Abstract
Pneumococcal meningitis is associated with high morbidity and mortality rates. Brain damage caused by this disease is characterized by apoptosis in the hippocampal dentate gyrus, a morphological correlate of learning deficits in experimental paradigms. The mood stabilizer lithium has previously been found to attenuate brain damage in ischemic and inflammatory diseases of the brain. An infant rat model of pneumococcal meningitis was used to investigate the neuroprotective and neuroregenerative potential of lithium. To assess an effect on the acute disease, LiCl was administered starting five days prior to intracisternal infection with live Streptococcus pneumoniae. Clinical parameters were recorded, cerebrospinal fluid (CSF) was sampled, and the animals were sacrificed 42 hours after infection to harvest the brain and serum. Cryosections of the brains were stained for Nissl substance to quantify brain injury. Hippocampal gene expression of Bcl-2, Bax, p53, and BDNF was analyzed. Lithium concentrations were measured in serum and CSF. The effect of chronic lithium treatment on spatial memory function and cell survival in the dentate gyrus was evaluated in a Morris water maze and by quantification of BrdU incorporation after LiCl treatment during 3 weeks following infection. In the hippocampus, LiCl significantly reduced apoptosis and gene expression of Bax and p53 while it increased expression of Bcl-2. IL-10, MCP-1, and TNF were significantly increased in animals treated with LiCl compared to NaCl. Chronic LiCl treatment improved spatial memory in infected animals. The mood stabilizer lithium may thus be a therapeutic alternative to attenuate neurofunctional deficits as a result of pneumococcal meningitis.
Highlights
Pneumococcal meningitis (PM) causes high mortality and morbidity and leads to persisting sequelae in up to 50% of affected children, including deficits in academic, executive and intellectual performance, which persist into adulthood [1,2,3,4]
Injury to the brain occurs in 3 specific forms characterized by sensorineural hearing loss due to damage to the inner ear, ischemic necrosis of the cortex and apoptosis in the dentate gyrus (DG) of the hippocampus
Lithium serum concentrations have to be closely monitored to prevent toxic effects which are observed above 1.5 mmol/l while neurological symptoms are associated with serum levels . 2 mmol/l [16,17]
Summary
Pneumococcal meningitis (PM) causes high mortality and morbidity and leads to persisting sequelae in up to 50% of affected children, including deficits in academic, executive and intellectual performance, which persist into adulthood [1,2,3,4]. Injury to the brain occurs in 3 specific forms characterized by sensorineural hearing loss due to damage to the inner ear, ischemic necrosis of the cortex and apoptosis in the dentate gyrus (DG) of the hippocampus. Lithium is water-soluble, does not bind to plasma proteins and rapidly reaches the brain where it has been described to accumulate in the cells [15] It is administrated in the form of lithium salts, e.g. LiCl and excreted without metabolization by the kidneys where around 80% are reabsorbed in the proximal tube [10]. GSK-3b is rapidly and reversibly inhibited by lithium through multiple pathways with an IC50,2 mmol/l, while the mood stabilizing effects are apparent after chronic administration aimed at concentrations of ,1 mmol/l and may involve different mechanisms [22,23,24].
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