Neuroinflammation and Endoplasmic Reticulum Stress Are Coregulated by Crocin To Prevent Demyelination and Neurodegeneration

Abstract

Endoplasmic reticulum (ER) stress is a homeostatic mechanism, which is used by cells to adapt to intercellular and intracellular changes. Moreover, ER stress is closely linked to inflammatory pathways. We hypothesized that ER stress is an integral component of neuroinflammation and contributes to the development of neurological diseases. In autopsied brain specimens from multiple sclerosis (MS) and non-MS patients, XBP-1 spliced variant (XBP-1/s) was increased in MS brains (p < 0.05) and was correlated with the expression of the human endogenous retrovirus-W envelope transcript, which encodes the glycoprotein, Syncytin-1 (p < 0.05). In primary human fetal astrocytes transfected with a Syncytin-1–expressing plasmid, XBP-1/s, BiP, and NOS2 were induced, which was suppressed by crocin treatment (p < 0.05). Crocin also protected oligodendrocytes exposed to cytotoxic supernatants derived from Syncytin-1–expressing astrocytes (p < 0.05) and NO-mediated oligodendrocytotoxicity (p < 0.05). During experimental autoimmune encephalomyelitis (EAE), the transcript levels of the ER stress genes XBP-1/s, BiP, PERK, and CHOP were increased in diseased spinal cords compared with healthy littermates (p < 0.05), although CHOP expression was not involved in the EAE disease phenotype. Daily treatment with crocin starting on day 7 post-EAE induction suppressed ER stress and inflammatory gene expression in spinal cords (p < 0.05), which was accompanied by preserved myelination and axonal density, together with reduced T cell infiltration and macrophage activation. EAE-associated neurobehavioral deficits were also ameliorated by crocin treatment (p < 0.05). These findings underscored the convergent roles of pathogenic ER stress and immune pathways in neuroinflammatory disease and point to potential therapeutic applications for crocin.

Endoplasmic reticulum stress response in the rat contusive spinal cord injury model-susceptibility in specific cell types

“…9,6 Apoptosis after central nervous system damage occurs through an extrinsic pathway involving the Fas ligand, an intrinsic pathway through ER stress response in the rat spinal cord injury model D Matsuyama et al Figure 5 Comparison of the GRP78 expression ratio between all cell types. The highest GRP78 expression ratio was observed at the acute phase of injury followed by a gradual declining trend in all cells.…”

“…8 Since the accumulation of unfolded proteins leads to apoptosis, the enhancement of GRP78 is a possible strategy to inhibit apoptotic cell death following neurotrauma and neurodegenerative disease. 5,9,10 Excessive accumulation of abnormal proteins leads to the expression of C/EBP homologous transcription factor protein (CHOP), which is a prominent proapoptotoc protein of the ER stress response. 11,12 Understanding of the precise mechanism of ER stressmediated apoptosis in SCI may lead to the development of novel treatment strategies.…”

Endoplasmic Reticulum Stress and Disrupted Neurogenesis in the Brain Are Associated with Cognitive Impairment and Depressive-Like Behavior after Spinal Cord Injury

“…There is substantial evidence to indicate that ER stress is linked to inflammation through several intersecting cellular pathways, particularly proinflammatory cytokines and reactive oxygen species. 27,63,64 Protein folding is an energy-demanding process that occurs in oxidizing conditions. 63 Many neurodegenerative diseases include inflammation and ER stress impacts inflammation.…”

The Effect of Saffron Aquatic Extract and Crocin on the Differentiation of Neural Stem Cells Into Oligodendrocyte Precursor Cells

“…In addition, inflammatory gene expression, endoplasmic reticulum stress in the spinal cord, and neurobehavioral deficits were ameliorated by crocin treatment in an experimental EAE model (34). Regarding the anti-inflammatory effect of crocin, Wang et al, reported that pretreatment with crocin resulted in neuroprotective effects on traumatic brain damage, and decreased microglial activation, proinflammatory cytokine release, and apoptosis by activating Notch signaling pathway (40).…”

“…In an experimental autoimmune encephalomyelitis (EAE) model, crocin could prevent demyelination and neurodegenerative activities (34). In addition, it has antiinflammatory effects on brain microglial cells (34,35).…”