Acute Intermittent Hypoxia Exerts Beneficial Effects and Promotes Repair in Male Mice in the Experimental Autoimmune Encephalomyelitis Model of Multiple Sclerosis.

Abstract

Multiple sclerosis (MS) affects women more frequently than men, but the disease progresses more aggressively in men. We have demonstrated that acute intermittent hypoxia (AIH), a noninvasive therapy, promotes repair and remyelination and alters disease course in the female MOGexperimental autoimmune encephalomyelitis (EAE) mouse model of MS. Given the importance of understanding sex-specific responses to potential MS therapies, we investigated whether AIH exerts similar therapeutic effects in male EAE mice. EAE was induced by MOGimmunization in C57BL/6 male mice. Male EAE mice received either AIH (10 cycles-5 min 11% oxygen alternating with 5 min 21% oxygen) or Normoxia (21% oxygen for same duration) once daily for 7d beginning at near peak EAE disease clinical score of 2.5. Mice were followed post-last treatment for an additional 7d or 14d before assessing histopathology. Clinical scores, inflammation, myelination, and neurorepair were evaluated. Compared to Normoxia, AIH significantly improved clinical scores in male EAE mice with mice exhibiting reduced inflammation and increased myelination/remyelination within inflamed regions. Further, AIH polarized remaining immune cells toward a pro-repair phenotype, promoted OPC recruitment to demyelinated regions, and increased the presence of mature, myelinating oligodendrocytes, and myelination. An axon protective phenotype was also significantly improved with AIH, supporting enhanced neuroprotection. Our findings reveal that AIH has comparable, albeit slightly less robust beneficial therapeutic effects in male as was previously shown in female EAE mice. Altogether, this study highlights the potential of AIH as a therapy for MS, capable of addressing the disease's differential impacts in both sexes.