We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Aprepitant limits in vivo neuroinflammatory responses in a rhesus model of Lyme neuroborreliosis.
- Authors
Martinez, Alejandra N.; Burmeister, Amanda R.; Ramesh, Geeta; Doyle-Meyers, Lara; Marriott, Ian; Philipp, Mario T.
- Abstract
<bold>Background: </bold>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.<bold>Methods: </bold>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.<bold>Results: </bold>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.<bold>Conclusions: </bold>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.
- Subjects
SUBSTANCE P receptors; CENTRAL nervous system; NEUROGLIA; TACHYKININS; GLIAL fibrillary acidic protein; CELL metabolism; RNA metabolism; GRAM-negative bacteria; HETEROCYCLIC compounds; ANALYSIS of variance; ANIMALS; BIOLOGICAL models; CELL receptors; CELLS; CYTOKINES; CYTOSKELETAL proteins; ENCEPHALITIS; SENSORY ganglia; INFLAMMATORY mediators; LYME neuroborreliosis; NEUROTRANSMITTER receptors; PRIMATES; RESEARCH funding; TIME; CENTRAL nervous system infections; CHEMICAL inhibitors; DISEASE complications; PHYSIOLOGY
- Publication
Journal of Neuroinflammation, 2017, Vol 14, p1
- ISSN
1742-2094
- Publication type
journal article
- DOI
10.1186/s12974-017-0813-x