title: Spreading depression transiently disrupts myelin via interferon-gamma signaling.
abstract: Multiple sclerosis and migraine with aura are clinically correlated and both show imaging changes suggestive of myelin disruption. Furthermore, cortical myelin loss in the cuprizone animal model of multiple sclerosis enhances susceptibility to spreading depression, the likely underlying cause of migraine with aura. Since multiple sclerosis pathology involves inflammatory T cell lymphocyte production of interferon-gamma and a resulting increase in oxidative stress, we tested the hypothesis that spreading depression disrupts myelin through similar signaling pathways. Rat hippocampal slice cultures were initially used to explore myelin loss in spreading depression, since they contain T cells, and allow for controlled tissue microenvironment. These experiments were then translated to the in vivo condition in neocortex. Spreading depression in slice cultures induced significant loss of myelin integrity and myelin basic protein one day later, with gradual recovery by seven days. Myelin basic protein loss was abrogated by T cell depletion, neutralization of interferon-gamma, and pharmacological inhibition of neutral sphingomyelinase-2. Conversely, one day after exposure to interferon-gamma, significant reductions in spreading depression threshold, increases in oxidative stress, and reduced levels of glutathione, an endogenous neutral sphingomyelinase-2 inhibitor, emerged. Similarly, spreading depression triggered significant T cell accumulation, sphingomyelinase activation, increased oxidative stress, and reduction of gray and white matter myelin in vivo. Myelin disruption is involved in spreading depression, thereby providing pathophysiological links between multiple sclerosis and migraine with aura. Myelin disruption may promote spreading depression by enhancing aberrant excitability. Thus, preservation of myelin integrity may provide novel therapeutic targets for migraine with aura.
authors.affiliation: Department of Neurology, The University of Chicago Medical Center, 5841 South Maryland Avenue, Chicago, IL 60637-1470, USA; The Committee on Neurobiology, The University of Chicago Medical Center, 5841 South Maryland Avenue, Chicago, IL 60637-1470, USA. Electronic address: aya.pusic@gmail.com.
authors.forename: Aya D
authors.initials: AD
authors.lastname: Pusic
authors.affiliation: Department of Neurology, The University of Chicago Medical Center, 5841 South Maryland Avenue, Chicago, IL 60637-1470, USA. Electronic address: heidi.marie.mitchell@gmail.com.
authors.forename: Heidi M
authors.initials: HM
authors.lastname: Mitchell
authors.affiliation: Department of Neurology, The University of Chicago Medical Center, 5841 South Maryland Avenue, Chicago, IL 60637-1470, USA. Electronic address: golgi61@aol.com.
authors.forename: Phillip E
authors.initials: PE
authors.lastname: Kunkler
authors.affiliation: Department of Neurology, The University of Chicago Medical Center, 5841 South Maryland Avenue, Chicago, IL 60637-1470, USA. Electronic address: nealklauer12@gmail.com.
authors.forename: Neal
authors.initials: N
authors.lastname: Klauer
authors.affiliation: Department of Neurology, The University of Chicago Medical Center, 5841 South Maryland Avenue, Chicago, IL 60637-1470, USA; The Committee on Neurobiology, The University of Chicago Medical Center, 5841 South Maryland Avenue, Chicago, IL 60637-1470, USA. Electronic address: rkraig@neurology.bsd.uchicago.edu.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Kraig
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001597:Benzylidene Compounds / Q000494:pharmacology; D013181:Cortical Spreading Depression / Q000502:physiology*; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000502:physiology; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism*; D008297:Male; D004676:Myelin Basic Protein / Q000378:metabolism; D009186:Myelin Sheath / Q000378:metabolism* / Q000648:ultrastructure; D019579:Neocortex / Q000502:physiology* / Q000648:ultrastructure; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology*; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism
chemical_list: D000814:Aniline Compounds; D000906:Antibodies; D001597:Benzylidene Compounds; D016207:Cytokines; D004791:Enzyme Inhibitors; C468773:GW 4869; D004676:Myelin Basic Protein; D007371:Interferon-gamma; D013108:Sphingomyelin Phosphodiesterase
keywords: Hippocampal slice cultures; Interferon-gamma; Migraine; Multiple sclerosis; Myelin; Oxidative stress; Sphingomyelinase-2; Spreading depression; T cells