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A combination of thalidomide plus antibiotics protects rabbits from mycobacterial meningitis-associated death
L Tsenova1, K Sokol, V H Freedman
1Laboratory of Cellular Physiology and Immunology, Laboratory Animal Research Center, Rockefeller University, New York, New York 10021, USA.
Abstract:
Tuberculous meningitis (TBM) is a devastating form of tuberculosis that occurs predominantly in children and in immunocompromised adults. To study the pathogenesis of TBM, a rabbit model of acute mycobacterial central nervous system infection was set up (8-day study). Inoculation of live Mycobacterium bovis Ravenel intracisternally induced leukocytosis (predominantly mononuclear cells), high protein levels, and release of tumor necrosis factor-alpha (TNF-alpha) into the cerebrospinal fluid within 1 day. Histologically, severe meningitis with thickening of the leptomeninges, prominent vasculitis, and encephalitis was apparent, and mortality was 75% by day 8. In animals treated with antituberculous antibiotics only, the inflammation and lesions of the brain persisted despite a decrease in mycobacteria; 50% of the rabbits died. When thalidomide treatment was combined with antibiotics, there was a marked reduction in TNF-alpha levels, leukocytosis, and brain pathology. With this combination treatment, 100% of the infected rabbits survived, suggesting a potential clinical use for thalidomide in TBM.
Insights
This study developed a rabbit model for tuberculous meningitis (TBM). Combining antibiotics with thalidomide significantly reduced inflammation and improved survival, suggesting thalidomide as a potential TBM treatment.
Area of Science:
- Neuroscience
- Infectious Diseases
- Immunology
Background:
- Tuberculous meningitis (TBM) is a severe form of tuberculosis affecting the central nervous system, particularly in children and immunocompromised individuals.
- Understanding TBM pathogenesis is crucial for developing effective treatments.
Purpose of the Study:
- To establish and utilize a rabbit model for acute mycobacterial central nervous system infection to study TBM pathogenesis.
- To evaluate the efficacy of combined antibiotic and thalidomide treatment in TBM.
Main Methods:
- Intracisternal inoculation of Mycobacterium bovis Ravenel in rabbits to induce acute TBM.
- Monitoring cerebrospinal fluid for leukocytosis, protein levels, and TNF-alpha.
- Histological examination of brain tissue for meningitis, vasculitis, and encephalitis.
- Assessing survival rates in untreated, antibiotic-treated, and combined antibiotic-thalidomide-treated groups.
Main Results:
- Intracisternal M. bovis induced rapid TBM with significant inflammation (leukocytosis, high protein, TNF-alpha), brain pathology, and 75% mortality by day 8.
- Antibiotic treatment alone reduced mycobacteria but failed to resolve inflammation and brain lesions, resulting in 50% mortality.
- Combination therapy with antibiotics and thalidomide markedly reduced TNF-alpha, leukocytosis, and brain pathology, achieving 100% survival.
Conclusions:
- The rabbit model effectively replicates key features of human TBM.
- Thalidomide, when combined with antibiotics, demonstrates significant therapeutic potential by mitigating inflammation and improving survival in TBM.
- This combination therapy warrants further investigation for clinical application in treating tuberculous meningitis.