Title: role of matrix metalloproteinase -9 in progression of tuberculous meningitis: a pilot study in patients at different stages of the disease.

S Majeed,P Singh,S Sharma,N Sharma

doi:10.1186/s12879-016-1953-9

S Majeed, P Singh + Show 2 more

Open Access

https://doi.org/10.1186/s12879-016-1953-9

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Abstract

BackgroundTBM (Tuberculous meningitis) is severe form of tuberculosis causing death of one third of the affected individuals or leaving two-third of the survivors disabled. MMP-9 (Matrix metalloproteinase-9) is produced by the central nervous system in a variety of inflammatory conditions and has a role in the breakdown of extracellular matrix and blood–brain barrier.MethodsIn this study, the levels of MMP-9 and its inhibitor, TIMP-1 (tissue inhibitor of metalloproteinases-1), were screened using zymography and reverse zymography in cerebrospinal fluid and serum of tuberculous meningitis patients at different stages of the disease. Further, role of MMP-9 as therapeutic target was studied in C6 glioma cells infected with Mycobacterium tuberculosis H37Rv. Cells were treated with dexamethasone or SB-3CT (specific inhibitor of MMP-9) in combination with conventional antitubercular drugs.ResultsMMP-9 levels in patients were increased as the disease progressed to advanced stages. The infection led to increased MMP-9 levels in C6 glioma cells and specific inhibition of MMP-9 by SB-3CT augmented bacillary clearance when used along with antitubercular drugs.ConclusionMMP-9 plays a prominent role in progression of tuberculous meningitis from initial to advanced stages. Increased levels of MMP-9 during advancement of the disease leads to degeneration of nervous tissue and blood brain barrier disruption. Hence, MMP-9 can be considered as a therapeutic target for efficient management of TBM and can be explored to inhibit further progression of the disease if used at an early stage.

Highlights

TBM (Tuberculous meningitis) is severe form of tuberculosis causing death of one third of the affected individuals or leaving two-third of the survivors disabled
Effect of specific inhibition of Matrix metalloproteinase-9 (MMP-9) on clearing the bacterial burden were further evaluated in C6 glioma cells infected with Mycobacterium tuberculosis H37Rv
The amount of MMP-9 in Cerebrospinal fluid (CSF) samples was quantified by comparing their densitomertic values with those of known concentration of MMP-9 standard

Summary

Introduction

TBM (Tuberculous meningitis) is severe form of tuberculosis causing death of one third of the affected individuals or leaving two-third of the survivors disabled. Severe clinical manifestations of tuberculous meningitis occur due to robust inflammatory response generated in the brain against pathogenic bacilli [3] During this process, microglial cells are activated to secrete proteases which have ability to degrade. Specific inhibitor of MMP-9, SB-3CT has come forth with desirable properties of crossing blood brain barrier and therapeutic effects for treating neurological diseases due to inflammation [10]. This inhibitor has been studied for ischemia of immature brain and found to work efficiently; showing its utility in pediatric cases [11]. Effect of specific inhibition of MMP-9 on clearing the bacterial burden were further evaluated in C6 glioma cells infected with Mycobacterium tuberculosis H37Rv

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