Thursday, January 12, 2017

Migraine- Research updates

Hey Awesomites

Now that we are clear on the basics, here's another post on recent updates and studies on the concepts of causation and treatment strategies of migraine.

Many Research studies and clinical trials have been conducted and lots of debates going on the underlying mechanisms of pathophysiology and treatment of migraine headaches. Various diagnostic tools have been used to detect and locate targeted proteins in tissues- Immunohistochemistry, RT-PCR, Western blot, ELISA. The findings and implications in some of these studies have been discussed here.


Role of neuropeptide modulators: (CGRP and SP)
Based on clinical and preclinical studies, the neuropeptide calcitonin- gene related peptide (CGRP) is proposed to play a central role in the underlying pathology of migraine. CGRP- containing sensory nerve fibres are predominantly expressed in cerebral vasculature and neuronal tissues including the trigeminal ganglia and caudal nucleus of trigeminal nerve. Peripheral release of CGRP from trigeminal nerve fibres within the dura and from the cell body of trigeminal ganglion neurons is likely to contribute to peripheral sensitization of trigeminal nociceptors.

Mechanism of action of CGRP- It acts by binding to three subtypes of G- protein coupled receptors viz. CGRP-1, CGRP-2, CGRP-3. This receptor- effector coupling results in stimulation of adenyl cyclase enzyme and an increase in cAMP production, thus leading to potent vasodilation (via direct relaxation of vascular smooth muscle).

A significant increase in levels of CGRP was demonstrated during the headache phase of migraine in recent neuroimaging studies and their role in neurogenic inflammation was strongly evidenced with i.v. infusion of the potent CGRP receptor antagonist Olcegepant which could abort acute migraine attack in susceptible individuals.

Substance P is often colacalized and coreleased with CGRP in the trigeminal ganglion and trigeminal nucleus caudalis. CGRP facilitates SP- induced plasma protein extravasation, dilation of cerebral and dural blood vessels and increased vascular permeability. Substance P is the prime mediator causing plasma leakage at the site of inflammation via Neurokinin -1 (NK-1) receptors whereas both CGRP and SP induce vasodilation.

Also, the involvement of SP in plasma leakage and neurogenic inflammation has been well- established by the ability of NK-1 receptor antagonists and SP immunoneutralization to attenuate neurogenic inflammatory responses to a variety of stimuli. But the recent clinical trials have revealed the failure of NK-1 antagonists (Aprepitant and Lanepitant) to abort the acute migraine attacks. Prophylactic intravenous administration of Lanepitant for 1 month had no effect on migraine frequency and severity of attacks when compared with placebo.


Role of non-neuropeptide modulators-

Serotonin (5-hydroxytryptamine):- 5-HT 1B, 1D and 1F receptors situated prejunctionally in the trigeminovascular system are thought to be involved in pain transmission. The serotonin -1B receptor and its mRNA are often colocalized with SP and CGRP in the trigeminal ganglia and trigeminal nerves.
Activation of receptor -1B by serotonin agonist Sumatriptan leads to inhibition of CGRP gene transcription and prevents CGRP release. This attenuates plasma- protein extravasation and other vascular consequences.
Evidence suggests that 5HT2B receptor expression and activation increases production and release of NO. NO in turn stimulates the release of neuropeptides resulting in neurogenic vasodilation and plasma protein extravasation, the two key elements implicated in the pathogenesis of migraine. Selective 5-HT2B receptor antagonists have been shown to inhibit m-chlorophenylpiperazine (A 5-HT2B receptor agonist) induced dural plasma protein extravasation in guinea pigs. Further clinical studies are awaited to find more potent drugs that readily bind on this receptor and prevent migraine attacks.

Nerve growth factor is another non- neuropeptide modulator that further increases synthesis of CGRP by binding to Tropomyosin receptor kinase A (TrkA receptor) in nociceptive sensory neurons particularly those containing SP and CGRP. Recent studies have suggested significantly high levels of neurotrophins (BDNF and NGF) in the CSF of patients suffering from chronic migraine and primary fibromyalgia syndrome.

Role of BDNF in migraine headache-
Neurogenic inflammation in trigeminovascular system exposes the neurons to a variety of inflammatory mediators. A study uncovered that the Brain derived neurotrophic factor (BDNF) levels in the trigeminal ganglion are elevated following the cell exposure to TNF-alpha and other mediators. Also CGRP levels rise with peripheral inflammatory reaction in the area of trigeminal nociceptors, which also increases BDNF release.
Higher BDNF levels have been correlated to increased glutamatergic transmission in hippocampal area CA1, CA2 and the dentate gurus. Glutamate acting as an enhanced excitatory neurotransmitter facilitates central sensitization and this, in addition to peripheral sensitization by cgrp is thought to be responsible for the headache phase of migraine. Thus the increased BDNF levels might trigger migraine attacks.

Nitric oxide also has an important trigger mechanism underlying primary vascular headaches such as migraine and cluster headache. It can induce the initial phase of migraine headache by inducing cerebral vasodilation via NO-cGMP pathway and may trigger the delayed phase of headache by stimulating CGRP release and sensitizing the perivascular nociceptors and central nociceptive neurons in the trigeminovascular system. Recent evidence suggests the role of nonselective nNOS inhibitors to partially attenuate neurogenic vasodilation.

Other non- neuropeptide modulators that may play a role in the pathogenesis of migraine attacks are Prostaglandins, Gamma- aminobutyric acid (GABA), Capsaicin.


RAS: a novel target for migraine prophylaxis
A new target which has recently caught the attention of neurologists in migraine is “Renin Angiotensin System”. The rationale for this was inhibition of carboxypeptidase, an enkephalin-inactivating enzyme. It has also been suggested that the effect of ACEI can be related to their ability to increase NE and 5-HT action on vascular tone. 
In human serum, ACE levels are genetically determined. Individuals who are homozygous for DD allele (deletion allele) have increased ACE activity. Migraine is more common in persons with DD allele, hence correlating higher ACE activity to more migraine attacks. 


Botulinum toxin as a treatment modality
Botulinum toxin (BoNT) injections are becoming a well- recognized therapeutic modality for the treatment of migraine headache, chronic daily headache, myofascial pain, painful dystonia, trigeminal neyralgia, facial chronic pain and pain related to spinal cord pathology. The peripheral nociceptive and anti- inflammatory effect of BoNT-A may be a result of inhibition of the release of neuropeptides (CGRP and SP).

Statin medications
Recently it has also been suggested that cholesterol- lowering statin medications might be useful in the treatment of diseases with prominent neurogenic inflammation due to their pleiotropic effects. Statins might act directly on sensory neurons to downregulate the expression of CGRP and SP.


Oestrogen levels and migraine attack
Several lines of evidence highlights the role of oestrogen as an important contributor to migraine. Human migraine has been found to be two to three times more prevalent in females than in males. The incidence is higher in reproductive age with a peak serum level of estrogen.
Reports from more than 50% of women patients show that migraine attacks are positively correlated with their menstrual cycle. Epidemiologic studies also manifest that combined hormonal contraceptives that mainly contain estrogen initiate or worsen migraine and headache in the susceptible women.
Research also suggests that ovariectomised female rats attenuates neuronal activation in nucleus trigeminalis caudalis of the brainstem as well as in paraventricular and supraoptic nucleus of the hypothalamus, whereas chronic intraperitoneal administration of estrogen restores the activation of neurons that is essential for the development of initial phase of migraine.

To conclude, the prospect of treatment modalities involving manipulation of neuroinflammatory response holds great promise but translating these ideas presented here into therapeutic benefits remains a major challenge. Research is still going on to amp up the promising drugs and prune back the drugs that are not much effective in the treatment of migraine headache.

Nutritional deficiencies
see here

Thats all
- Jaskunwar Singh and Vinayak.

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