Neurogenic inflammation

Neurogenic inflammation is inflammation arising from the local release of inflammatory mediators from afferent neurons 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][7][8][9] psoriasis,[10][11][12] asthma,[13] fibromyalgia, eczema, rosacea, dystonia, and multiple chemical sensitivity.[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]

Discovery and advances in understanding

In a 2012 article[19] in Nature Neuroscience Chiu et al. discuss the development of science related to neurogenic inflammation and provide a graphic[20] illustrating key discoveries leading toward the current understanding of neurogenic inflammation, its mechanisms, and the conditions caused by its disorder.

Treatment

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.[21]

A recent (2010) study of the treatment of migraine with CGRP blockers shows promise.[22] In early trials, the first oral nonpeptide CGRP antagonist, MK-0974 (Telcagepant), was shown effective in the treatment of migraine attacks,[23] 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.[24]

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,[25] 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.[26]

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."[27][28]

Statins appear to "decrease expression of the proinflammatory neuropeptides calcitonin gene-related peptide and substance P in sensory neurons,"[29] and so might be of use in treating diseases presenting with predominant neurogenic inflammation.

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.[30] 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.[31]

References

  1. Peroutka, Stephen J. (October 2005). "Neurogenic inflammation and migraine: implications for the therapeutics". Molecular Interventions (Mol Interv.). 5 (5): 304–311. doi:10.1124/mi.5.5.10. PMID 16249526. Retrieved 21 September 2014.
  2. Chen, Ying; Lyga, John (June 2014). "Brain-Skin Connection: Stress, Inflammation and Skin Aging". Inflamm Allergy Drug Targets. 13 (3): 177–190. doi:10.2174/1871528113666140522104422. PMC 4082169Freely accessible. 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. "TRPA1 channels mediate acute neurogenic inflammation and pain produced by bacterial endotoxins". Nature Communications. 5: 3125. doi:10.1038/ncomms4125.
  5. Rosa, AC (Sep 2013). "The role of histamine in neurogenic inflammation". Br J Pharmacol. 170 (1): 38–45. doi:10.1111/bph.12266. PMC 3764847Freely accessible. PMID 23734637.
  6. Peroutka, Stephen J. (October 2005). "Neurogenic inflammation and migraine: implications for the therapeutics". Molecular Interventions (Mol Interv.). 5 (5): 304–311. doi:10.1124/mi.5.5.10. PMID 16249526. Retrieved 21 September 2014.
  7. Frediani, F; Villani, V; Casucci, G (2008). "Peripheral mechanism of action of antimigraine prophylactic drugs". Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. 29 Suppl 1: S127–30. doi:10.1007/s10072-008-0903-8. PMID 18545913.
  8. Peroutka, SJ (2005). "Neurogenic inflammation and migraine: implications for the therapeutics". Molecular interventions. 5 (5): 304–11. doi:10.1124/mi.5.5.10. PMID 16249526.
  9. Geppetti, P; Capone, JG; Trevisani, M; Nicoletti, P; Zagli, G; Tola, MR (2005). "CGRP and migraine: neurogenic inflammation revisited". The journal of headache and pain. 6 (2): 61–70. doi:10.1007/s10194-005-0153-6. PMC 3452316Freely accessible. PMID 16362644.
  10. Chen, Ying; Lyga, John (June 2014). "Brain-Skin Connection: Stress, Inflammation and Skin Aging". Inflamm Allergy Drug Targets. 13 (3): 177–190. doi:10.2174/1871528113666140522104422. PMC 4082169Freely accessible. PMID 24853682.
  11. Schön and Boehncke, Psoriasis: Neurogenic inflammation and other mechanisms NEJM 352:1899-1912, Number 18, 2005
  12. Saraceno, R; Kleyn, CE; Terenghi, G; Griffiths, CE (2006). "The role of neuropeptides in psoriasis". The British journal of dermatology. 155 (5): 876–82. doi:10.1111/j.1365-2133.2006.07518.x. PMID 17034513.
  13. 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.
  14. Orriols, Ramon; Costa, Roser; Cuberas, Gemma; Jacas, Carlos; Castell, Joan; Sunyer, Jordi (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.
  15. Bascom, R; Meggs, WJ; Frampton, M; Hudnell, K; Killburn, K; Kobal, G; Medinsky, M; Rea, W (1997). "Neurogenic inflammation: with additional discussion of central and perceptual integration of nonneurogenic inflammation". Environmental Health Perspectives. 105 Suppl 2: 531–7. doi:10.2307/3433365. PMC 1469802Freely accessible. PMID 9167992.
  16. Arun A Kalra, AA; Debra Elliott, D (June 2007). "Acute migraine: Current treatment and emerging therapies". Ther Clin Risk Manag. Dove Medical Press Limited. 3 (3): 449–459. PMC 2386351Freely accessible. PMID 18488069.
  17. Andrea Stephanie Link, AS; Anikó Kuris et. al, A; Edvinsson, L (23 January 2008). "Treatment of migraine attacks based on the interaction with the trigemino-cerebrovascular system". J Headache Pain. Biomedical Center Lund. 9 (1): 5–12. doi:10.1007/s10194-008-0011-4. PMC 2245994Freely accessible. 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. Neurogenic Inflammation – The Peripheral Nervous System’s Role in Host Defense and Immunopathology (Chiu et al., Nature Neuroscience, 2012, PMCID PMC3520068; NIHMSID NIHMS379003)
  20. Fig. 3 of article (Chiu et al.: Neurogenic Inflammation – The Peripheral Nervous System’s Role in Host Defense and Immunopathology. Nature Neuroscience, 2012, PMCID PMC3520068)
  21. "Direct evidence for neurogenic inflammation and its prevention by denervation and by pretreatment with capsaicin". Br J Pharmacol Chemother. 31 (1): 138–51. September 1967. doi:10.1111/j.1476-5381.1967.tb01984.x. PMC 1557289Freely accessible. PMID 6055248.
  22. Durham, PL; Vause, CV (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 3138175Freely accessible. PMID 20433208.
  23. Farinelli, I; Missori, S; Martelletti, P (2008). "Proinflammatory mediators and migraine pathogenesis: moving towards CGRP as a target for a novel therapeutic class". Expert Review of Neurotherapeutics. 8 (9): 1347–54. doi:10.1586/14737175.8.9.1347. PMID 18759547.
  24. Farinelli, I; De Filippis, S; Coloprisco, G; Missori, S; Martelletti, P (2009). "Future drugs for migraine". Internal and emergency medicine. 4 (5): 367–73. doi:10.1007/s11739-009-0273-0. PMID 19551474.
  25. Saraceno, R; Kleyn, CE; Terenghi, G; Griffiths, CE (2006). "The role of neuropeptides in psoriasis". The British Journal of Dermatology. 155 (5): 876–82. doi:10.1111/j.1365-2133.2006.07518.x. PMID 17034513.
  26. Clinical trial number NCT00816517 for "Use of Botulinum Toxin to Treat Psoriasis" at ClinicalTrials.gov
  27. Product Information: Astelin, azelastine. Wallace Laboratories, Cranbury, NJ. (PI Revised 08/2000) PI Reviewed 01/2001
  28. Vasomotor rhinitis: clinical efficacy of azelastine nasal spray in comparison with placebo.
  29. Bucelli, RC; Gonsiorek, EA; Kim, WY; Bruun, D; Rabin, RA; Higgins, D; Lein, PJ (2008). "Statins decrease expression of the proinflammatory neuropeptides calcitonin gene-related peptide and substance P in sensory neurons". The Journal of Pharmacology and Experimental Therapeutics. 324 (3): 1172–80. doi:10.1124/jpet.107.132795. PMID 18079356.
  30. Weglicki WB, Phillips TM. Pathobiology of magnesium deficiency: a cytokine/neurogenic inflammation hypothesis PMID 1384353 Am J Physiol. 1992 Sep;263(3 Pt 2):R734-7
  31. 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.

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