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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS050325-08
Application #
8848896
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Wong, May
Project Start
2004-12-01
Project End
2016-05-31
Budget Start
2015-06-01
Budget End
2016-05-31
Support Year
8
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of North Carolina Charlotte
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
066300096
City
Charlotte
State
NC
Country
United States
Zip Code
28223
Martinez, Alejandra N; Burmeister, Amanda R; Ramesh, Geeta et al. (2017) Aprepitant limits in vivo neuroinflammatory responses in a rhesus model of Lyme neuroborreliosis. J Neuroinflammation 14:37
Burmeister, Amanda R; Johnson, M Brittany; Chauhan, Vinita S et al. (2017) Human microglia and astrocytes constitutively express the neurokinin-1 receptor and functionally respond to substance P. J Neuroinflammation 14:245
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Jeffries, Austin M; Marriott, Ian (2017) Human microglia and astrocytes express cGAS-STING viral sensing components. Neurosci Lett 658:53-56
Martinez, Alejandra N; Philipp, Mario T (2016) Substance P and Antagonists of the Neurokinin-1 Receptor in Neuroinflammation Associated with Infectious and Neurodegenerative Diseases of the Central Nervous System. J Neurol Neuromedicine 1:29-36
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Martinez, Alejandra N; Ramesh, Geeta; Jacobs, Mary B et al. (2015) Antagonist of the neurokinin-1 receptor curbs neuroinflammation in ex vivo and in vitro models of Lyme neuroborreliosis. J Neuroinflammation 12:243
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Chauhan, Vinita S; Kluttz, John M; Bost, Kenneth L et al. (2011) Prophylactic and therapeutic targeting of the neurokinin-1 receptor limits neuroinflammation in a murine model of pneumococcal meningitis. J Immunol 186:7255-63
Furr, Samantha R; Chauhan, Vinita S; Moerdyk-Schauwecker, Megan J et al. (2011) A role for DNA-dependent activator of interferon regulatory factor in the recognition of herpes simplex virus type 1 by glial cells. J Neuroinflammation 8:99

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