title: Prophylactic and therapeutic targeting of the neurokinin-1 receptor limits neuroinflammation in a murine model of pneumococcal meningitis.
abstract: There is increasing evidence that the tachykinin substance P (SP) can augment inflammatory immune responses within the CNS. We have recently demonstrated that resident CNS cells express high-affinity receptors for this neuropeptide (neurokinin-1 receptors [NK-1R]), and we have shown that SP can significantly augment glial inflammatory responses to clinically relevant Gram-negative bacteria. Furthermore, we provided evidence that endogenous SP/NK-1R interactions are an essential component in the initiation and/or progression of CNS inflammation following in vivo exposure to these pathogens. In this study, we demonstrate that SP similarly enhances inflammatory glial responses to the major Gram-positive causative agent of bacterial meningitis, Streptococcus pneumoniae, and show that endogenous SP/NK-1R interactions play a critical role in the development of CNS inflammation in an in vivo model of pneumococcal meningitis. Importantly, we provide the first demonstration, to our knowledge, that pharmacological targeting of the NK-1R not only prevents the development of damaging inflammation when administered prophylactically, but can also limit or reverse neuroinflammation associated with an established streptococcal CNS infection when delivered therapeutically. We show that an NK-1R antagonist attenuates increases in CNS inflammatory cytokine levels and decreases in immunosuppressive cytokine production associated with an ongoing S. pneumoniae infection. Furthermore, we demonstrate that such a therapeutic intervention reverses infection-associated gliosis and demyelination in the absence of changes in CNS bacterial burden. Together, these results suggest that targeting SP/NK-1R interactions is a strategy worthy of further study for the treatment of microbially induced neuroinflammation.
authors.affiliation: Department of Biology, University of North Carolina at Charlotte, Charlotte, NC 28223, USA.
authors.forename: Vinita S
authors.initials: VS
authors.lastname: Chauhan
authors.forename: John M
authors.initials: JM
authors.lastname: Kluttz
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Bost
authors.forename: Ian
authors.initials: I
authors.lastname: Marriott
mesh_terms: D000818:Animals; D002490:Central Nervous System / Q000473:pathology; D016207:Cytokines / Q000096:biosynthesis / Q000187:drug effects; D003711:Demyelinating Diseases; D006090:Gram-Negative Bacteria / Q000187:drug effects; D007249:Inflammation / Q000188:drug therapy* / Q000382:microbiology; D008586:Meningitis, Pneumococcal / Q000188:drug therapy*; D051379:Mice; D064729:Neurokinin-1 Receptor Antagonists
chemical_list: D016207:Cytokines; D064729:Neurokinin-1 Receptor Antagonists