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, the 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 wasabi receptor TRPA1. [5] [6] [7] TRPA1 channels stimulated by lipopolysaccharides may also cause acute neurogenic inflammation. [8] Once released, these neuropeptides induce the release of histamine from nearby mast cells. In turn, histamine evokes the release of substance P and CGRP; thus, a bidirectional link between histamine and neuropeptides in neurogenic inflammation is established. [9]

Contents

Neurogenic inflammation appears to play a role in the pathogenesis of numerous disorders, 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 the release of neuropeptides, including substance P, nitric oxide, vasoactive intestinal polypeptide, 5-HT, neurokinin A, and CGRP. [20] [21] [22]

Prevention

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

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

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

  1. 1 2 Peroutka SJ (October 2005). "Neurogenic inflammation and migraine: implications for the therapeutics". Mol. Interv. 5 (5): 304–11. doi:10.1124/mi.5.5.10. PMID   16249526.
  2. 1 2 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.
  3. ↑ Geppetti P, Nassini R, Materazzi S, Benemei S (March 2008). "The concept of neurogenic inflammation". BJU Int. 101 (Suppl 3): 2–6. doi:10.1111/j.1464-410X.2008.07493.x. PMID   18307678. S2CID   1096295.
  4. ↑ Caterina, M. J.; Leffler, A.; Malmberg, A. B.; Martin, W. J.; Trafton, J.; Petersen-Zeitz, K. R.; Koltzenburg, M.; Basbaum, A. I.; Julius, D. (2000-04-14). "Impaired nociception and pain sensation in mice lacking the capsaicin receptor". Science. 288 (5464): 306–313. Bibcode:2000Sci...288..306C. doi:10.1126/science.288.5464.306. ISSN   0036-8075. PMID   10764638.
  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.
  6. ↑ Zhao, Jianhua; King, John V. Lin; Cheng, Yifan; Julius, David (2019-12-27). "Mechanisms governing irritant-evoked activation and calcium modulation of TRPA1". bioRxiv: 2019.12.26.888982. doi: 10.1101/2019.12.26.888982 .
  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. Bibcode:2020Natur.585..141Z. doi:10.1038/s41586-020-2480-9. ISSN   0028-0836. PMC   7483980 . PMID   32641835.
  8. ↑ Meseguer V, Alpizar YA, Luis E, Tajada S, Denlinger B, Fajardo O, et al. (2014). "TRPA1 channels mediate acute neurogenic inflammation and pain produced by bacterial endotoxins". Nat Commun. 5: 3125. Bibcode:2014NatCo...5.3125M. doi:10.1038/ncomms4125. PMC   3905718 . PMID   24445575.
  9. ↑ Rosa AC, Fantozzi R (September 2013). "The role of histamine in neurogenic inflammation". Br. J. Pharmacol. 170 (1): 38–45. doi:10.1111/bph.12266. PMC   3764847 . PMID   23734637.
  10. ↑ Malhotra R (2016). "Understanding migraine: Potential role of neurogenic inflammation". Ann Indian Acad Neurol. 19 (2): 175–82. doi: 10.4103/0972-2327.182302 . PMC   4888678 . PMID   27293326.
  11. ↑ Frediani F, Villani V, Casucci G (May 2008). "Peripheral mechanism of action of antimigraine prophylactic drugs". Neurol. Sci. 29 (Suppl 1): S127–30. doi:10.1007/s10072-008-0903-8. PMID   18545913. S2CID   24156261.
  12. ↑ Geppetti P, Capone JG, Trevisani M, Nicoletti P, Zagli G, Tola MR (April 2005). "CGRP and migraine: neurogenic inflammation revisited". J Headache Pain. 6 (2): 61–70. doi:10.1007/s10194-005-0153-6. PMC   3452316 . PMID   16362644.
  13. ↑ Schön and Boehncke, Psoriasis: Neurogenic inflammation and other mechanisms NEJM 352:1899-1912, Number 18, 2005
  14. 1 2 Saraceno R, Kleyn CE, Terenghi G, Griffiths CE (November 2006). "The role of neuropeptides in psoriasis". Br. J. Dermatol. 155 (5): 876–82. doi:10.1111/j.1365-2133.2006.07518.x. PMID   17034513. S2CID   9257957.
  15. ↑ Verones B, Oortgiesen M (December 2001). "Neurogenic inflammation and particulate matter (PM) air pollutants". Neurotoxicology. 22 (6): 795–810. doi:10.1016/S0161-813X(01)00062-6. PMID   11829413.
  16. ↑ Knipping S, Holzhausen HJ, Riederer A, Schrom T (August 2008). "[Ultrastructural changes in allergic rhinitis vs. idiopathic rhinitis]". HNO (in German). 56 (8): 799–807. doi:10.1007/s00106-008-1764-4. PMID   18651116. S2CID   24135943.
  17. ↑ Meggs, William J. The Role of Neurogenic Inflammation in Chemical Sensitivity (2017) EcopsychologyVol. 9, No. 2 Published Online:1 Jun 2017 https://doi.org/10.1089/eco.2016.0045
  18. ↑ Orriols R, Costa R, Cuberas G, Jacas C, Castell J, Sunyer J (December 2009). "Brain dysfunction in multiple chemical sensitivity". J. Neurol. Sci. 287 (1–2): 72–8. doi:10.1016/j.jns.2009.09.003. PMID   19801154. S2CID   28255407.
  19. ↑ Bascom R, Meggs WJ, Frampton M, Hudnell K, Killburn K, Kobal G, Medinsky M, Rea W (March 1997). "Neurogenic inflammation: with additional discussion of central and perceptual integration of nonneurogenic inflammation". Environ. Health Perspect. 105 (Suppl 2): 531–7. doi:10.1289/ehp.97105s2531. PMC   1469802 . PMID   9167992.
  20. ↑ Kalra AA, Elliott D (June 2007). "Acute migraine: Current treatment and emerging therapies". Ther Clin Risk Manag. 3 (3): 449–59. PMC   2386351 . PMID   18488069.
  21. ↑ Link AS, Kuris A, Edvinsson L (February 2008). "Treatment of migraine attacks based on the interaction with the trigemino-cerebrovascular system". J Headache Pain. 9 (1): 5–12. doi:10.1007/s10194-008-0011-4. PMC   2245994 . PMID   18217201.
  22. ↑ Grossmann, MD, Werner; Schmidramsl, MD, Hanns (2001). "An Extract of Petasites hybridus Is Effective in the Prophylaxis of Migraine" (PDF). Alternative Medicine Review. 6 (3): 303–10. PMID   11410074 . Retrieved 14 June 2015.
  23. ↑ Weglicki WB, Phillips TM (September 1992). "Pathobiology of magnesium deficiency: a cytokine/neurogenic inflammation hypothesis". Am. J. Physiol. 263 (3 Pt 2): R734–7. doi:10.1152/ajpregu.1992.263.3.R734. PMID   1384353.
  24. ↑ Rude RK, Singer FR, Gruber HE (April 2009). "Skeletal and hormonal effects of magnesium deficiency". J Am Coll Nutr. 28 (2): 131–41. doi:10.1080/07315724.2009.10719764. PMID   19828898. S2CID   43556609.
  25. ↑ "UpToDate".
  26. ↑ The Race to Offer CGRP for Migraine Migraine.com Editorial Team July 21, 2017
  27. ↑ Jancsó N, Jancsó-Gábor A, Szolcsányi J (September 1967). "Direct evidence for neurogenic inflammation and its prevention by denervation and by pretreatment with capsaicin". Br J Pharmacol Chemother. 31 (1): 138–51. doi:10.1111/j.1476-5381.1967.tb01984.x. PMC   1557289 . PMID   6055248.
  28. ↑ Durham PL, Vause CV (July 2010). "Calcitonin gene-related peptide (CGRP) receptor antagonists in the treatment of migraine". CNS Drugs. 24 (7): 539–48. doi:10.2165/11534920-000000000-00000. PMC   3138175 . PMID   20433208.
  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.
  30. ↑ Farinelli I, De Filippis S, Coloprisco G, Missori S, Martelletti P (October 2009). "Future drugs for migraine". Intern Emerg Med. 4 (5): 367–73. doi:10.1007/s11739-009-0273-0. PMID   19551474. S2CID   26070466.
  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. ↑ Chiu IM, von Hehn CA, Woolf CJ (2012). "Neurogenic inflammation and the peripheral nervous system in host defense and immunopathology". Nat Neurosci. 15 (8). Figure 3. doi:10.1038/nn.3144. PMC   3520068 . PMID   22837035.
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