Neuronal complexity is attenuated in preclinical models of migraine and restored by HDAC6 inhibition

Autor: Zachariah Bertels, Pavel A. Petukhov, Bhargava Karumudi, Wiktor D Witkowski, Alycia F Tipton, Mark M. Rasenick, Pal Shah, Zoie Sheets, Elizaveta Mangutov, Harinder Singh, Serapio M. Baca, Amynah A. Pradhan, Isaac Dripps, Valentina Petukhova, Mei Ao, Catherine Conway, Kendra Siegersma
Jazyk: angličtina
Rok vydání: 2021
Předmět:
0301 basic medicine
Male
Photophobia
Mouse
Aura
Histone Deacetylase 6
Microtubules
Nitroglycerin
0302 clinical medicine
Tubulin
migraine
pain
Biology (General)
Neurons
education.field_of_study
Neuronal Plasticity
Behavior
Animal
General Neuroscience
Cortical Spreading Depression
Brain
cytoskeleton
Acetylation
Pain Perception
General Medicine
Allodynia
Cortical spreading depression
Medicine
Female
medicine.symptom
Research Article
Pain Threshold
QH301-705.5
Science
Migraine Disorders
Population
Neuronal Outgrowth
Sensory system
General Biochemistry
Genetics and Molecular Biology
03 medical and health sciences
aura
Calcitonin Gene-Related Peptide Receptor Antagonists
medicine
Animals
Migraine treatment
education
allodynia
General Immunology and Microbiology
business.industry
medicine.disease
Histone Deacetylase Inhibitors
Mice
Inbred C57BL
Disease Models
Animal
030104 developmental biology
Migraine
business
Neuroscience
Protein Processing
Post-Translational
030217 neurology & neurosurgery
Receptors
Calcitonin Gene-Related Peptide
Zdroj: eLife
eLife, Vol 10 (2021)
ISSN: 2050-084X
Popis: Migraine is the sixth most prevalent disease worldwide but the mechanisms that underlie migraine chronicity are poorly understood. Cytoskeletal flexibility is fundamental to neuronal-plasticity and is dependent on dynamic microtubules. Histone-deacetylase-6 (HDAC6) decreases microtubule dynamics by deacetylating its primary substrate, α-tubulin. We use validated mouse models of migraine to show that HDAC6-inhibition is a promising migraine treatment and reveal an undiscovered cytoarchitectural basis for migraine chronicity. The human migraine trigger, nitroglycerin, produced chronic migraine-associated pain and decreased neurite growth in headache-processing regions, which were reversed by HDAC6 inhibition. Cortical spreading depression (CSD), a physiological correlate of migraine aura, also decreased cortical neurite growth, while HDAC6-inhibitor restored neuronal complexity and decreased CSD. Importantly, a calcitonin gene-related peptide receptor antagonist also restored blunted neuronal complexity induced by nitroglycerin. Our results demonstrate that disruptions in neuronal cytoarchitecture are a feature of chronic migraine, and effective migraine therapies might include agents that restore microtubule/neuronal plasticity.
eLife digest Migraines are a common brain disorder that affects 14% of the world’s population. For many people the main symptom of a migraine is a painful headache, often on one side of the head. Other symptoms include increased sensitivity to light or sound, disturbed vision, and feeling sick. These sensory disturbances are called aura and they often occur before the headache begins. One particularly debilitating subset of migraines are chronic migraines, in which patients experience more than 15 headache days per month. Migraine therapies are often only partially effective or poorly tolerated, making it important to develop new drugs for this condition, but unfortunately, little is known about the molecular causes of migraines. To bridge this gap, Bertels et al. used two different approaches to cause migraine-like symptoms in mice. One approach consisted on giving mice nitroglycerin, which dilates blood vessels, produces hypersensitivity to touch, and causes photophobia in both humans and mice. In the second approach, mice underwent surgery and potassium chloride was applied onto the dura, a thick membrane that surrounds the brain. This produces cortical spreading depression, an event that is linked to migraine auras and involves a wave of electric changes in brain cells that slowly propagates across the brain, silencing brain electrical activity for several minutes. Using these approaches, Bertels et al. studied whether causing chronic migraine-like symptoms in mice is associated with changes in the structures of neurons, focusing on the effects of migraines on microtubules. Microtubules are cylindrical protein structures formed by the assembly of smaller protein units. In most cells, microtubules assemble and disassemble depending on what the cell needs. Neurons need stable microtubules to establish connections with other neurons. The experiments showed that provoking chronic migraines in mice led to a reduction in the numbers of connections between different neurons. Additionally, Bertels et al. found that inhibiting HDAC6 (a protein that destabilizes microtubules) reverses the structural changes in neurons caused by migraines and decreases migraine symptoms. The same effects are seen when a known migraine treatment strategy, known as CGRP receptor blockade, is applied. These results suggest that chronic migraines may involve decreased neural complexity, and that the restoration of this complexity by HDAC6 inhibitors could be a potential therapeutic strategy for migraine.
Databáze: OpenAIRE
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