Abstract
Multiple sclerosis (MS) is a chronic autoimmune and degenerative disease of the central nervous system, and conventional treatments have limited efficacy or side effects. Ghrelin, a 28-amino acid octanoylated peptide, has been reported to have neuroprotective effects, including anti-oxidation, anti-inflammation, and anti-apoptosis. Pyroptosis, also called inflammatory cell death, is triggered by overly active inflammasomes and accompanied by the production of numerous cytokines. As immune dysfunction is primarily involved in the pathogenesis of MS, this study aimed to explore the therapeutic effects and precise functional mechanisms of ghrelin against the nod-like receptor protein 3 (NLRP3) inflammasome and pyroptosis in experimental autoimmune encephalomyelitis (EAE). Sprague Dawley rats were immunized with guinea pig spinal cord homogenates and pertussis toxin to develop an EAE model. All rats were randomly divided into four groups: normal control group, EAE group, EAE + ghrelin group, and ghrelin control group. EAE rats showed abnormal behavioral scores and body weight changes. Histologic analysis displayed severe inflammatory infiltration and demyelination in the brain and spinal cord of EAE rats. Ghrelin treatments potently restored these abnormal changes. In addition, the ghrelin-treated EAE group showed significantly downregulated expression of inflammatory cytokines. The expression of proteins involved in the NLRP3 signaling pathway and pyroptosis was decreased as well. We also found that the anti-inflammatory effect of ghrelin was associated with inhibition of nuclear factor (NF)-κB activation. Compared with rats in the healthy control group, rats in the ghrelin control group did not show statistically significant changes in histologic examinations, pro-inflammatory cytokines production, or molecules involved in the NLRP3 signaling pathway, which indicated that ghrelin induced no side effects in the animals of our study. Our findings provide more insight into the use of ghrelin as a novel candidate for MS.
Highlights
Multiple sclerosis (MS) is a chronic autoimmune and degenerative disease of the central nervous system (CNS) that mainly occurs in young adults, with a female predominance (Lassmann, 1999)
EAE rat body weights began to decrease at day 12, which was later than untreated EAE rats
Ghrelin-treated EAE rats appeared to have an uncoordinated performance even later, and daily mean neurologic scores were lower compared with those of the untreated EAE rats. These results demonstrated that ghrelin treatments delayed the onset of EAE and alleviated the symptoms of EAE rats
Summary
Multiple sclerosis (MS) is a chronic autoimmune and degenerative disease of the central nervous system (CNS) that mainly occurs in young adults, with a female predominance (Lassmann, 1999). Excessive inflammation leads to cell death and tissue damage, such as demyelinating lesions and axonal injuries. The nod-like receptor protein 3 (NLRP3) inflammasome, a promoter involved in innate immune response initiation, has been reported to participate in the progression of many neurodegenerative diseases, including MS (Inoue and Shinohara, 2013; Song et al, 2017; Wang et al, 2019). Pyroptosis is a newly discovered form of inflammatory cell death that can be triggered by activation of the NLRP3 inflammasome (Shi et al, 2017a). Once the NLRP3 inflammasome is assembled, functional caspase-1 is released, activating interleukin (IL)-1β, IL-18, and gasdermin D (GSDMD), an important downstream target protein in pyroptosis (He et al, 2015; Semino et al, 2018). Blocking the NLRP3 signaling pathway and pyroptosis is expected to alleviate neuroinflammation and disease progression
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