMP inhibition as a therapeutic intervention for NP. Take home message: Targeted therapy using specific MMP inhibitors, siRNAs, peptide inhibitors and monoclonal antibodies can provide a better way of treatment by blocking a single MMP and can reduce the side effects of broad-spectrum MMP inhibitors.