CGRP-Receptor Antagonists — A Fresh Approach to Migraine Therapy?
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《新英格兰医药杂志》
Migraine is a chronic disease that affects 12 percent of the general population. In addition to severe, debilitating headache, patients with migraines may experience nausea, vomiting, and sensitivity to light and sound. Migraine remains one of the most underdiagnosed and undertreated neurologic conditions and has substantial socioeconomic effects in developed countries. It is now considered to be a neurovascular disorder because its pathology involves important interactions between the cerebral nerves and blood vessels.
Current theories propose that migraine-specific triggers promote primary brain dysfunction, which evokes changes in the dilation of meningeal blood vessels and the activation of perivascular trigeminal nerves. These nerves provide sensory information from the major blood vessels that are responsible for regulating cerebral blood flow and from smaller blood vessels located within the pain-sensitive meninges. Activated trigeminal nerve terminals release vasoactive neuropeptides within the meninges, mediating neurogenic inflammation that is characterized by vasodilation, vessel leakage, and mast-cell degranulation. In addition, neuropeptides relay nociceptive impulses to the central nervous system, leading to severe migraine pain; to central sensitization, which lowers the pain-response threshold; and to allodynia, which causes previously innocuous stimuli, such as combing one's hair or sneezing, to be painful.
The release of the neuropeptide calcitonin gene–related peptide (CGRP) from trigeminal nerves is now thought to play a central role in the underlying pathophysiology of migraine. The serum levels of CGRP in the external jugular vein are elevated in patients during all forms of vascular headaches, including migraines (with or without aura) and cluster headaches. Further evidence of the function of CGRP in migraine comes from clinical studies in which triptans — drugs that are used to treat migraine and that block the release of CGRP — returned CGRP levels to base-line values as they alleviated headache pain. CGRP was recently demonstrated to have a causative role in migraine, when the infusion of CGRP induced headaches and migraines in susceptible persons.
How, exactly, does CGRP function in migraine pathology? This multifunctional 37-amino-acid neuropeptide is expressed in trigeminal ganglia nerves and is released after nerve activation. Physiological studies have demonstrated that CGRP is a potent dilator of cerebral and dural vessels and, therefore, has an important function in regulating blood flow to the brain and pain-sensitive meninges. CGRP can also cause degranulation and subsequent release of inflammatory agents from meningeal mast cells. In addition, CGRP is involved in the transmission of painful stimuli from intracranial vessels to the central nervous system. These findings suggest that CGRP-receptor antagonists might be effective in treating migraine by blocking the pathophysiological activities of CGRP.
The first CGRP-receptor antagonists were shortened fragments of the CGRP peptide. CGRP(8–37), which includes all but the first seven amino acids, functions as a potent antagonist of CGRP receptors by blocking the binding of endogenous full-length CGRP. Although CGRP(8–37) effectively inhibits vasodilation and neurogenic inflammation, it has a short half-life and therefore has not proved to be clinically effective. However, studies using truncated forms of CGRP have provided evidence that the blockage of CGRP receptors by nonpeptide molecules could be beneficial in treating migraine. To this end, the nonpeptide CGRP-receptor antagonist, BIBN 4096 BS, which exhibits high affinity for human CGRP receptors, was recently developed. BIBN 4096 BS was shown to be at least as effective as triptans in blocking or reversing the dilation of intracranial vessels and inhibiting neurogenic inflammation after the stimulation of the trigeminal nerves.
Although triptans have proved to be an effective treatment for migraine, they have an affinity for multiple serotonin (5-hydroxytryptamine ) receptors, including 5-HT1B, 5-HT1D, and 5-HT1F. The triptan-induced activation of 5-HT1 receptors blocks the release of several neuropeptides and selectively constricts cerebral vessels, but it also causes vasoconstrictive effects in coronary vessels. BIBN 4096 BS, on the other hand, reportedly blocks only CGRP receptors and has no unwanted cardiovascular side effects, such as changes in the blood pressure or heart rate. The absence of vasoconstrictor activity may prove to be a major advantage for the use of CGRP-receptor antagonists in the treatment of migraine. However, larger clinical trials will be required in order to test the validity of this claim.
In this issue of the Journal, Olesen and colleagues (pages 1104–1110) present data demonstrating that the CGRP-receptor antagonist BIBN 4096 BS is an effective, well-tolerated treatment for migraine. They report a response rate of 60 percent two hours after treatment, which is similar to the efficacy rates reported with the original triptans. Moreover, in this study, BIBN 4096 BS was effective in treating migraine attacks that were rated as moderate to severe and that had not improved over the course of six hours from the time of onset. Surprisingly, recent clinical studies have shown that patients who take triptans during the mild phase of an attack are more likely to have rapid relief of headache and lower rates of recurrence. Thus, it is possible that the response to BIBN 4096 BS may be even greater if patients can be treated during the early phases of an attack when pain is mild.
As Olesen et al. note, it will be particularly interesting to determine whether patients who do not have a response to triptans might be effectively treated with BIBN 4096 BS. An improved response may be unlikely if the antimigraine effect of triptans is mediated primarily through the inhibition of CGRP release and BIBN 4096 BS blocks CGRP-receptor function. According to functional studies of CGRP, there are several potential sites of action for BIBN 4096 BS (see Figure). Blocking the CGRP receptors would be likely to inhibit the dilation of major cerebral vessels, diminish neurogenic inflammation within the meninges, and block the activation of nociceptive neural pathways. Thus, the ability of both triptans and CGRP-receptor antagonists to alleviate migraine pain may be mediated by the same molecular targets — that is, pathways that are activated following CGRP-receptor activation.
Figure. Possible Sites of Action of the Nonpeptide CGRP-Receptor Antagonist BIBN 4096 BS.
The binding of the calcitonin gene–related peptide (CGRP) antagonist to receptors on major cerebral vessels would decrease blood flow to the brain. Binding to meningeal blood vessels and mast cells would inhibit neurogenic inflammation, and binding to receptors on second-order neurons would inhibit the transmission of pain.
BIBN 4096 BS is the first CGRP-receptor antagonist for which significant efficacy in the treatment of migraine has been demonstrated; this efficacy provides further evidence of the critical role of CGRP in the pathology of migraine. Given the apparent absence of vasoconstrictor activity with this agent, BIBN 4096 BS and possibly other CGRP-receptor antagonists may provide an alternative for the treatment of migraine that rivals triptans, although a formulation that may be administered as easily as the current triptans must first be developed. It will be interesting to see whether CGRP-receptor antagonists also prove beneficial in treating other prevalent diseases, such as arthritis and temporomandibular-joint disorders, in which CGRP levels are elevated. The therapeutic benefit of this potential new class of drugs for treating migraine appears very promising.
Source Information
From the Department of Biology, Southwest Missouri State University, Springfield.(Paul L. Durham, Ph.D.)
Current theories propose that migraine-specific triggers promote primary brain dysfunction, which evokes changes in the dilation of meningeal blood vessels and the activation of perivascular trigeminal nerves. These nerves provide sensory information from the major blood vessels that are responsible for regulating cerebral blood flow and from smaller blood vessels located within the pain-sensitive meninges. Activated trigeminal nerve terminals release vasoactive neuropeptides within the meninges, mediating neurogenic inflammation that is characterized by vasodilation, vessel leakage, and mast-cell degranulation. In addition, neuropeptides relay nociceptive impulses to the central nervous system, leading to severe migraine pain; to central sensitization, which lowers the pain-response threshold; and to allodynia, which causes previously innocuous stimuli, such as combing one's hair or sneezing, to be painful.
The release of the neuropeptide calcitonin gene–related peptide (CGRP) from trigeminal nerves is now thought to play a central role in the underlying pathophysiology of migraine. The serum levels of CGRP in the external jugular vein are elevated in patients during all forms of vascular headaches, including migraines (with or without aura) and cluster headaches. Further evidence of the function of CGRP in migraine comes from clinical studies in which triptans — drugs that are used to treat migraine and that block the release of CGRP — returned CGRP levels to base-line values as they alleviated headache pain. CGRP was recently demonstrated to have a causative role in migraine, when the infusion of CGRP induced headaches and migraines in susceptible persons.
How, exactly, does CGRP function in migraine pathology? This multifunctional 37-amino-acid neuropeptide is expressed in trigeminal ganglia nerves and is released after nerve activation. Physiological studies have demonstrated that CGRP is a potent dilator of cerebral and dural vessels and, therefore, has an important function in regulating blood flow to the brain and pain-sensitive meninges. CGRP can also cause degranulation and subsequent release of inflammatory agents from meningeal mast cells. In addition, CGRP is involved in the transmission of painful stimuli from intracranial vessels to the central nervous system. These findings suggest that CGRP-receptor antagonists might be effective in treating migraine by blocking the pathophysiological activities of CGRP.
The first CGRP-receptor antagonists were shortened fragments of the CGRP peptide. CGRP(8–37), which includes all but the first seven amino acids, functions as a potent antagonist of CGRP receptors by blocking the binding of endogenous full-length CGRP. Although CGRP(8–37) effectively inhibits vasodilation and neurogenic inflammation, it has a short half-life and therefore has not proved to be clinically effective. However, studies using truncated forms of CGRP have provided evidence that the blockage of CGRP receptors by nonpeptide molecules could be beneficial in treating migraine. To this end, the nonpeptide CGRP-receptor antagonist, BIBN 4096 BS, which exhibits high affinity for human CGRP receptors, was recently developed. BIBN 4096 BS was shown to be at least as effective as triptans in blocking or reversing the dilation of intracranial vessels and inhibiting neurogenic inflammation after the stimulation of the trigeminal nerves.
Although triptans have proved to be an effective treatment for migraine, they have an affinity for multiple serotonin (5-hydroxytryptamine ) receptors, including 5-HT1B, 5-HT1D, and 5-HT1F. The triptan-induced activation of 5-HT1 receptors blocks the release of several neuropeptides and selectively constricts cerebral vessels, but it also causes vasoconstrictive effects in coronary vessels. BIBN 4096 BS, on the other hand, reportedly blocks only CGRP receptors and has no unwanted cardiovascular side effects, such as changes in the blood pressure or heart rate. The absence of vasoconstrictor activity may prove to be a major advantage for the use of CGRP-receptor antagonists in the treatment of migraine. However, larger clinical trials will be required in order to test the validity of this claim.
In this issue of the Journal, Olesen and colleagues (pages 1104–1110) present data demonstrating that the CGRP-receptor antagonist BIBN 4096 BS is an effective, well-tolerated treatment for migraine. They report a response rate of 60 percent two hours after treatment, which is similar to the efficacy rates reported with the original triptans. Moreover, in this study, BIBN 4096 BS was effective in treating migraine attacks that were rated as moderate to severe and that had not improved over the course of six hours from the time of onset. Surprisingly, recent clinical studies have shown that patients who take triptans during the mild phase of an attack are more likely to have rapid relief of headache and lower rates of recurrence. Thus, it is possible that the response to BIBN 4096 BS may be even greater if patients can be treated during the early phases of an attack when pain is mild.
As Olesen et al. note, it will be particularly interesting to determine whether patients who do not have a response to triptans might be effectively treated with BIBN 4096 BS. An improved response may be unlikely if the antimigraine effect of triptans is mediated primarily through the inhibition of CGRP release and BIBN 4096 BS blocks CGRP-receptor function. According to functional studies of CGRP, there are several potential sites of action for BIBN 4096 BS (see Figure). Blocking the CGRP receptors would be likely to inhibit the dilation of major cerebral vessels, diminish neurogenic inflammation within the meninges, and block the activation of nociceptive neural pathways. Thus, the ability of both triptans and CGRP-receptor antagonists to alleviate migraine pain may be mediated by the same molecular targets — that is, pathways that are activated following CGRP-receptor activation.
Figure. Possible Sites of Action of the Nonpeptide CGRP-Receptor Antagonist BIBN 4096 BS.
The binding of the calcitonin gene–related peptide (CGRP) antagonist to receptors on major cerebral vessels would decrease blood flow to the brain. Binding to meningeal blood vessels and mast cells would inhibit neurogenic inflammation, and binding to receptors on second-order neurons would inhibit the transmission of pain.
BIBN 4096 BS is the first CGRP-receptor antagonist for which significant efficacy in the treatment of migraine has been demonstrated; this efficacy provides further evidence of the critical role of CGRP in the pathology of migraine. Given the apparent absence of vasoconstrictor activity with this agent, BIBN 4096 BS and possibly other CGRP-receptor antagonists may provide an alternative for the treatment of migraine that rivals triptans, although a formulation that may be administered as easily as the current triptans must first be developed. It will be interesting to see whether CGRP-receptor antagonists also prove beneficial in treating other prevalent diseases, such as arthritis and temporomandibular-joint disorders, in which CGRP levels are elevated. The therapeutic benefit of this potential new class of drugs for treating migraine appears very promising.
Source Information
From the Department of Biology, Southwest Missouri State University, Springfield.(Paul L. Durham, Ph.D.)