Neurogenic inflammation

Type of 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]

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

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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

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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

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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

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1. ^ a b 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. ^ 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.
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. ^ a b 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 28255407.1–2&rft.pages=72-8&rft.date=2009-12&rft_id=https://api.semanticscholar.org/CorpusID:28255407#id-name=S2CID&rft_id=info:pmid/19801154&rft_id=info:doi/10.1016/j.jns.2009.09.003&rft.aulast=Orriols&rft.aufirst=R&rft.au=Costa,+R&rft.au=Cuberas,+G&rft.au=Jacas,+C&rft.au=Castell,+J&rft.au=Sunyer,+J&rfr_id=info:sid/en.wikipedia.org:Neurogenic+inflammation" class="Z3988">
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.

## External links

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* Bronchial asthma and other neurogenic diseases: migraine, trigeminal neuralgia and epilepsy
* Schön and Boehncke, Psoriasis: Neurogenic inflammation and other mechanisms NEJM 352:1899–1912, Number 18, 2005