The tachykinin, substance P (SP) mediates a variety of biological effects via high affinity neurokinin-1 receptors (NK-1R), and NK-1R antagonists have been extensively studied for use in the treatment of a variety of disease conditions. We have assembled a compelling body of evidence indicating that SP/NK-1R interactions exacerbate classical inflammation within the central nervous system (CNS). During the previous funding period, we have shown that SP exacerbates the inflammatory responses of isolated murine microglia and astrocytes to clinically relevant bacterial pathogens. Furthermore, we have demonstrated that endogenous SP/NK-1R interactions are required for maximal inflammation and CNS damage in murine models of bacterial meningitis. Most importantly, we have shown that systemic prophylactic or therapeutic administration of an NK-1R antagonist can markedly attenuate bacterially-induced neuroinflammation in our mouse models. For this continuation application, we have established an exciting new collaboration between uniquely qualified researchers to perform a comprehensive preclinical evaluation of the ability of SP to augment classical inflammation in isolated primary human CNS cells and a non-human primate (NHP) model of bacterial meningitis. We will test the hypothesis that inhibition of SP/NK-1R interactions attenuates immune responses of human and NHP microglia and astrocytes to clinically relevant bacterial pathogens thereby limiting inflammatory CNS damage. These experiments build upon our recent rodent studies and their performance will contribute significantly to our understanding of the role played by this neuropeptide in the initiation and/or exacerbation of the immune functions of resident human/NHP CNS cells that occur in response to bacterial infection. As such, these studies will provide essential information in resolving the cellular mechanisms that precipitate classical inflammation within the human/NHP brain during disease states. Furthermore, these studies represent a substantial and possibly final preclinical and translational phase to evaluate the therapeutic potential of NK-1 receptor antagonists in the treatment of classical CNS inflammation prior to human trials.
Substance P (SP) mediates a variety of biological effects via high affinity neurokinin-1 receptors (NK-1R), and NK-1R antagonists have been extensively studied for use in the treatment of a variety of disease conditions. We have assembled a compelling body of evidence indicating that SP/NK-1R interactions exacerbate classical inflammation within the central nervous system (CNS). The experiments proposed in this competing continuation will provide essential information in resolving the cellular mechanisms that precipitate classical inflammation within brain during disease states. More importantly, these studies represent a substantial and possibly final preclinical and translational phase to evaluate the therapeutic potential of NK-1R antagonists in the treatment of classical CNS inflammation prior to human trials.
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