Novel Therapeutic Targets Against Spreading Depression

Chen, Shih‐Pin; Ayata, Cenk

doi:10.1111/head.13154

Cited by 19 publications

(16 citation statements)

References 171 publications

(279 reference statements)

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“…The cortical spreading depression procedure used is based on previous work by Charles 25 and Ayata 22 , 53 which is an established model for screening potential migraine preventative compounds. Further this model was previously used in our own work 8 .…”

Section: Methodsmentioning

confidence: 99%

Forebrain delta opioid receptors regulate the response of delta agonist in models of migraine and opioid-induced hyperalgesia

Dripps

Bertels

Moye

et al. 2020

Sci Rep

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Delta opioid receptor (DOR) agonists have been identified as a promising novel therapy for headache disorders. DORs are broadly expressed in several peripheral and central regions important for pain processing and mood regulation; and it is unclear which receptors regulate headache associated symptoms. In a model of chronic migraine-associated pain using the human migraine trigger, nitroglycerin, we observed increased expression of DOR in cortex, hippocampus, and striatum; suggesting a role for these forebrain regions in the regulation of migraine. To test this hypothesis, we used conditional knockout mice with DORs deleted from forebrain GABAergic neurons (Dlx-DOR), and investigated the outcome of this knockout on the effectiveness of the DOR agonist SNC80 in multiple headache models. In DOR loxP controls SNC80 blocked the development of acute and chronic cephalic allodynia in the chronic nitroglycerin model, an effect that was lost in Dlx-DOR mice. In addition, the anti-allodynic effects of SNC80 were lost in a model of opioid induced hyperalgesia/medication overuse headache in Dlx-DOR conditional knockouts. In a model reflecting negative affect associated with migraine, SNC80 was only effective in loxP controls and not Dlx-DOR mice. Similarly, SNC80 was ineffective in the cortical spreading depression model of migraine aura in conditional knockout mice. Taken together, these data indicate that forebrain DORs are necessary for the action of DOR agonists in relieving headache-related symptoms and suggest that forebrain regions may play an important role in migraine modulation.

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Section: Methodsmentioning

confidence: 99%

Forebrain delta opioid receptors regulate the response of delta agonist in models of migraine and opioid-induced hyperalgesia

Dripps

Bertels

Moye

et al. 2020

Sci Rep

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“…The procedure for the cortical spreading depression (CSD) model is based on work previously published by Ayata [81] that is commonly used to screen potential migraine preventatives and further used in our own work Pradhan and colleagues [42]. Mice were grouped into sham and CSD groups and then further subdivide into ACY-738 (50 mg/kg, IP) or vehicle (i.e., Sham-ACY, Sham-Veh, CSD-ACY, CSD-Veh).…”

Section: Cortical Spreading Depression Modelmentioning

confidence: 99%

Neuronal complexity is attenuated in chronic migraine and restored by HDAC6 inhibition

Bertels

Grewal

Dripps

et al. 2020

Preprint

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Migraine is the third most prevalent disease worldwide and current therapies provide only partial relief. Greater insight into molecular migraine mechanisms would create novel therapies. Cytoskeletal flexibility is fundamental to neuronal-plasticity and is dependent on microtubule dynamicity. Histone-deacetylase-6 (HDAC6) decreases microtubule dynamics by deacetylating its primary substrate, α-tubulin. We use validated models of chronic migraine to show that HDAC6-inhibition is an effective 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 pain-processing regions, and these were reversed by HDAC6 inhibition.Cortical spreading depression (CSD), a physiological correlate of migraine aura, also caused decreased cortical neurite growth, while administration of HDAC6-inhibitor restored neuronal complexity and decreased CSD. Our results demonstrate that disruptions in neuronal cytoarchitecture are a feature of chronic migraine, and evolving migraine therapies might include agents that restore microtubule stability and neuronal plasticity.

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“…Although direct electrophysiological evidence of SD in patients with migraine is still lacking, SD has attracted considerable attention for its translational relevance [45]. Experimental models of SD have recapitulated multiple clinical characteristics of migraine in human subjects and have been used to explore the basic mechanisms, genetic and hormonal modulators, and potential physiological or pharmacological inhibitors of migraine [45, 46]. SD susceptibility is one measure used to examine such relationships.…”

Section: Sd Susceptibility and Its Clinical Translatabilitymentioning

confidence: 99%

“…The study of SD susceptibility involves the exploration of the vulnerability of brain tissues to occurrence, propagation and recurrence. Depending on the detection method, various SD susceptibility measurements have been used to study the physical and biochemical attributes of SD [45, 47]. The stimulus intensity used to evoke SD is one of the most relevant attributes of SD susceptibility.…”

Section: Sd Susceptibility and Its Clinical Translatabilitymentioning

confidence: 99%

Spreading depression as a preclinical model of migraine

et al. 2019

Self Cite

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Spreading depression (SD) is a slowly propagating wave of near-complete depolarization of neurons and glial cells across the cortex. SD is thought to contribute to the underlying pathophysiology of migraine aura, and possibly also an intrinsic brain activity causing migraine headache. Experimental models of SD have recapitulated multiple migraine-related phenomena and are considered highly translational. In this review, we summarize conventional and novel methods to trigger SD, with specific focus on optogenetic methods. We outline physiological triggers that might affect SD susceptibility, review a multitude of physiological, biochemical, and behavioral consequences of SD, and elaborate their relevance to migraine pathophysiology. The possibility of constructing a recurrent episodic or chronic migraine model using SD is also discussed.

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Novel Therapeutic Targets Against Spreading Depression

Cited by 19 publications

References 171 publications

Forebrain delta opioid receptors regulate the response of delta agonist in models of migraine and opioid-induced hyperalgesia

Forebrain delta opioid receptors regulate the response of delta agonist in models of migraine and opioid-induced hyperalgesia

Neuronal complexity is attenuated in chronic migraine and restored by HDAC6 inhibition

Spreading depression as a preclinical model of migraine

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