Phasic Treatment with Interferon Gamma Stimulates Release of Exosomes that Protect Against Spreading Depression

The detrimental effects of T-cell-secreted interferon gamma (IFN) on oxidative stress (OS) and demyelination in multiple sclerosis (MS) are well recognized. Recently, we demonstrated that IFN-mediated damage to myelin also increases susceptibility to spreading depression (SD; the likely basis of migraine with aura). However, before onset of MS, induction of physiological levels of IFN, like that produced by environmental enrichment (EE), protects against demyelination and OS. Accordingly, we focused on the potential for physiological levels of IFN to protect against SD. EE, which occurs with a moderate and phasic increase in proinflammatory cytokines, reduces migraine frequency. Thus, we applied phasic or pulsed IFN to brain slice cultures to emulate EE. This treatment reduced OS, increased myelin basic protein, a marker for myelin, and reduced susceptibility to SD. Building on our research on exosomes in EE-based neuroprotection, we found that IFN stimulation of slice cultures induced release of exosomes, likely from the microglia that produce the same protective effects as IFN treatment when applied to naive cultures. Finally, nasal administration of IFN to rats recapitulated in vitro effects, reducing OS, increasing myelin, and reducing SD. These results support phasic IFN signaling as a therapeutic target for prevention of SD and, by extension, migraine.