There are fewer reports of brain infection by Klebsiella pneumoniae than there are in other organs, but an increase incidence and morbidity has been noted. We have previously developed a rat model of K. pneumoniae meningoencephalitis. Cortistatin (CST) is a recently discovered neuropeptide with endocrine activities in humans. In this study, we found that brain infection by K. pneumoniae increased endogenous prepro-CST messenger RNA expression, which occurred earlier than did leukocyte infiltration in vivo and also occurred in cultured neuron-glia. Postinfection treatment with CST (either intracerebroventricularly or intraperitoneally), but not somatostatin, reduced leukocyte recruitment and clinical illness as revealed by fever and clinical score in vivo. Postinfection increases of proinflammatory cytokine messenger RNA levels were attenuated by CST in neuron-glia cultures, further confirming a direct effect on neuroinflammation. Administration of CST resulted in less postinfection neuronal loss in vitro, suggesting a direct neuroprotective effect and potential as an adjuvant for treating bacterial meningoencephalitis.