Novel Migraine Treatment Target

Migraine headache is a complex, recurrent headache disorder that is one of the most common complaints in medicine. In the United States, more than 30 million people have 1 or more migraine headaches per year.

Migraine was previously considered to be a vascular phenomenon that resulted from intracranial vasoconstriction followed by rebound vasodilation. Currently, however, the neurovascular theory describes migraine as primarily a neurogenic process with secondary changes in cerebral perfusion associated with a sterile neurogenic inflammation.

Symptomatology

Migraine is characterized most often by unilateral head pain that is moderate to severe, throbbing, and aggravated by activity. It may also be associated with various visual or sensory symptoms, which occur most often before the headache component but which may occur during or after the headache; these are collectively known as an aura. Most commonly, the aura consists of visual manifestations, such as scotomas, photophobia, or visual scintillations (eg, bright zigzag lines).

The head pain may also be associated with weakness. This form of migraine is termed hemiplegic migraine.

The diagnosis of migraine is clinical in nature, based on criteria established by the International Headache Society

The treatment for this disease depends on the severity of the pain and symptoms, it goes from low, mild and severe migraine.

Simple analgesics alone or in combination with other compounds have provided relief for mild to moderately severe headaches and sometimes even for severe headaches. Analgesics used in migraine include acetaminophen, NSAIDs, and narcotic analgesics (eg, oxycodone, morphine sulfate). 

For severe or urgent episodes of migraine, opioids and triptans are the most common medication used. Nonetheless, with the chronic use of these drugs , a resistance to the medication may be developed for the patients, and the need to increase the doses sometimes is not effective to reduce the symptoms.

All the triptans are most effective when taken early during a migraine and all may be repeated in 2 hours as needed, with a maximum of 2 doses daily. While different formulations of a specific triptan may be used in the same 24-hour period, only 1 triptan may be used during this time frame.

New study show possible new treatment target for migraine

The structure of the cell is maintained by its cytoskeleton which is made up of the protein, tubulin. Tubulin is in a constant state of flux, waxing and waning to change the size and shape of the cell. This dynamic property of the cell allows the nervous system to change in response to its environment.

Tubulin is modified in the body through a chemical process called acetylation. When tubulin is acetylated it encourages flexible, stable cytoskeleton; while tubulin deacetylation, induced by histone deacetylase 6, or HDAC6, promotes cytoskeletal instability.

Amynah Pradhan, associate professor of psychiatry at the University of Illinois Chicago and his team, use  mice models to show that decreased neuronal complexity may be a feature, or mechanism, of chronic migraine.  When HDAC6 is inhibited, tubulin acetylation and cytoskeletal flexibility is restored. Additionally, HDAC6 reversed the cellular correlates of migraine and relieved migraine-associated pain.

Once out of the cycle of decreased neuronal complexity, the brain may become more responsive to pain management therapies

This work suggests that the chronic migraine state may be characterized by decreased neuronal complexity, and that restoration of this complexity could be a hallmark of anti-migraine treatments. This work also forms the basis for development of HDAC6 inhibitors as a novel therapeutic strategy for migraine.

HDAC6 inhibitors are currently in development for cancer, and HDCA6 as a target has been identified for other types of pain.

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SOURCE:

Zachariah Bertels, Harinder Singh, Isaac Dripps, Kendra Siegersma, Alycia F Tipton, Wiktor D Witkowski, Zoie Sheets, Pal Shah, Catherine Conway, Elizaveta Mangutov, Mei Ao, Valentina Petukhova, Bhargava Karumudi, Pavel A Petukhov, Serapio M Baca, Mark M Rasenick, Amynah A Pradhan (April 15, 2021). Neuronal complexity is attenuated in preclinical models of migraine and restored by HDAC6 inhibition. eLife. Retrieved from: https://elifesciences.org/articles/63076 

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Photo by  Adrian Swancar on Unsplash