DEXAMETHASONE TREATMENT OF LIPOPOLYSACCHARIDE-INDUCED MENINGITIS IN RABBITS THAT MIMICS MAGNIFICATION OF INFLAMMATION FOLLOWING ANTIBIOTIC-THERAPY

The objective of adjunct anti-inflammatory therapy of bacterial mening itis is the containment of heightened inflammation caused by lysis of bacteria by antibiotics. This can be modelled by giving two consecutiv e intra-cisternal injections of lipopolysaccharide (LPS) to rabbits, t he first at Oh to induce inflammation to mimic that occurring during t he proliferation of bacteria in the cerebrospinal fluid (CSF), and the second at 6 h to mimic inflammation subsequent to antibiotic-induced bacterial lysis: Injection of 2.5 ng of LPS induced pleocytosis at 4 h which was preceded by a peak of tumour necrosis factor (TNF) activity at 2 h. A subsequent injection of 25 ng of LPS at 6 h induced second peaks of pleocytosis and CSF TNF. Dexamethasone (1.5 mg/kg, i.v.) admi nistered 15 min or 1 h before the second injection of LPS tended only to reduce CSF TNF, but effectively prohibited further pleocytosis. Bra in TNF alpha mRNA levels were unchanged at 6 and 7 h after LPS injecti on, and were unaffected by dexamethasone. These results indicate that the subarachnoid space is distinct from the general circulation in tha t the TNF-producing cells present do not display a hypo-responsive sta te towards LPS as occurs when LPS is injected systemically. Furthermor e, dexamethasone is able to attenuate the secondary inflammatory respo nse resulting from a second LPS injection without eliminating a second peak of TNF activity.