A combination of thalidomide plus antibiotics protects rabbits from mycobacterial meningitis-associated death.
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.
Tsenova
L
L
Laboratory of Cellular Physiology and Immunology, Laboratory Animal Research Center, Rockefeller University, New York, New York 10021, USA.
Sokol
K
K
Freedman
V H
VH
Kaplan
G
G
D000818:Animals; D000904:Antibiotics, Antitubercular / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007538:Isoniazid / Q000627:therapeutic use*; D009163:Mycobacterium bovis; D011817:Rabbits; D012293:Rifampin / Q000627:therapeutic use*; D013792:Thalidomide / Q000627:therapeutic use*; D014390:Tuberculosis, Meningeal / Q000188:drug therapy* / Q000473:pathology
D000904:Antibiotics, Antitubercular; D007166:Immunosuppressive Agents; D013792:Thalidomide; D007538:Isoniazid; D012293:Rifampin