Introduction:
Migraine is one of the most common neurological complications. Almost 15 percent of the world's population suffers from this condition. However, the exact etiology is still not known. As a result, different therapeutic approaches have been tried over many years. However, the desired clinical results have still not been achieved.
What Is Migraine Headache?
Migraine or migraine headache is a type of neuralgic pain. This type of headache is episodic and is characterized by moderate-to-severe headaches. Migraine is one of the most prevalent causes of disability in the world. It is one of the main causes of loss of work, functionality, and functional impairment.
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Pathophysiology:
The causative factor of the migraine is not known. According to researchers, genetic factors are the most important causative factor associated with migraine. Mutation in chromosome 19 is associated with the pathogenesis of migraine. Also, a mutation in the calcium channel CACNA1A gene and FHM-I is related. However, triggering factors play a pivotal role in the pathogenesis of this condition. External factors like hormonal changes, stress, tension, anxiety, food, and light are responsible for changes in the brain. According to the vascular theory of migraine activation of perivascular nerves, the innervating major cerebral vessels are responsible for vascular changes in the various brain regions. This is responsible for cerebrovascular and neural changes in the brain. These changes are seen mainly in the subcortical sites below the level of the diencephalon (a part of the central nervous system in the brain). This causes activation of the brainstem trigeminovascular neurons.
Apart from the vascular changes, inflammatory damage of the neurons is responsible for this condition. Recently, scientists have discovered the role of neuropeptides in this condition's pathogenesis. The neuropeptide calcitonin gene-related peptide (CGRP) is the main neuropeptide associated with migraine. This amino acid helps to increase the diameter of the vessels and is produced by the neurons in both the central and peripheral nervous systems. The dilatation of the blood vessels by this compound causes activation of the perivascular trigeminal sensory nerve fibers. These nerve fibers are responsible for pain sensations. All these factors lead to the further release of the chemicals called substance P and CGRP from trigeminal fibers. These chemicals are responsible for inflammation in the neurons and are associated with the leakage of the blood vessels and degranulation of the mast cells. The serum concentration of CGRP in patients suffering from migraine is also high.
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Symptoms:
The symptoms of migraine mainly depend on the clinical presentation of the disorder. The symptoms of the migraine can be divided into four phases. Prodrome is the earliest stage and is associated with symptoms like mood changes, lethargy, and light sensitivity. Aura encompasses a second set of symptoms. These include it is caused by changes in the blood circulation and neurovascular changes. It is associated with a tingling sensation in the face and the limbs. In certain cases, certain changes in the visual fields can be seen. In the second phase, headache is observed. The headache is observed in various parts of the head, like the frontal or side portion. This is associated with symptoms like vomiting, sensitivity toward light, and secretion of tears. After the cessation of a headache, some associated symptoms like dizziness and mood swings can be seen.
What Are CGRP Antagonists?
As already discussed, the Calcitonin gene-related peptide is one of the chemical compounds associated with the pathogenesis of migraine. CGRP is distributed both in the central and peripheral nervous system. These are expressed mainly in C and A-delta nerve fibers. The receptors for CGRP are of three types. The CGRP-1 is a G protein-coupled receptor. This is also known as the calcitonin-like receptor. The second class of receptors is known as RAMP1. These receptors help in the formation of functional CGRP receptors. Another important CGRP receptor is the RCP receptor, which is important for G-protein signaling. However, CGRP receptors also play an important role in the pathogenesis of migraine. The function of the CGRP antagonists is to prevent the functioning of these receptors. Chemically, these antagonists are nothing but N-terminal truncated fragments of the CGRP peptide. The available CGRP antagonists that can be used for the treatment of migraine are;
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Olcegepant: This is the first CGRP receptor antagonist. It is a selective antagonist that works mainly on RAMP1 and is administered intravenously. This drug directly competes with the CGRP molecule and prevents physiological and cellular changes caused by CGRP. However, According to some researchers, the ability of this drug to constrict the blood vessels is very minimal.
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Telcegepant: This is also a selective CGRP receptor antagonist, which is given orally. This drug also acts on RAMP1 receptors. 300-milligram dose of this drug is useful to provide migraine pain relief for 24 hours. This drug dose does not cause a significant amount of vasoconstriction.
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Ubrogepant: This is an orally administered small molecule antagonist of the CGRP receptor. Though the drug is still in the clinical trial phase, it has shown relief from acute pain for 48 hours. Nausea, dry mouth, and tiredness are the potential side effects of this drug. The maximum dose for 24 hours is 200 milligrams.
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Rimegepant: This drug got approval from the FDA in 2020. It is known for blocking the action of the CGRP-1 receptor. It is useful in treating conditions like migraine with or without aura. The maximum dose for 24 hours is 75 milligrams.
Apart from this, another group is useful to reduce the amount of CGRp in the body. These drugs are known as Calcitonin Gene‑Related Peptide (CGRP)‑targeted monoclonal antibodies (mAbs).
What Are the Side Effects?
As most of these drugs are in clinical trial phases, the side effects or adverse reactions associated with these drugs are not known. However, most of these drugs are known for dry mouth, nausea, vomiting, and tiredness. Rimegepant is known for liver toxicity in higher doses due to the alteration of the functioning of the liver enzymes.
Conclusion:
Migraine is associated with neurovascular changes in the brain. One of the most common chemicals associated with this is CGRP, which is associated with the dilation of blood vessels. CGRP antagonists are a new generation of drugs that prevent the action of the molecules. These drugs act on the receptor site of the molecule and prevent its functioning.
