Neurogenic inflammation

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] TRPA1 channels stimulated by lipopolysaccharide (LPS) may also cause acute neurogenic inflammation.[4] 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.[5]

Neurogenic inflammation appears to play an important role in the pathogenesis of numerous diseases including migraine,[6][1][7][8] psoriasis,[2][9][10] asthma,[11] vasomotor rhinitis,[12] fibromyalgia, eczema, rosacea, dystonia, and multiple chemical sensitivity. [13][14][15]

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.[16][17] leading to a "sterile neurogenic inflammation."[18]

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.[19] 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.[20]

Treatment

As of September 2018, two CGRP blockers have been approved by the FDA for the treatment of migraine.[21] Additional CGRP blockers are progressing through clinical trials.[22]

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.[23]

A recent (2010) study of the treatment of migraine with CGRP blockers shows promise.[24] In early trials, the first oral nonpeptide CGRP antagonist, MK-0974 (Telcagepant), was shown effective in the treatment of migraine attacks,[25] 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.[26]

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,[10] 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.[27]

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."[28][29]

Statins appear to "decrease expression of the proinflammatory neuropeptides calcitonin gene-related peptide and substance P in sensory neurons,"[30] and so might be of use in treating diseases presenting with predominant neurogenic inflammation.

Research

In a 2012 article[31] in Nature Neuroscience Chiu et al. discuss the development of science related to neurogenic inflammation and provide a graphic[32] illustrating key discoveries leading toward the current understanding of neurogenic inflammation, its mechanisms, and the conditions caused by its disorder.

References
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  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.
  4. 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. doi:10.1038/ncomms4125. PMC 3905718. PMID 24445575.
  5. 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.
  6. 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.
  7. 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.
  8. 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.
  9. Schön and Boehncke, Psoriasis: Neurogenic inflammation and other mechanisms NEJM 352:1899-1912, Number 18, 2005
  10. 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.
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  13. 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
  14. 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.
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  17. 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.
  18. 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. Retrieved 14 June 2015.
  19. 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.
  20. Rude RK, Singer FR, Gruber HE (April 2009). "Skeletal and hormonal effects of magnesium deficiency". J Am Coll Nutr. 28 (2): 131–41. PMID 19828898.
  21. Ajovy Approved by FDA as Second CGRP Blocker for Migraine Prevention By Emily Downward at Migraine.com Published September 14, 2018
  22. The Race to Offer CGRP for Migraine Migraine.com Editorial Team July 21, 2017
  23. 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.
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  25. 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.
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  27. Clinical trial number NCT00816517 for "Use of Botulinum Toxin to Treat Psoriasis" at ClinicalTrials.gov
  28. Product Information: Astelin, azelastine. Wallace Laboratories, Cranbury, NJ. (PI Revised 08/2000) PI Reviewed 01/2001
  29. 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.
  30. 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.
  31. 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.
  32. Fig. 3 of article Chiu IM, von Hehn CA, Woolf CJ. "Neurogenic inflammation and the peripheral nervous system in host defense and immunopathology". Nat Neurosci. 15: 1063–7. doi:10.1038/nn.3144. PMC 3520068. PMID 22837035.
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