Immunomodulatory therapy with glatiramer acetate reduces endoplasmic reticulum stress and mitochondrial dysfunction in experimental autoimmune encephalomyelitis

Abstract

Endoplasmic reticulum (ER) stress and mitochondrial dysfunction are found in lesions of multiple sclerosis (MS) and animal models of MS such as experimental autoimmune encephalomyelitis (EAE), and may contribute to the neuronal loss that underlies permanent impairment. We investigated whether glatiramer acetate (GA) can reduce these changes in the spinal cords of chronic EAE mice by using routine histology, immunostaining, and electron microscopy. EAE spinal cord tissue exhibited increased inflammation, demyelination, mitochondrial dysfunction, ER stress, downregulation of NAD+ dependent pathways, and increased neuronal death. GA reversed these pathological changes, suggesting that immunomodulating therapy can indirectly induce neuroprotective effects in the CNS by mediating ER stress.

Potential Crosstalk between the PACAP/VIP Neuropeptide System and Endoplasmic Reticulum Stress—Relevance to Multiple Sclerosis Pathophysiology

“…A study by Lin et al discovered that in EAE models of MS, IFN-γ-specific UPR responses were protective, and that PERK activation resulted in improved OL survival [51]. Therefore, although it is well recognized that ER stress is initially neuroprotective, chronic ER stress from persistent pro-inflammatory cytokine production leads to prolonged UPR activation, leading to increased cellular apoptosis; this is confirmed by the increased levels of CHOP and is responsible for fueling disease progression [52].…”