Sildenafil ameliorates EAE by decreasing apoptosis in the spinal cord of C57BL/6 mice

Duarte-Silva, Eduardo; Araújo, Shyrlene Meiry da Rocha; Oliveira, W.; Lós, Deniele Bezerra; França, Maria Eduarda Rocha de; Bonfanti, Amanda Pires; Peron, Gabriela; Thomaz, Livia de Lima; Verinaud, Liana; Nunes, Ana Karolina de Santana; Peixoto, Christina Alves

doi:10.1016/j.jneuroim.2018.06.002

Cited by 25 publications

(16 citation statements)

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“…After transfection of miR-15a, there was no expression of Bcl-2, and apoptosis was induced. However, in transgenic mice overexpressing Bcl-2, the inflammatory infiltration, demyelination, and axonal injury associated with EAE were significantly decreased [50]. Bcl-2 could protect neurons from apoptosis and reduce ROS-induced injury [51].…”

Section: Regulation Of Mirs In Exosomes From Mouse Serum By Bsyscmentioning

confidence: 98%

Bu-Shen-Yi-Sui Capsule, an Herbal Medicine Formula, Promotes Remyelination by Modulating the Molecular Signals via Exosomes in Mice with Experimental Autoimmune Encephalomyelitis

Zhao

Liu

et al. 2020

Oxidative Medicine and Cellular Longevity

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Multiple sclerosis (MS) is a common inflammatory demyelinating disorder of the central nervous system. Bu-shen-yi-sui capsule (BSYSC) could significantly reduce the relapse rate, prevent the progression of MS, and enhance remyelination following neurological injury in experimental autoimmune encephalomyelitis (EAE), an established model of MS; however, the mechanism underlying the effect of BSYSC on remyelination has not been well elucidated. This study showed that exosomes carrying biological information are involved in the pathological process of MS and that modified exosomes can promote remyelination by modulating related proteins and microRNAs (miRs). Here, the mechanism by which BSYSC promoted remyelination via exosome-mediated molecular signals was investigated in EAE mice and oligodendrocyte progenitor cells (OPCs) in vitro. The results showed that BSYSC treatment significantly improved the body weight and clinical scores of EAE mice, alleviated inflammatory infiltration and nerve fiber injury, protected the ultrastructural integrity of the myelin sheath, and significantly increased the expression of myelin basic protein (MBP) in EAE mice. In an in vitro OPC study, BSYSC-containing serum, especially 20% BSYSC, promoted the proliferation and migration of OPCs and induced OPCs to differentiate into mature oligodendrocytes that expressed MBP. Furthermore, BSYSC treatment regulated the expression of neuropilin- (NRP-) 1 and GTX, downregulated the expression of miR-16, let-7, miR-15, miR-98, miR-486, and miR-182, and upregulated the level of miR-146 in serum exosomes of EAE mice. In conclusion, these results suggested that BSYSC has a neuroprotective effect and facilitates remyelination and that the mechanism underlying the effect of BSYSC on remyelination probably involves regulation of the NRP-1 and GTX proteins and miRs in serum exosomes, which drive promyelination.

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Section: Regulation Of Mirs In Exosomes From Mouse Serum By Bsyscmentioning

confidence: 98%

Bu-Shen-Yi-Sui Capsule, an Herbal Medicine Formula, Promotes Remyelination by Modulating the Molecular Signals via Exosomes in Mice with Experimental Autoimmune Encephalomyelitis

Zhao

Liu

et al. 2020

Oxidative Medicine and Cellular Longevity

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“…The EAE was induced as described elsewhere using naïve mice as controls ( 9 ). On the last day of the experiment, mice were anesthetized, and the spinal cord was harvested and used for the analysis of the nitrosative stress and autophagy pathways.…”

Section: Methodsmentioning

confidence: 99%

“…Sildenafil treatment (25mg/kg) (Viagra ® , Pfizer) was administered on day post-induction 3 for a total of 21 days always during the daytime as previously described ( 9 ).…”

Section: Methodsmentioning

confidence: 99%

“…In this study, Sildenafil at a dose of 10mg/kg was administered subcutaneously (s.c.) after disease onset and the spinal cord was analyzed. However, a previous study by our group has shown that Sildenafil at a dose of 25 mg/kg s.c. also has neuroprotective effects because it inhibits demyelination, neuroinflammation and apoptosis in the spinal cord of EAE mice, which is directly related to the motor dysfunction observed in EAE mice ( 9 ). These different studies highlighted different aspects of the same pathology and contributed to our understanding of how the disease evolves and how it could be treated, since they also highlighted different molecular targets.…”

Section: Introductionmentioning

confidence: 99%

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Sildenafil Alleviates Murine Experimental Autoimmune Encephalomyelitis by Triggering Autophagy in the Spinal Cord

et al. 2021

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Multiple Sclerosis (MS) is a neuroinflammatory and chronic Central Nervous System (CNS) disease that affects millions of people worldwide. The search for more promising drugs for the treatment of MS has led to studies on Sildenafil, a phosphodiesterase type 5 Inhibitor (PDE5I) that has been shown to possess neuroprotective effects in the Experimental Autoimmune Encephalomyelitis (EAE), an animal model of MS. We have previously shown that Sildenafil improves the clinical score of EAE mice via modulation of apoptotic pathways, but other signaling pathways were not previously covered. Therefore, the aim of the present study was to further investigate the effects of Sildenafil treatment on autophagy and nitrosative stress signaling pathways in EAE. 24 female C57BL/6 mice were divided into the following groups: (A) Control - received only water; (B) EAE - EAE untreated mice; (C) SILD - EAE mice treated with 25mg/kg of Sildenafil s.c. The results showed that EAE mice presented a pro-nitrosative profile characterized by high tissue nitrite levels, lowered levels of p-eNOS and high levels of iNOS. Furthermore, decreased levels of LC3, beclin-1 and ATG5, suggests impaired autophagy, and decreased levels of AMPK in the spinal cord were also detected in EAE mice. Surprisingly, treatment with Sildenafil inhibited nitrosative stress and augmented the levels of LC3, beclin-1, ATG5, p-CREB and BDNF and decreased mTOR levels, as well as augmented p-AMPK. In conclusion, we propose that Sildenafil alleviates EAE by activating autophagy via the eNOS-NO-AMPK-mTOR-LC3-beclin1-ATG5 and eNOS-NO-AMPK-mTOR-CREB-BDNF pathways in the spinal cord.

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“…There are controversial studies about the mechanism of apoptosis in the progression course of EAE. [12][13][14] Cytotoxic immunosuppressants are often used for the treatment of MS patients, in whom the immunemodulatory therapies fail. [15] Cyclophosphamide and azathioprine are traditionally used for the treatment of MS; however, mitoxantrone has been reported to slow the progression and reduce the relapse rate in the disease.…”

Section: Introductionmentioning

confidence: 99%

Shikonin ameliorates experimental autoimmune encephalomyelitis (EAE) via immunomodulatory, anti-apoptotic and antioxidative activity

Sabet

Biglari

Khorshid³

et al. 2020

Journal of Pharmacy and Pharmacology

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Objectives Multiple sclerosis is a common autoimmune inflammatory disease of the central nervous system. There are several underlying mechanisms for the pathogenesis of the disease, including inflammation, oligodendrocyte apoptosis and oxidative stress. Methods The mechanism of action of shikonin was investigated in the C57BL/6 experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis. Key findings The results revealed that EAE induction significantly increased the extent of demyelination in the corpus callosum tissues of the animals, while treatment of the mice with shikonin significantly decreased the extent of demyelination. Real-time polymerase chain reaction-based analysis of the brain samples from the EAE mice revealed significant enhancement in the expression levels of tumour necrosis factor-a (TNF-a), interferon-c (IFN-c) and Bax genes as well as a reduction in the expression levels of transforming growth factor-ß (TGF-b) and Bcl2. But, shikonin treatment significantly reduced the expression levels of TNF-a, IFN-c and Bax. On the other hand, the expression levels of TGF-b and Bcl2 as well as the activity of glutathione peroxidase-1 (GPX-1) enzyme were significantly increased following the shikonin treatment. Conclusions This study emphasized the immune-modulatory and antioxidative effects of shikonin, which may have an important healing effect on the severity of EAE.

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Sildenafil ameliorates EAE by decreasing apoptosis in the spinal cord of C57BL/6 mice

Cited by 25 publications

References 73 publications

Bu-Shen-Yi-Sui Capsule, an Herbal Medicine Formula, Promotes Remyelination by Modulating the Molecular Signals via Exosomes in Mice with Experimental Autoimmune Encephalomyelitis

Bu-Shen-Yi-Sui Capsule, an Herbal Medicine Formula, Promotes Remyelination by Modulating the Molecular Signals via Exosomes in Mice with Experimental Autoimmune Encephalomyelitis

Sildenafil Alleviates Murine Experimental Autoimmune Encephalomyelitis by Triggering Autophagy in the Spinal Cord

Shikonin ameliorates experimental autoimmune encephalomyelitis (EAE) via immunomodulatory, anti-apoptotic and antioxidative activity

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