Migraine a deficiency disorder of neurochemicals ijrpp

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International Journal of Research in Pharmacology and Pharmacotherapeutics (Review article)

MIGRAINE: A DEFICIENCY DISORDER OF NEUROCHEMICALS *1

Vivek Sharma, 2Ankita Gupta, 3Kalpana Sharma, 4Ranjit Singh Govt. College of Pharmacy, Rohru, Distt. Shimla-171207, Himachal Pradesh, India

ABSTRACT Headaches have afflicted man throughout history, and Migraine is a common, but under diagnosed and under treated type of headache that has a strong social impact, influencing both quality of life and work productivity. Stress, food allergies, neuro endocrine imbalances and nutritional deficiencies all may contribute to migraine attacks. Several mechanisms have been implicated in migraine patho physiology including inflammation, mitochondrial dysfunction, abnormal neuronal excitability and vascular events. Drugs from different pharmacological classes are used for migraine prophylaxis and these agents may normalize neuronal excitability by modulating distinct ionic channels and various neurotransmitter systems. They can also block cortical spreading depression; prevent peripheral and/or central pain sensitization. Over the last two decades, the results from clinical studies have provided evidence of efficacy of allopathic and herbal drugs which have shown a considerable relief in complications of migraine yet a lot of pathological mechanisms and resultant sufferings remain unresolved.

KEYWORDS: Migraine, Headache, Triptans, CGRP, Serotonin

INTRODUCTION There are many types of headaches, each with its own set of causes, symptoms and points of pain. The more common types include tension, cluster, migraine, allergy/sensitivity, sinus, trauma, and eyestrain headaches 1.The term migraine is originated from Greek word “hemicrania”2 meaning “one side of the head’’. Migraine is the most common of the disabling primary headache syndromes3 that affect around 12% of the general population4. It has a strong social impact, influencing both quality of life and work productivity5 and is ranked as the 19th leading cause of disability worldwide6,7. Migraine, a common chronic, incapacitating neurovascular and neurological disorder is characterized by autonomic nervous system dysfunction and intense, unilateral, throbbing, pulsatile headache attacks, lasting for 4-72 _________________________________ *Corresponding author: Vivek Sharma Department of Pharmacology, Govt. College of Pharmacy, Rohru, Distt Shimla-171207, Himachal Pradesh, India E mail: viveksharma_pharmacy@yahoo.co.in

hours, accompanied by anorexia, nausea, vomiting, photophobia, phonophobia7 and osmophobia8,9. These symptoms distinguish migraine from tension-type and other rare forms of primary headache, which lack these associated features. Because of its high prevalence among population and considerable burden on the society, the therapy of migraine is an issue of high importance. Although homeopathy did not show any efficacy in migraine prophylaxis in controlled trials10,11 the drugs from allopathic and ayurvedic system are successfully used in treatment as well as minimizing symptoms of migraine.

Migraine is currently considered a complex interplay of different processes such as an alteration of pain and sensory input, increased sensitivity of the cortex leading to aura phenomena, central pain facilitation,

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neurogenic inflammation and brainstem nociceptor sensitization12, it affects mainly the brainstem and diencephalon13 and is an example of abnormal amplification and sensitization of pain pathways in these regions14.

HISTORY History has troubled mankind from the dawn of civilization. The earliest symptoms in migraine were those of supernatural and migraine was believed to be due to malevolent beings within the head; treatment based on this idea included incantations and application to the head of substances intended to drive out the demons and spirits16. Around 400 BC, the ancient Greek physician, Hippocrates, released migraine from the realms of the supernatural by attributing it to vapors rising from the stomach to the head and described, for the first time, the visual symptoms (“aura”) of migraine15,16. Galen wrote of “a painful disorder affecting approximately one-half of the head”17 his term for this, “hemicrania," was gradually transmuted into “migraine." The hippocratic/galenic concept of migraine survived into the 17thcentury, when Thomas Willis published in 1664 his hypothesis that “megrim” was due to dilatation of blood vessels within the head (the first enunciation of a vascular theory)15,16. Moebius stated in 1898 that “parenchyma is the master, circulation the servant," and that both brain and blood vessels dysfunctions were necessary to produce an attack of migraine 16. Almost simultaneously, ergot (the product of the fungus Claviceps purpurea that grows upon rye) was introduced in 1884 by W.H. Thomson as an effective remedy for migraine 18. Ergotism is characterized by gangrene of the feet, legs, hands and arms due to a potent and long-lasting vasoconstriction. Thus, the introduction of ergot and the subsequent isolation of the first pure ergot alkaloid, ergotamine, by Stoll in1920 19, represented a remarkable accomplishment as the beginning of an effective therapy for the treatment of migraine.

However, the wide array of cardiovascular unwanted effects produced by this ergot 20 prompted the search for more selective antimigraine agents. These attempts ultimately led to the development of sumatriptan as the first selective 5-HT1 receptor agonist effective in the acute treatment of migraine 21.

However, its short half-life and low oral bioavailability stimulated the development of

compounds with longer half-life and higher oral bioavailability, presently known as “secondgeneration triptans” 22.

EPIDEMIOLOGY AND CO MORBIDITIES OF MIGRAINE It is apparently a global disorder, occurring in all races, cultures, and geographical locations. Current figures suggest that 18 percent of women and six percent of men suffer from migraine and those numbers are increasing 23. The worldwide prevalence of headache for all age-group is considered to be more than 47%, and of migraine is 10.3%24 and is more prevalent in females than in males (15-18% vs.

6%)23. The incidence of migraine begins earlier in males than in females, and Migraine with Aura begins earlier than Migraine without Aura 25. For both men and women, the prevalence of migraine rises throughout early adult life and falls after midlife. In girls and women, the rate almost triples between age 10 and 30 years26. The term ‘comorbidity’ refers to the greater-than coincidental association of two or more conditions in the same person. Migraine is co-morbid with a number of neurological and psychiatric disorders, including, among other things, stroke, epilepsy, depression and anxiety disorders27. Migraine also appears to be associated with irritable bowel syndrome, mitral valve prolapse,28, low-tension glaucoma29 and Raynaud phenomenon30. Hypertension, diabetes, asthma, and obesity are other co-morbid conditions with migraine24. Migraine is classified into two major types-migraine without aura and migraine with aura 7.

PATHOBIOLOGY OF MIGRAINE Migraine is best understood as a primary disorder of the brain. It is a form of neurovascular headache: a disorder in which neural events result in the dilation of blood vessels, which, in turn, results in pain and further nerve activation31. A potential cause of migraine is any change in the stability of pathways either directly or via trigemino cervical pain system.

This could be inherited as a low activation threshold.

Migraine attacks are believed to be caused by activation of the trigeminal nerve and trigemino vascular system, leading to the release of several neurotransmitters (calcitonin gene-related peptide, substance P) that affect vasomotor tone, causing neurogenic inflammation of intracranial and

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extracranial cerebral vessels32. This leads to vasodilation, mast cell degranulation, increased vascular permeability and meningeal edema, resulting in neurogenic inflammation. This nociceptive information is transmitted from the trigeminal nerve to brainstem nuclei, thalamic nuclei and the cortex, where migraine pain is ultimately perceived33. The locus coeruleus, dorsal raphe, and the periaqueductal gray also play modulator roles in the transmission of pain34.

Cortical spreading depression is another theory that could result in aura by a spreading wave of depolarization35. Aura is accompanied with a localized decrease followed by an increase in blood flow in parieto-occipital cortex which leads to activation followed by depression of neurological activity over a cortical area. It could result in the release of some inflammatory mediators that irritates cranial nerves root, mostly the trigeminal nerve that transmits the sense of face and most of the head.

There are some experiments supporting involvement of cortical event in the initiation of headache as well 36 .The aura is thought to be caused by cortical spreading depression, a slowly propagating wave of intense neuronal and glial depolarization progressing over the cortex and followed by a period of inactivity 37 .Mitochondrial dysfunction, which leads to impaired oxygen metabolism, has been speculated to play a role in migraine pathophysiology 38 and this is the basis for the use of supplements that enhance mitochondrial function in the treatment of migraine, such as riboflavin,CoQ10, and alpha lipoic acid 26 .The mechanism by which fasting and skipping meals triggers headaches may be related to alterations in serotonin and norepinephrine in brainstem pathways39 or the release of stress hormones such as cortisol.

TRIGGERS Any factor, which on exposure or withdrawal, alone or in combination, leads to the development of an acute migraine headache, is known as migraine trigger40. Migraine triggers could influence the cerebral cortex, organizations innervated by the terminal nerve (i.e. dural arteries), the trigeminal pain pathway (trigeminal nerve, thalamic nuclei), and regulatory pathway within the brain stem or the limbic system contributes to migraine. Therefore, migraine triggers aggravate migraine headache in a

number of diverse ways, including: (i)direct effect on excitatory or inhibitory neuro receptors; (ii) release of internal neuropeptides or neurotransmitters and nitric oxide; and (iii) direct excitation of neurons40,41. The most common external triggers for migraine attacks in decreasing frequency are, stress (80%), hormonal fluctuations in women (65%), skipping meals (57%), changes in weather (53%), lack of sleep (50%), perfumes or odors (44%), neck pain (38%), certain foods (27%) and physical activity (22%)9,42. Besides this, Cheese, chocolate, red wine and beer and several other food substances contain vasoactive amines, such as tyramine, which constrict arteries, the first step of migraine process. Others believe that foods cause headaches by setting off an allergic reaction in susceptible people. Food-triggered migraine usually occurs soon after eating43.

APPROACHES TO MANAGEMENT Acute treatment is classified into nonspecific treatments, including non-steroidal anti-inflammatory drugs (NSAIDs), and migraine-specific treatments, including ergot derivatives and the triptans. However, only one third of patients in clinical trials feel painfree 2 hours after taking a triptan orally, so novel treatment options are still required. Recently, new drugs have been developed by targeting neural sites.

Interestingly, safety and efficiency of some of these drugs have been confirmed in phase II and some other in phase III clinical trials 44.The management of migraine can be divided into acute (abortive) and preventive treatment. Patients with frequent and severe headaches often require both approaches 45.

Many agents are used to treat acute severe migraine and clinical guidelines recommend non-steroidal antiinflammatory drugs (NSAIDs), sumatriptan, dihydroergotamine, ergotamine, chlorpromazine and prochlorperazine, amongst others 46.

PROPHYLAXIS OF MIGRAINE Currently, the major classes of conventional migraine preventive drugs include antidepressants, βadrenergic blockers (BABs), calcium channel blockers (CCBs), and antiepileptic drugs (AEDs) to be effective; however, their clinical use is limited 47.

Emerging treatments are: angiotensin converting enzyme (ACE) inhibitors, angiotensin II type 1 receptor blockers (ARB), and botulinum toxin type A (BTX-A)48,49 dopamine antagonists, and Îł-amino

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butyric acid agonists50,51. Unfortunately, many of these treatments are nonspecific and not always effective 52. As drugs of first choice, the β-blockers propranolol and metoprolol, the calcium overloads blocker flunarizine and in recent years, the anticonvulsant drugs valproic acid and topiramate have been established. Drugs of second choice have either shown fewer efficacies in clinical trials than the drugs of first choice or have only been tested in a small number of less well-designed trials Amitriptyline, Venlafaxine, Naproxen and Acetylsalicylic acid are used 53.

MIGRAINE AND DEFICIENCY NEUROCHEMICALS (PEPTIDES NEUROTRANSMITTERS IN BRAIN)

OF AND

Calcitonin Gene-Related Peptide Calcitonin gene related peptide is a 37-amino acid neuropeptide, member of the calcitonin family of peptide, which plays an important role in regulation of vascular tone and modulation of pain perception 54.

Calcitonin gene related peptide was originally thought to contribute to migraine and elevated level of this peptide has been reported in this disease 54, 55.

Calcitonin gene related peptide can lead to enhancement of cerebral circulation, transmission of pain-related impulses and neurogenic inflammation 54 . Calcitonin gene related peptide activates adenylate cyclase and enhanced cyclic adenosine mono phosphate production is believed to be involved in increase of blood circulation. Moreover, the cyclic adenosine monophosphate production can cause enhancement of nitric oxide synthase activity and nitric oxide production followed by the increase in cyclic guanosine mono phosphate production as a secondary messenger for nitric oxide. The enhancement of cyclic guanosine monophosphate production was connected to vasodilation and increase in cerebral circulation. Calcitonin gene related peptide - mediated neurogenic inflammation is followed by degranulation of mast cells and the release of inflammatory agents 54,55.

SEROTONIN Serotonin or 5-hydroxytryptamine is synthesized from tryptophan, in various tissues including brain.

There are some controversies regarding the role of serotonin in migraine. It has been shown that there

are the gender and seasonal variations of serotonin neurotransmission in human such as 5hydroxytryptamine receptor hypersensitivity and its decreased cerebrospinal fluid level in women and 5hydroxytryptamine receptor hyposensitivity in summer. On the other hand, the higher frequency of migraine in women and higher frequency of its attacks in summer compared with winter, and autumn has been reported in most studies. Also, nowadays, the triptan, a selective serotonin 5-hydroxytryptamine (1B/1C) agonist is being used in the treatment of acute migraine attacks. In spite of controversial results about mentioned issues, the importance of the failure of a serotonergic system in migraine pathogenesis is significant. Accordingly, the serotonin system is considered to be involved in migraine 56. Recent advances in basic and applied clinical neuroscience have led to the development of a new class of selective serotonin(5hydroxytryptamine 5-HT) receptor agonists that activate 5-HT and 5-HT1D(5-HT 1B/1D) receptors and are known as the triptans; these agents have changed the lives of countless patients with migraine.

Triptans have three potential mechanisms of action: cranial vasoconstriction57, peripheral neuronal inhibition58 and inhibition of transmission through second-order neurons of the trigeminocervical complex59.

MELATONIN The synthesis of melatonin or N-acetyl-5methyoxytryptamine from serotonin occurs in the pineal gland and other tissues in humans60 and indole amine has been identified in numerous taxa including bacteria, unicellular eukaryotes60,61 and plants62.

Melatonin may play a significant role in sleep and circadian rhythm regulation, improvement of immune system and antioxidant activity 61. It has been found that plasma and urinary levels of melatonin63 and nocturnal urinary 6-sulfatoxy melatonin concentration64 decrease inpatients with migraine.

Melatonin receptors are present in trigeminal ganglion and trigeminal nucleus of mammals that could explain its action. Also trigeminovascular nociception that is induced by cortical spreading depression in rats is attenuated by melatonin65.

Therefore, melatonin has been suggested as a possible biomarker for migraine 66 and there is a great potential for using melatonin in acute or prophylactic

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treatment of migraine headache67. Melatonin because of its anti-inflammatory and antioxidant effects such as reduction in pro-inflammatory factors and scavenging toxic free radicals, potentiation of gamma aminobutyric acid and opioid analgesia, suppression of nitric oxide synthase activity, inhibition of dopamine release, protection against glutamate neurotoxicity, and regulation of neurovascular regulation has been suggested a target with a lot of potential in migraine68.

NITRIC OXIDE Nitric oxide functions as the modulator of cellular toxicity, inflammatory responses, release of calcitonin gene related peptides as a potent peptide vasodilator, platelet function, endothelium-dependent vasodilatation, and transmission of pain impulses 69.

Nitric oxide as a diatomic molecule is synthesized by nitric oxide synthases from L-arginine. Changes in plasma and platelet70 levels of nitric oxide in migraine sufferers have been shown. Abnormalities in nitric oxide signaling pathway and increase in activity of nitric oxide synthase has been shown to be associated with enhanced susceptibility to migraine 69.

The oral administration of nitroglycerin as a nitric oxide donor induces headaches, which resembles to spontaneous migraine attacks. Also, in migraineurs, nitroglycerine inhibitors attenuated these 69 nitroglycerin-induced attacks and as a result nitric oxide is suggested as fundamental biomarker for migraine 66.

DOPAMINE Migraine is often associated with yawning, drowsiness, mood changes, irritability, and hyperactivity in the premonitory phase71. Dopamine was proposed to have a role in inducing migraine’s nausea, vomiting, and blood pressure changes72.

Studies suggest that migraineurs are hypersensitive to dopamine agonists73.

endogenous opioid system in migraine and beta endorphin levels in plasma and cerebrospinal fluid were found to decrease in migrainous subjects during headache free periods and/or during attacks (10, 14– 19) and patients with lower beta endorphin level had longer duration of headache76.

SUBSTANCE P In 1931, Von and Gaddum discovered a substance named substance P in the intestine and brain of the horse that could cause contraction of smooth intestinal muscle, vasodilation and reduction of blood pressure77. Multiple lines of evidence have shown that SP can trigger neurogenic inflammation, including vasodilation, plasma extravasation and mast cell degranulation, thereby leading to hyperalgia. A study showed higher plasma SP levels in migraine patients compared with healthy individuals 78.

CONCLUSION It seems that future research should be emphasized to unravel the hidden and mysterious area of migraine pathophysiology using metabolomics and proteomics study, which could also lead to find some bio markers to discriminate patient and healthy people.

Future targets have also been identified and new emerging treatments proposed according to basic mechanisms which, in the majority of cases, target specific receptors of neurotransmitter and biochemical pathways. They need to be further explored in preclinical studies and in the case of promising positive results relevant for migraine so identification of these migraines specific loci hopefully will help to develop individualized pharmacotherapeutic.

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