Deciphering Tuberculous Meningitis: From Clinical Challenges to Novel Models and Pathogenic Pathways.

During and after the COVID-19 pandemic,Tuberculosis (TB) has reestablished with higher figures due to interruptions in the Directly Observed Treatment Short course (DOTS) despite underreporting. The rising consequences would have extended to extra-pulmonary forms of TB as well, including Tuberculous Meningitis (TBM). Considering the fact that TBM is the most dangerous and worst form of TB, we found the need to scan the literature to highlight various aspects of TBM. Epidemiology of TBM is proportionally less frightening, but the consequent mortalities and morbidities are more alarming than pulmonary TB. Here, we address critical research gaps in Tuberculous Meningitis that warrant further investigations. The highlighted aspects encompass a comprehensive understanding of TBM's clinical presentation and improved diagnostic tools for timely detection, the exploration of innovative chemotherapies and surgical interventions, the unraveling of the role of the blood-brain barrier in disease onset, investigating of the contributions of various brain cells to TBM development, deciphering the complex inflammatory response, exploring the involvement of Matrix Metalloproteinases in tissue damage, delving into host-pathogen genetics influencing susceptibility, utilizing robust in-vivo and in-vitro models for mechanistic insights, and more importantly between TBM and SARS-COVID-19 are discussed. Addressing these gaps will substantially advance our understanding of TBM's complex pathogenesis, contributing to more effective diagnostic, therapeutic, and preventive strategies against this debilitating disease.

Therapeutic implications of nano-encapsulated rifabutin, azithromycin & ethambutol against experimental Mycobacterium avium infection in mice.

Background & objectives: Mycobacterium avium causes atypical infection in both immunocompetent and immunocompromised individuals. Conventional chemotherapy for M. avium infection is not efficient due to lengthy course of treatment and drug-associated toxic side effects. The present study was aimed at reducing dosing frequency of antimicrobial regimen consisting of azithromycin (AZM), rifabutin (RBT) and ethambutol (EMB) by encapsulation of drugs in nanoparticles (NPs) in experimental M. avium infection in mice. Methods: Poly (DL-lactide-co-glycolide) NPs containing anti-M. avium drugs were prepared, characterized and studied for their pharmacokinetics and pharmacodynamics parameters. Drug-loaded NPs were further analyzed for their therapeutic efficacy against experimental M. avium infection in mice. Results: Drug-loaded NPs were of size 227.3±16.4 for RBT, 334.35±11.7 for AZM and 509.85±20.5 for EMB with smooth surface morphology and negative zeta potential. AZM, EMB and RBT from NPs were detectable for 6, 4 and 5 days, respectively, in the mice plasma, whereas free drugs were cleared from mice circulation within 24 h. Chemotherapeutic effects of weekly administered drug-loaded NPs were equivalent to daily administered free drugs. Interpretation & conclusions: Our findings showed that NPs gave sustained release of drugs inside plasma and organs, thus decreasing dosage frequency, and their weekly dosage had therapeutic efficacy equivalent to daily dosage of free drugs.

Adjunctive role of MMP-9 inhibition along with conventional anti-tubercular drugs against experimental tuberculous meningitis.

Tuberculous meningitis (TBM) is an outcome of neuroinflammatory degeneration caused due to Mycobacterium tuberculosis infection and leads to death or neurological disabilities in the affected individuals. It causes the highest morbidity and mortality amongst all forms of tuberculosis. Matrix metalloproteinase-9 levels increase and cause inflammatory destruction during progression of the disease. Although corticosteroids are usually given as an adjuvant therapy to overcome these complications, treatment outcome is contradictory. This study was designed to evaluate whether specific inhibition of MMP-9 can be beneficial in management of the disease. MMP-9 levels were inhibited using SB-3CT or dexamethasone along with conventional drugs for treatment of tuberculous meningitis. Both SB-3CT and dexamethasone decreased the elevated levels of MMP-9 in sera and tissues of the infected mice. However, dexamethasone administration had an inhibitory effect on bacillary clearance, while SB-3CT potentiated the bacillary clearance, suggesting that MMP-9, if specifically inhibited, can be beneficial in the management of TBM.