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Substance P and Antagonists of the Neurokinin-1 Receptor In Martinez AN and Philipp MT, J Neurol Neuromed (2016) 1(2): 29-36 Neuromedicine www.jneurology.com www.jneurology.com Journal of Neurology & Neuromedicine Mini Review Article Open Access Substance P and Antagonists of the Neurokinin-1 Receptor in Neuroinflammation Associated with Infectious and Neurodegenerative Diseases of the Central Nervous System Alejandra N. Martinez1 and Mario T. Philipp1,2* 1Division of Bacteriology & Parasitology, Tulane National Primate Research Center, Covington, LA, USA 2Department of Microbiology and Immunology, Tulane University Medical School, New Orleans, LA, USA Article Info ABSTRACT Article Notes This review addresses the role that substance P (SP) and its preferred receptor Received: May 03, 2016 neurokinin-1 (NK1R) play in neuroinflammation associated with select bacterial, Accepted: May 18, 2016 viral, parasitic, and neurodegenerative diseases of the central nervous system. *Correspondence: The SP/NK1R complex is a key player in the interaction between the immune Division of Bacteriology and Parasitology and nervous systems. A common effect of this interaction is inflammation. For Tulane National Primate Research Center this reason and because of the predominance in the human brain of the NK1R, Covington, LA, USA its antagonists are attractive potential therapeutic agents. Preventing the Email: [email protected] deleterious effects of SP through the use of NK1R antagonists has been shown © 2016 Philipp MT. This article is distributed under the terms of to be a promising therapeutic strategy, as these antagonists are selective, the Creative Commons Attribution 4.0 International License potent, and safe. Here we evaluate their utility in the treatment of different neuroinfectious and neuroinflammatory diseases, as a novel approach to Keywords clinical management of CNS inflammation. Substance P NK1R antagonist Central Nervous System Neuroinflammation Neurodegeneration Pathogens Page 29 of 36 Martinez AN and Philipp MT, J Neurol Neuromed (2016) 1(2): 29-36 Journal of Neurology & Neuromedicine Introduction Neuroinflammation and Substance P The SP/NK1R system plays an important role in Acute insults to the CNS can be caused by injury or neuroinflammation. SP is encoded by the TAC1 gene and infection and are usually accompanied by inflammatory belongs to a large family of structurally related peptides, responses. Classical neuroinflammatory responses are the tachykinins.1 These are small peptides broadly characterized by glial activation, proliferation of9 microglia, distributed in the central (CNS) and peripheral nervous leukocyte recruitment, and up-regulation and secretion of systems (PNS) . The major mammalian tachykinin peptides mediators such as cytokines and chemokines . SP plays a 2 include SP, neurokinin A (NKA), and neurokinin B (NKB),2 major pathogenic role as it is an important mediator of both together with NH -terminally extended forms of NKA, inflammation and increased10 blood-brain barrier (BBB) neuropeptide K (NPK),3 and neuropeptide γ (NKγ) . The permeability in the CNS . In addition, SP is a potent initiator primary structures of SP, NKA and NKB are very similar in of neurogenic inflammation, which differs from classical all mammalian species . inflammation in that it is neurally elicited and results in vasodilation, plasma extravasation, tissue swelling, mast SP has a high affinity for the NK1 receptor, to which4 it binds preferentially. It also binds to the other tachykinin cell degranulation, and increased permeability4,11 of the BBB receptors, NK2R and NK3R, with lower affinity . SP through the release of neuropeptides . In this context, SP is increasingly being recognized as an important element and its cognate5 receptors are present in neurons, as well as in microglia, endothelial cells, and peripheral in the pathogenesis of many neurological diseases. immune cells . Due in part to its diverse anatomical SP is widely distributed 12throughout the CNS, PNS, and distribution, the SP/NK1R system is found to be involved enteric nervous systems. It is present in dorsal root ganglia in a variety of complex physiological responses including (primary sensory) neurons , as well as in many regions pain, emotion, neuroinflammation, and microvascular of the CNS, including the hippocampus, cortex, basal permeability. Preventing the actions of SP through the use ganglia, hypothalamus, amygdala, caudate nucleus, and of NK1 receptor antagonists is emerging as a promising spinal cord. It is more abundant in the grey 13matter, more therapeutic approach for treatment of neuroinflammatory specifically, in the substantia nigra (SN), which contains a conditions. Thus, we reviewed preclinical and clinical disproportionately high density of microglia . Therefore, studies on the effectiveness of NK1R antagonist treatment SP and its preferred receptor, NK1R, are key mediators in of CNS inflammation due to bacterial, viral, parasitic or the interaction between the immune and nervous systems. 2 neurodegenerativeStructure and Processing diseases. of SP and the NK1R SP signaling can activate different pathways depending on the cell type involved . Once released, SP may have direct post-synaptic actions as a neurotransmitter, modulatory SP, an undecapeptide,6 is derived from the function at post-synaptic11,14 sites, or other functions on non- preprotachykinin-A gene, which is differentially spliced neuronal targets . The major pathways activated by the to form different mRNAs . It is synthesized, mostly by SP/NK1R complex lead to phosphoinositide hydrolysis, neurons, as a large protein, and is transported to the calcium mobilization, and15,16 mitogen-activated protein neuronal terminal endings, where it is enzymatically kinase (MAPK) activation . These pathways are involved converted into the active form and stored in vesicles ready in neuroinflammation,14,17,18 neuronal excitation, cell survival for release. Its preferred endogenous receptor, NK1R, is a and cell migration . SP is capable of activating NFkB, G protein-coupled receptor with seven transmembrane which affects the regulation19 of various inflammatory domains 7and diverse downstream pathways, which genes, thus explaining its effects on chemotaxis and other vary depending upon the cell type where the receptor inflammatory mechanisms . The role of SP can be best is located . There are two NK1R isoforms: a truncated described as that of a pleiotropic immune regulator. isoform (311 aa) that lacks most of the intracellular C-tail and a full-length form (407 aa). The full-length form is SP exacerbates neurodegeneration in several expressed in several brain regions, with the exception neuroinflammatory conditions that are initiated in of the cerebellum. The truncated form is predominately response to a variety of cues, including infection with found in peripheral tissues,8 elicits a diminished calcium bacteria, viruses, or parasites, traumatic20 brain injury, response and has a 10-fold lower binding affinity to SP toxic metabolites, or autoimmunity . There are unique than the full-length form . Upon SP stimulation, NK1R is2 relationships between tachykinins andBorrelia CNS invasionburgdorferi by internalized by the clathrin-dependent mechanism to the bacteria. Studies involving bacterial infections have 21shown acidified endosomes, where the complex disassociates . that SP can synergistically augment The fate of the internalized receptor depends on the induced expression of COX-2 in murinein vivo microglia , and stimulation conditions. Thus, low concentrations of SP that endogenousNeisseria SP/NK1R meningitidis interactions or B.are burgdorferi required for lead to its degradation and recycling of NK1R to the cell maximal inflammatory responsesB. burgdorferi to challenge with22,23 surface. Conversely, after sustained 2incubation with high bacteria such as . SP concentrations, as may occur during inflammation, Similarly, the interaction of with cultured NK1R is ubiquitinated and degraded . rhesus macaque DRG neurons and DRG tissue explants in Page 30 of 36 Martinez AN and Philipp MT, J Neurol Neuromed (2016) 1(2): 29-36 Journal of Neurology & Neuromedicine the presence and absence of an NK1R antagonist23 indicated High levels of SP are present in the SN, where it binds to that activation of the NK1R by SP may contribute to the NK1Rs expressed on dopaminergic neurons. Subsequent topathophysiology Streptococcus ofpneumonia Lyme neuroborreliosis . Also, SP has intointernalization the striatum of the SP/NK1R complex activates a been shown to enhance inflammatory22 glial responses cascade of events40 that lead to the release of dopamine , the major Gram-positive . SP and dopamine regulation work in a causative agent of bacterial meningitis . positive feedback38,41 mechanism as dopamine can potentiate the release of SP42-44 . Therefore, SP decline is seen in post- SP has also been studied in the context of neuroparasitic mortem PD brains and in models that replicate the late stages infections. It has been linked to24 the induction of seizures the helminth Taenia crassiceps of the disease , as a secondary effect of dopaminergic in a rodent model of neurocysticercosis (NCC), caused by degeneration. The functional role of SP in the regulation . SP was also implicated Trypanosoma of neuroinflammation and dopaminergic neuron survival45 in the development of post-treatment inflammatory brucei remains elusive. One study showed that SP helps to restore encephalopathy (PTRE) in a murine model of dopamine deficit in the brain in an animal model of PD . infection.
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