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]

Contents

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

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.

Related Research Articles

<span class="mw-page-title-main">Substance P</span> Chemical compound (polypeptide neurotransmitter)

Substance P (SP) is an undecapeptide and a type of neuropeptide, belongings to the tachykinin family of neuropeptides. It is acts as a neurotransmitter and a neuromodulator. Substance P and its closely related neurokinin A (NKA) are produced from a polyprotein precursor after alternative splicing of the preprotachykinin A gene. The deduced amino acid sequence of substance P is as follows:

<span class="mw-page-title-main">Itch</span> Sensation that causes desire or reflex to scratch

Itch is a sensation that causes the desire or reflex to scratch. Itches have resisted many attempts to be classified as any one type of sensory experience. Itches have many similarities to pain, and while both are unpleasant sensory experiences, their behavioral response patterns are different. Pain creates a withdrawal reflex, whereas itches leads to a scratch reflex.

<span class="mw-page-title-main">Rhinitis</span> Irritation and inflammation of the mucous membrane inside the nose

Rhinitis, also known as coryza, is irritation and inflammation of the mucous membrane inside the nose. Common symptoms are a stuffy nose, runny nose, sneezing, and post-nasal drip.

<span class="mw-page-title-main">Sumatriptan</span> 5-HT receptor agonist medication used for migraines & cluster headaches

Sumatriptan, sold commonly under brand names Imitrex and Treximet among others, is a medication used to treat migraine headaches and cluster headaches. It is taken orally, intranasally, or by subcutaneous injection. Therapeutic effects generally occur within three hours.

<span class="mw-page-title-main">Nasal spray</span> Spray that delivers medications locally in the nasal cavities or systemically

Nasal sprays are used to deliver medications locally in the nasal cavities or systemically. They are used locally for conditions such as nasal congestion and allergic rhinitis. In some situations, the nasal delivery route is preferred for systemic therapy because it provides an agreeable alternative to injection or pills. Substances can be assimilated extremely quickly and directly through the nose. Many pharmaceutical drugs exist as nasal sprays for systemic administration. Other applications include hormone replacement therapy, treatment of Alzheimer's disease and Parkinson's disease. Nasal sprays are seen as a more efficient way of transporting drugs with potential use in crossing the blood–brain barrier.

<span class="mw-page-title-main">Calcitonin gene-related peptide</span> Peptide hormone in animals

Calcitonin gene-related peptide (CGRP) is a member of the calcitonin family of peptides consisting of calcitonin, amylin, adrenomedullin, adrenomedullin 2 (intermedin) and calcitonin‑receptor‑stimulating peptide. Calcitonin is mainly produced by thyroid C cells whilst CGRP is secreted and stored in the nervous system. This peptide, in humans, exists in two forms: CGRP alpha, and CGRP beta. α-CGRP is a 37-amino acid neuropeptide and is formed by alternative splicing of the calcitonin/CGRP gene located on chromosome 11. β-CGRP is less studied. In humans, β-CGRP differs from α-CGRP by three amino acids and is encoded in a separate, nearby gene. The CGRP family includes calcitonin (CT), adrenomedullin (AM), and amylin (AMY).

<span class="mw-page-title-main">Antimigraine drug</span> Medication intended to reduce the effects or intensity of migraine headache

Antimigraine drugs are medications intended to reduce the effects or intensity of migraine headache. They include drugs for the treatment of acute migraine symptoms as well as drugs for the prevention of migraine attacks.

<span class="mw-page-title-main">CALCRL</span> Mammalian protein found in Homo sapiens

Calcitonin receptor-like (CALCRL), also known as the calcitonin receptor-like receptor (CRLR), is a human protein; it is a receptor for calcitonin gene-related peptide.

<span class="mw-page-title-main">RCP9</span> Protein-coding gene in the species Homo sapiens

DNA-directed RNA polymerase III subunit RPC9 is an enzyme that in humans is encoded by the CRCP gene.

<span class="mw-page-title-main">TAC1</span> Protein-coding gene in humans

Preprotachykinin-1,, is a precursor protein that in humans is encoded by the TAC1 gene.

Zucapsaicin (Civanex) is a medication used to treat osteoarthritis of the knee and other neuropathic pain. It is applied three times daily for a maximum of three months. Zucapsaicin is a member of phenols and a member of methoxybenzenes It is a modulator of transient receptor potential cation channel subfamily V member 1 (TRPV-1), also known as the vanilloid or capsaicin receptor 1 that reduces pain, and improves articular functions. It is the cis-isomer of capsaicin. Civamide, manufactured by Winston Pharmaceuticals, is produced in formulations for oral, nasal, and topical use.

Calcitonin gene-related peptide (CGRP) receptor antagonists are a class of drugs that act as antagonists of the calcitonin gene-related peptide receptor (CGRPR).

<span class="mw-page-title-main">Olcegepant</span> Chemical compound

Olcegepant is a calcitonin gene-related peptide receptor antagonist being studied as a potential treatment for migraines.

Neuropeptide K, is a protein encoded by the TAC1 gene. It is an elongated derivative of the N-terminus of neurokinin A as the final post-translational processing product of beta-preprotachykinin.

Fremanezumab, sold under the brand name Ajovy, is a medication used to prevent migraines in adults. It is given by injection under the skin.

<span class="mw-page-title-main">Ubrogepant</span> Medication for migraine headache acute treatment

Ubrogepant, sold under the brand name Ubrelvy, is a medication used for the acute (immediate) treatment of migraine with or without aura in adults. It is not indicated for the preventive treatment of migraine. Ubrogepant is a small-molecule calcitonin gene-related peptide receptor antagonist. It is the first drug in this class approved for the acute treatment of migraine.

<span class="mw-page-title-main">Wasabi receptor toxin</span>

Wasabi receptor toxin (WaTx) is the active component of the venom of the Australian black rock scorpion Urodacus manicatus. WaTx targets TRPA1, also known as the wasabi receptor or irritant receptor. WaTx is a cell-penetrating toxin that stabilizes the TRPA1 channel open state while reducing its Ca2+-permeability, thereby eliciting pain and pain hypersensitivity without the neurogenic inflammation that typically occurs in other animal toxins.

Susan Diana Brain is a professor of pharmacology at the School of Cardiovascular Medicine and Sciences at King's College London where she has worked since 1989.

<span class="mw-page-title-main">Iain Macintyre</span> British endocrinologist

Iain Macintyre FRS was a British endocrinologist who made important contributions to the understanding of calcium regulation and bone metabolism. Shortly after the hormone calcitonin had been described by Harold Copp, Macintyre's team was the first to isolate and sequence the hormone and to demonstrate its origin in the parafollicular cells of the thyroid gland. He subsequently analysed its physiological actions. Along with H. R. Morris he isolated and sequenced calcitonin gene-related peptide. Later research centred on the role played by nitric oxide on bone metabolism.

<span class="mw-page-title-main">A-967079</span> Chemical compound

A-967079 is a drug which acts as a potent and selective antagonist for the TRPA1 receptor. It has analgesic and antiinflammatory effects and is used in scientific research, but has not been developed for medical use.

References

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