In a model of cerebral ischemia, reduction of infarct size and improved neurological outcome after pre-treatment for 16 days with lithium has been described. In the present study, injury to the cortex was only modestly reduced in lithium treated animals. Whether reduced inflammation observed in some other experimental settings is a primary effect of lithium application or results from less injury is unknown. Lithium has been described to act both, pro- and anti-inflammatory and it is known to induce leukocytosis. In the present study,Eupalinilide-D significant up-regulation of TNF, IL-10, and MCP-1 during acute PM was observed in lithium-treated animals, indicating a higher degree of inflammation while IL-1b and IFN-c were down-regulated without reaching statistical significance. Other reports described increasing IL-10 and decreasing TNF concentrations after lithium treatment. However, the effect of lithium on these and other cytokines varied under different conditions. For example, one study reported Eupalinilide-C increased TNF secretion by neutrophils after lithium treatment during an acute inflammatory reaction. In this study, mRNA levels of TNF were not altered, indicating a post-transcriptional regulation. TNF is an early response cytokine triggering an intense immune response and has been targeted in meningitis models as a therapeutic approach. Though, inhibition of TNF activity may be a double-edged sword and interventions aimed at specific immunological mechanisms need to be well balanced. Lithium may increase inflammation locally, evidenced in the present study by raised cyto-/chemokines in CSF samples, while having specific anti-apoptotic properties and preventing hippocampal damage, but not cortical necrosis. In summary, LiCl was able to reduce apoptosis in the hippocampus by favorably modulating the expression of genes involved in the apoptotic machinery. In contrast, LiCl treatment had no impact on weight loss or clinical score. Furthermore, inflammation was not attenuated by LiCl administration and no significant effect on cortical damage could be observed. These proof-of-concept experiments were the basis to investigate the effects of lithium in an adjuvant setting with a clinically relevant treatment regimen.