Migraine is a neurological disease that is characterized by severe episodic headaches lasting from 4 to 72 hours. A third of patients with migraine headaches are preceded by focal neurological symptoms – the aura of migraine.
The most likely cause of aura and migraine pain is spreading depression (SD) – a wave of neuronal and glial cell hyperactivity slowly spreading through the cortex, followed by a wave of inhibition.
After SD, production of a pro-inflammatory cytokine tumor necrosis factor-alpha (TNFα) increases. TNFα enhances the efficiency of nerve impulse transmission through the synapse by increasing the membrane expression of excitatory AMPA receptors and reducing the membrane expression of inhibitory GABA receptors. Increased excitability of neurons, in turn, leads to an increase in the production of reactive oxygen species, which contribute to the subsequent occurrence of SD. This cycle can turn rare migraine attacks into regular and chronic migraines.
Migraine will be defeated by sports, study, sociality – or a drug based on interferon-gamma
Many studies have shown that increased physical, intellectual, and social activity has beneficial effects in neurological diseases such as Huntington’s disease, Alzheimer’s disease, and traumatic brain injuries, protects against dementia, and improves schizophrenia, depression, and migraines. However, the clinical implementation of this approach is problematic. This inspired scientists from the Department of Neurology at the University of Chicago in the United States to search for an adequate drug alternative.
The researchers used mice kept in an environment enriched in comparison with standard laboratory conditions for the study. These mice are kept in large cages and large groups with tunnels, nest materials, and toys. Thus, an enriched environment provides increased physical, intellectual, and social activity. Exposure to an enriched environment causes neuroanatomic and behavioral changes, such as increased dendrite branching, gliogenesis, neurogenesis, and improved learning ability.
The researchers examined exosomes – microscopic vesicles that secrete cells into the extracellular environment. Exosomes transmit information between cells, deliver the necessary proteins to the cells, and regulate immune responses. The scientists obtained exosomes from rat serum contained in an enriched medium. When applied to cultures of hippocampal slices or nasal administration to normal rats, these exosomes significantly increased the myelin content, the levels of oligodendrocyte progenitor cells and nerve stem cells, and also reduced oxidative stress.
Then, as a source of similar exosomes that promote the myelination of neurons, the scientists used dendritic cells (DC) from rat bone marrow. Primary DC cultures of rats were stimulated with low levels of interferon-gamma – IFN-gamma, a pro-inflammatory cytokine that gradually increases during the maintenance of animals in enriched conditions. Exosomes released by IFN-gamma-stimulated DCS (IFNy-DC-Exos) also increase myelination and reduce oxidative stress in vitro and in vivo.
Since the enriched environment reduces the frequency of migraines, the researchers investigated whether the enriched environment can mitigate the cause of migraines-pervasive depression. The study showed that the enriched environment significantly reduces the susceptibility to SD in rats. When scientists mimicked cytokine signals in an enriched environment by injecting interleukin-11, insulin-like growth factor-1, or phasing in IFN-gamma, this also reduced susceptibility to SD.
Scientists were faced with the question: can IFNy-DC-Exos, as an alternative to an enriched medium, protect against SD?
IFNy-DC-Exos reduce sensitivity to Spreading Depression
In sections of the hippocampus, IFNy-DC-Exos reduce the sensitivity to SD by 12 times. When administered intranasally to rats-57 times, and the effect is much more stable. Although the level of protection against SD is comparable to the level observed with nasal administration of IFN-gamma (∼63 times), IFNy-DC-Exos has fewer side effects.
IFNy-DC-Exos protect neurons from damage
One of the causes of damage and death of neurons is an excess of nitric oxide (NO). NO activates the transmission of nerve impulses in the central nervous system and is also a signaling molecule. The physiological level of NO supports cognitive functions. However, in high concentrations, it causes neurodegenerative diseases.
The iNOS enzyme enhances the production of nitric oxide. The primary source of iNOS in the central nervous system is microglia. Microglia are cells of the innate immune system of the brain. By continuously analyzing the extracellular environment, microglia protects the brain from pathogens. In infection, stroke, trauma, and neurodegenerative diseases, microglia are activated and acquire a state of either classical activation (M1-microglia) or alternative activation (M2a-microglia). M1-microglia has pro-inflammatory functions, while M2a – microglia has anti-inflammatory functions.
Spreading depression causes the appearance of M1-microglia, which can increase the susceptibility to subsequent spreading depression. M1-microglia produces reactive oxygen species and pro-inflammatory cytokines, including TNFa, which can increase the excitability of neurons and promote the initiation of SD. This pro-inflammatory environment may also be responsible for the temporary destruction of gray matter myelin after SD. Moreover, demyelination, in turn, increases the susceptibility to SD.
When administered intranasally, IFNy-DC-Exos reduce iNOS levels and reduce oxidative stress. Compared to normal rats, rats kept in an enriched environment and, therefore, more protected from SD had lower levels of M1-microglia and higher levels of M2a-microglia. It proves that the enriched medium protects against SD due to the reduced formation of oxidants and pro-inflammatory cytokines from M1 microglia. These results suggest that IFNy-DC-Exos are effective against SD and could be a new migraine treatment.
Source
IFNγ-Stimulated Dendritic Cell Exosomes for Treatment of Migraine Modeled Using Spreading Depression
