title: Aprepitant limits in vivo neuroinflammatory responses in a rhesus model of Lyme neuroborreliosis.
abstract: Substance P (SP) is produced at high levels in the central nervous system (CNS), and its target receptor, neurokinin 1 receptor (NK-1R), is expressed by glia and leukocytes. This tachykinin functions to exacerbate inflammatory responses at peripheral sites. Moreover, SP/NK-1R interactions have recently been associated with severe neuroinflammation and neuronal damage. We have previously demonstrated that NK-1R antagonists can limit neuroinflammatory damage in a mouse model of bacterial meningitis. Furthermore, we have since shown that these agents can attenuate Borrelia burgdorferi-induced neuronal and glial inflammatory mediator production in non-human primate brain explants and isolated neuronal cells.
  
  
  
  In the present study, we have assessed the role played by endogenous SP/NK-1R interactions in damaging CNS inflammation in an established rhesus macaque model that faithfully reproduces the key clinical features of Lyme neuroborreliosis, using the specific NK-1R antagonist, aprepitant. We have utilized multiplex ELISA to quantify immune mediator levels in cerebrospinal fluid, and RT-PCR and immunoblot analyses to quantify cytokine and NK-1R expression, respectively, in brain cortex, dorsal root ganglia, and spinal cord tissues. In addition, we have assessed astrocyte number/activation status in brain cortical tissue by immunofluorescence staining and confocal microscopy.
  
  
  
  We demonstrate that aprepitant treatment attenuates B. burgdorferi-induced elevations in CCL2, CXCL13, IL-17A, and IL-6 gene expression in dorsal root ganglia, spinal cord, and/or cerebrospinal fluid of rhesus macaques at 2 to 4 weeks following intrathecal infection. In addition, we demonstrate that this selective NK-1R antagonist also prevents increases in total cortical brain NK-1R expression and decreases in the expression of the astrocyte marker, glial fibrillary acidic protein, associated with B. burgdorferi infection.
  
  
  
  The ability of a centrally acting NK-1R inhibitor to attenuate B. burgdorferi-associated neuroinflammatory responses and sequelae raises the intriguing possibility that such FDA-approved agents could be repurposed for use as an adjunctive therapy for the treatment of bacterial CNS infections.
authors.affiliation: Division of Bacteriology and Parasitology, Tulane National Primate Research Center, 18703 Three Rivers Rd., Covington, LA, 70433, USA.
authors.forename: Alejandra N
authors.initials: AN
authors.lastname: Martinez
authors.affiliation: Department of Biology, University of North Carolina at Charlotte, 9201 University City Blvd., Charlotte, NC, 28223, USA.
authors.forename: Amanda R
authors.initials: AR
authors.lastname: Burmeister
authors.affiliation: Division of Bacteriology and Parasitology, Tulane National Primate Research Center, 18703 Three Rivers Rd., Covington, LA, 70433, USA.
authors.forename: Geeta
authors.initials: G
authors.lastname: Ramesh
authors.affiliation: Division of Bacteriology and Parasitology, Tulane National Primate Research Center, 18703 Three Rivers Rd., Covington, LA, 70433, USA.
authors.forename: Lara
authors.initials: L
authors.lastname: Doyle-Meyers
authors.affiliation: Department of Biology, University of North Carolina at Charlotte, 9201 University City Blvd., Charlotte, NC, 28223, USA. imarriot@uncc.edu.
authors.forename: Ian
authors.initials: I
authors.lastname: Marriott
authors.affiliation: Division of Bacteriology and Parasitology, Tulane National Primate Research Center, 18703 Three Rivers Rd., Covington, LA, 70433, USA. philipp@tulane.edu.
authors.forename: Mario T
authors.initials: MT
authors.lastname: Philipp
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000077608:Aprepitant; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D025065:Borrelia burgdorferi / Q000502:physiology; D018932:Chemokine CCL2 / Q000134:cerebrospinal fluid; D054382:Chemokine CXCL13 / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004660:Encephalitis / Q000188:drug therapy* / Q000209:etiology* / Q000473:pathology; D005260:Female; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D020852:Lyme Neuroborreliosis / Q000150:complications*; D008253:Macaca mulatta; D008297:Male; D009025:Morpholines / Q000627:therapeutic use*; D064729:Neurokinin-1 Receptor Antagonists / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D018040:Receptors, Neurokinin-1 / Q000235:genetics / Q000378:metabolism; D013997:Time Factors
chemical_list: D018932:Chemokine CCL2; D054382:Chemokine CXCL13; D016207:Cytokines; D005904:Glial Fibrillary Acidic Protein; D009025:Morpholines; D064729:Neurokinin-1 Receptor Antagonists; D012333:RNA, Messenger; D018040:Receptors, Neurokinin-1; D000077608:Aprepitant
keywords: Borrelia burgdorferi; Lyme neuroborreliosis; NK-1R antagonist; Neuroinflammation; Substance P