Neurogenic inflammation

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Neurogenic inflammation is inflammation arising from the local release by afferent neurons of inflammatory mediators such as Substance P, Calcitonin Gene-Related Peptide (CGRP), neurokinin A (NKA), and endothelin-3 (ET-3).[1][2][3] In such neurons, release of these pro-inflammatory mediators is thought to be triggered by the activation of ion channels that are the principal detectors of noxious environmental stimuli. In particular, the heat/capsaicin receptor TRPV1[4] and the irritant/wasabi receptor TRPA1.[5][6][7] TRPA1 channels stimulated by lipopolysaccharide (LPS) may also cause acute neurogenic inflammation.[8] Once released, these neuropeptides induce the release of histamine from adjacent mast cells. In turn, histamine evokes the release of substance P and calcitonin gene-related peptide; thus, a bidirectional link between histamine and neuropeptides in neurogenic inflammation is established.[9]

Neurogenic inflammation appears to play an important role in the pathogenesis of numerous diseases including migraine,[10][1][11][12] psoriasis,[2][13][14] asthma,[15] vasomotor rhinitis,[16] fibromyalgia, eczema, rosacea, dystonia, and multiple chemical sensitivity. [17][18][19]

In migraine, stimulation of the trigeminal nerve causes neurogenic inflammation via release of neuropeptides including Substance P, nitric oxide, vasoactive intestinal polypeptide, 5-HT, Neurokinin A and CGRP.[20][21] leading to a "sterile neurogenic inflammation."[22]

Prevention[edit]

Magnesium deficiency causes neurogenic inflammation in a rat model. Researchers have theorized that since substance P which appears at day five of induced magnesium deficiency, is known to stimulate in turn the production of other inflammatory cytokines including IL-1, Interleukin 6 (IL-6), and TNF-alpha (TNFα), which begin a sharp rise at day 12, substance P is a key in the path from magnesium deficiency to the subsequent cascade of neuro-inflammation.[23] In a later study, researchers provided rats dietary levels of magnesium that were reduced but still within the range of dietary intake found in the human population, and observed an increase in substance P, TNF alpha (TNFα) and Interleukin-1 beta (IL-1β), followed by exacerbated bone loss. These and other data suggest that deficient dietary magnesium intake, even at levels not uncommon in humans, may trigger neurogenic inflammation and lead to an increased risk of osteoporosis.[24]

Treatment[edit]

In 2018, three CGRP blockers were approved by the FDA for the prevention of migraine: erenumab; fremanezumab; and galcanezumab.

The calcitonin gene-related peptide (CGRP) is a therapeutic target in migraine because of its hypothesized role in mediating trigeminovascular pain transmission and the vasodilatory component of neurogenic inflammation (see "Pathophysiology, clinical manifestations, and diagnosis of migraine in adults", section on 'Role of calcitonin gene-related peptide'). In 2018, the US Food and Drug Administration (FDA) approved the CGRP antagonists erenumab [36], fremanezumab [37], and galcanezumab [38] for migraine prevention.
Smith, "Preventive treatment of migraine in adults" UpToDate 2019[25]

Additional CGRP blockers are progressing through clinical trials.[26]

Anticipating later botox therapy for migraine, early work by Jancsó et al. found some success in treatment using denervation or pretreatment with capsaicin to prevent uncomfortable symptoms of neurogenic inflammation.[27]

A 2010 study of the treatment of migraine with CGRP blockers had shown promise for CGRP blockers.[28] In early trials, the first oral nonpeptide CGRP antagonist, MK-0974 (Telcagepant), was shown effective in the treatment of migraine attacks,[29] but elevated liver enzymes in two participants were found. Other therapies and other links in the neurogenic inflammatory pathway for interruption of disease are under study, including migraine therapies.[30]

Noting that botulinum toxin has been shown to have an effect on inhibiting neurogenic inflammation, and evidence suggesting the role of neurogenic inflammation in the pathogenesis of psoriasis,[14] the University of Minnesota has a pilot clinical trial underway to follow up on the observation that patients treated with botulinum toxin for dystonia had dramatic improvement in psoriasis.[31]

Astelin (Azelastine) "is indicated for symptomatic treatment of vasomotor rhinitis including rhinorrhea, nasal congestion, and post nasal drip in adults and children 12 years of age and older."[32][33]

Statins appear to "decrease expression of the proinflammatory neuropeptides calcitonin gene-related peptide and substance P in sensory neurons,"[34] and so might be of use in treating diseases presenting with predominant neurogenic inflammation.

Research[edit]

In a 2012 article[35] in Nature Neuroscience Chiu et al. discuss the development of science related to neurogenic inflammation and provide a graphic[36] illustrating key discoveries leading toward the current understanding of neurogenic inflammation, its mechanisms, and the conditions caused by its disorder.

References[edit]

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  2. ^ a b Chen Y, Lyga J (2014). "Brain-skin connection: stress, inflammation and skin aging". Inflamm Allergy Drug Targets. 13 (3): 177–90. doi:10.2174/1871528113666140522104422. PMC 4082169. PMID 24853682.
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  5. ^ Lin King, John V.; Emrick, Joshua J.; Kelly, Mark J. S.; Herzig, Volker; King, Glenn F.; Medzihradszky, Katalin F.; Julius, David (2019-09-05). "A Cell-Penetrating Scorpion Toxin Enables Mode-Specific Modulation of TRPA1 and Pain". Cell. 178 (6): 1362–1374.e16. doi:10.1016/j.cell.2019.07.014. ISSN 1097-4172. PMC 6731142. PMID 31447178.
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  7. ^ Zhao, Jianhua; Lin King, John V.; Paulsen, Candice E.; Cheng, Yifan; Julius, David (2020-07-08). "Irritant-evoked activation and calcium modulation of the TRPA1 receptor". Nature. 585 (7823): 141–145. doi:10.1038/s41586-020-2480-9. ISSN 0028-0836. PMC 7483980. PMID 32641835.
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  13. ^ Schön and Boehncke, Psoriasis: Neurogenic inflammation and other mechanisms NEJM 352:1899-1912, Number 18, 2005
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  25. ^ [1]
  26. ^ The Race to Offer CGRP for Migraine Migraine.com Editorial Team July 21, 2017
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  29. ^ Farinelli I, Missori S, Martelletti P (September 2008). "Proinflammatory mediators and migraine pathogenesis: moving towards CGRP as a target for a novel therapeutic class". Expert Rev Neurother. 8 (9): 1347–54. doi:10.1586/14737175.8.9.1347. PMID 18759547. S2CID 207195138.
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  31. ^ Clinical trial number NCT00816517 for "Use of Botulinum Toxin to Treat Psoriasis" at ClinicalTrials.gov
  32. ^ Product Information: Astelin, azelastine. Wallace Laboratories, Cranbury, NJ. (PI Revised 08/2000) PI Reviewed 01/2001
  33. ^ Gehanno P, Deschamps E, Garay E, Baehre M, Garay RP (2001). "Vasomotor rhinitis: clinical efficacy of azelastine nasal spray in comparison with placebo". ORL J. Otorhinolaryngol. Relat. Spec. 63 (2): 76–81. doi:10.1159/000055714. PMID 11244365. S2CID 23292869.
  34. ^ Bucelli RC, Gonsiorek EA, Kim WY, Bruun D, Rabin RA, Higgins D, Lein PJ (March 2008). "Statins decrease expression of the proinflammatory neuropeptides calcitonin gene-related peptide and substance P in sensory neurons". J. Pharmacol. Exp. Ther. 324 (3): 1172–80. doi:10.1124/jpet.107.132795. PMID 18079356. S2CID 1001915.
  35. ^ Chiu IM, von Hehn CA, Woolf CJ (July 2012). "Neurogenic inflammation and the peripheral nervous system in host defense and immunopathology". Nat. Neurosci. 15 (8): 1063–7. doi:10.1038/nn.3144. PMC 3520068. PMID 22837035.
  36. ^ Fig. 3 of article Chiu IM, von Hehn CA, Woolf CJ (2012). "Neurogenic inflammation and the peripheral nervous system in host defense and immunopathology". Nat Neurosci. 15 (8): 1063–7. doi:10.1038/nn.3144. PMC 3520068. PMID 22837035.

External links[edit]