Neurogenic Inflammation and Migraine - PowerPoint Presentation

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Neurogenic Inflammation and Migraine

Zeinab GhorbaniPh.D Candidate in Nutritional Sciences, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS).

Introduction

Top 10 level-4 causes of disability in GBD 2016 (global, both sexes, all ages)

Low back painMigraine

Age-related hearing loss

Iron-deficiency anaemia

Major depression

Neck pain

Other musculoskeletal disorders

Diabetes

Anxiety disorders

Falls

Migraine

first cause of disability in < 50s

affects 11% of the adults in the world

Introduction

Although much efforts have been made to elucidate migraine pathogenesis, its exact underlying mechanism remained to be understood.

To date, different mechanisms have been proposed,

such as:

Vascular dysfunction,

activation of the

trigeminovascular

system

neurogenic inflammation

Introduction

Neurogenic inflammation

Inflammation in the meningeDeveloping head pain in migraine.Activation of trigeminal nociceptors Release of vasoactive neuropeptides

Stress

Changes in hormone concentrations (especially Estrogen in females)

Cortical spreading depression (CSD) especially in migraine with aura

meningeal nociceptors’ activation

Introduction

Increasing the secretion of vasodilator neuropeptides in peripheral trigeminal afferents

Causing intra-cranial mast cells degranulation

Enhancing the release of pro-inflammatory factors.

CSD: cortical spreading depression, CGRP: calcitonin gene related peptide, NK-1: neurokinin 1, CLR: calcitonin-like receptor, RAMP1: receptor activity modulating protein 1, RCP: receptor component protein

Mechanistic hypothesis of neurogenic inflammation in the

dural vasculature

Neurogenic inflammation in Migraine

↑↑

inflammatory factors and

vasodilatory

neuropeptides:

IL-6, IL-1β, TNFα, SP, CGRP, NKA, Glutamate, serotonin, NO, COX enzymes, prostaglandins, NGF, PACAP and VIP in the CSF and plasma of migraine patients

↑

Release of HMGB1 and HSP70 during CSD

↑

Expression of TLR4 and NF-kB on primary afferent neurons, microglia, and astrocytes

Induce dilation of arteriescause plasma leakage trigger releasing the contents of mast cells

Activation of astrocytes, microglia, and mast cells, which under inflammatory conditions are able to pass the BBB.

Sensitization of trigeminal nociceptors and raising local inflammatory state

Increased glutamatergic transmission in migraine can induce and maintain the production and release of CGRP and SP causing vasodilation and plasma protein extravasation.

Serotonin, due to its nociceptive and vasoactive properties, has been long implicated in migraine pathophysiology.

There is substantial evidence for the role of NO in migraine that is a potent vasodilator which mediates its effect via CGRP and SP release from perivascular nociceptive afferents via signaling through MAP kinase pathwaysNO acts on dural vessels and contributes to the amplification of these afferent signals by enhancing the release of proinflammatory factors including CGRP leading to neurogenic inflammationInfluence of non-peptidergic molecules on mediating neurogenic inflammation

Neurogenic inflammation in Migraine

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CGRP

A potent vasodilator and is released from intracranial afferents during the course of migraine attack

SP A far less potent vasoactive molecule as compared to CGRP. Limited studies supportThough both CGRP and SP are released into the dural vasculature from the afferents, SP is the prime mediator in causing plasma protein leakage by acting on the NK-1 receptors expressed on the micro-vascular blood vesselsIt has been shown to be blocked by triptans and NSAIDs, selectively in the dura mater but not in the extracranial structures or in the brain or brain vasculatureKey characteristic of neurogenic inflammation in migraine

Vasodilation

Plasma protein extravasation

Activation

and degranulation

of mast cells via one of several pathways can release of a plethora of pro-nociceptive mediators:histamine, serotonin, pro-inflammatory cytokines (TNF-α, IL-1, and IL-6 ), kinins, and proteases that are stored in secretory granules Recent hypotheses state that mast cells can per se contribute to the sterile inflammatory state in the meninges thereby promoting sensitization of meningeal afferents, leading to orthograde traffic in trigeminal vascular afferents and local (meningeal) release of products such as SP and CGRP. Mast cell degranulationKey characteristic of neurogenic inflammation in migraine

Mechanistic hypothesis of neurogenic inflammation in the

dural

vasculatureActivated neuron injury signals release neurotransmitterwhich induce mast cell and microglia activation and release of proinflammatory cytokines/chemokines involved in migraine.

Drug therapy in migraine according to the hypothesis of neurogenic inflammation

One major aim in acute treatment of migraine is to have

pathophysiologically active drugs,Acute migraine treatment remains then bonded to triptans and NSAID use, with the well-known limits due to their side effects, cardiovascular for the first and GI for the latter.

Drug therapy in migraine according to the hypothesis of neurogenic inflammation

The new migraine treatment drugs

certainly interfere with signaling pathways of CGRP, a vasodilatory neuropeptide expressed in the cranial sensory nerves

and PACAP

, a parasympathetic vasodilator peptide that is linked to cranial autonomic symptoms in migraine.

Drug therapy in migraine according to the hypothesis of neurogenic inflammation

CGRP receptor antagonists, anti-CGRP antibodies and anti-CGRP receptor antibodies have proved effective for migraine pain relief, strongly supporting the hypothesis

that CGRP and the subsequent inflammatory state have a major role in migraine pathophysiology.

Conclusion

The current evidence emphasizes that the migraine pain phenotype reflects the anomalous activation of

trigeminovascular afferents projecting to the second order neurons in the brainstem and also indicates several contributing factors of neurogenic inflammation and suggests the involvement of neuroimmune interactions in mediating pain in migraine headache.

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