Effect of sildenafil on neuroinflammation and synaptic plasticity pathways in experimental autoimmune encephalomyelitis

Araújo, Shyrlene Meiry da Rocha; Duarte-Silva, Eduardo; Marinho, Crislayne Gonçalo de Santana; Oliveira, W.; França, Maria Eduarda Rocha de; Lós, Deniele Bezerra; Peron, Gabriela; Tomaz, Livia; Bonfanti, Amanda Pires; Verinaud, Liana; Peixoto, Christina Alves

doi:10.1016/j.intimp.2020.106581

Cited by 10 publications

(10 citation statements)

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“…Interestingly, AMPK is activated in response to IL-10 and favors macrophage polarization towards the anti-inflammatory or M2 phenotype ( 42 ). This is corroborated by our previous study ( 11 ) and this suggests that the switching of microglia to the M2 phenotype is probably due to the increased levels of IL-10 and p-AMPK in mice treated with Sildenafil. Furthermore, we showed that EAE is characterized by lowered expression of p-eNOS, but high levels of iNOS and NO, which favors nitrosative stress and protein aggregation.…”

Section: Discussionsupporting

confidence: 90%

“…However, Sildenafil administration led to elevated expression of LC3, beclin-1 and ATG5, while displaying reduced mTOR levels. Furthermore, we previously reported increased IL-10 levels followed by Sildenafil treatment ( 11 ), which can further suppress the activity of mTOR and increase autophagy and mitophagy ( 57 ). Although the functional consequences of the activation of the autophagy pathways were not investigated here, one could reasonably argue that this process may lead to the removal of protein aggregates previously reported to occur during EAE and which are responsible for neuronal death by apoptosis ( 12 , 13 ).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, we have also demonstrated similar findings in the cuprizone model of MS ( 10 ). More recently, we demonstrated that Sildenafil at the same dose and route of administration has neuroprotective effects in the hippocampus of EAE mice, since it reduced the number of infiltrating T CD4 + lymphocytes, inhibited neuroinflammation and modulated synaptic plasticity and neurotransmission ( 11 ). However, other signaling pathways responsible for the mechanism of action of Sildenafil have not been explored.…”

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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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

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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“…It is confirmed that the frequency of AMPA receptor-mediated sEPSC is increased at preclinical stage in the striatum of EAE mice with altered GluA1 protein composition of postsynaptic density (PSD) ( 50 ). Moreover, in a previous study, mice with EAE showed increased AMPA receptor expression in hippocampus, and sildenafil was able to reduce excitotoxicity by decreasing expression of the receptors ( 51 ). Because activated immune cells release large quantities of glutamate, AMPA/kainite antagonists can reduce autoimmune demyelination and result in substantial amelioration ( 52 ).…”

Section: Discussionmentioning

confidence: 96%

Arctigenin Exerts Neuroprotective Effect by Ameliorating Cortical Activities in Experimental Autoimmune Encephalomyelitis In Vivo

et al. 2021

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Multiple sclerosis (MS) is a chronic disease in the central nervous system (CNS), characterized by inflammatory cells that invade into the brain and the spinal cord. Among a bulk of different MS models, the most widely used and best understood rodent model is experimental autoimmune encephalomyelitis (EAE). Arctigenin, a botanical extract from Arctium lappa, is reported to exhibit pharmacological properties, including anti-inflammation and neuroprotection. However, the effects of arctigenin on neural activity attacked by inflammation in MS are still unclear. Here, we use two-photon calcium imaging to observe the activity of somatosensory cortex neurons in awake EAE mice in vivo and found added hyperactive cells, calcium influx, network connectivity, and synchronization, mainly at preclinical stage of EAE model. Besides, more silent cells and decreased calcium influx and reduced network synchronization accompanied by a compensatory rise in functional connectivity are found at the remission stage. Arctigenin treatment not only restricts inordinate individually neural spiking, calcium influx, and network activity at preclinical stage but also restores neuronal activity and communication at remission stage. In addition, we confirm that the frequency of AMPA receptor-mediated spontaneous excitatory postsynaptic current (sEPSC) is also increased at preclinical stage and can be blunted by arctigenin. These findings suggest that excitotoxicity characterized by calcium influx is involved in EAE at preclinical stage. What is more, arctigenin exerts neuroprotective effect by limiting hyperactivity at preclinical stage and ameliorates EAE symptoms, indicating that arctigenin could be a potential therapeutic drug for neuroprotection in MS-related neuropsychological disorders.

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“…Moreover, in a previous study, mice with EAE showed increased AMPA receptor expression in hippocampus and sildena l was able to reduce excitotoxicity by decreasing expression of the receptors [46]. Since activated immune cells release large quantities of glutamate, AMPA/kainite antagonists can reduce autoimmune demyelination and result in substantial amelioration [47].…”

Section: Ampa Receptor Is Involved In Excitotoxicity Of Early Eaementioning

confidence: 93%

Arctigenin Exerts Neuroprotective Effect By Ameliorating Cortical Activities in Experimental Autoimmune Encephalomyelitis in Vivo

Wei

Xue

Lan

et al. 2021

Preprint

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Background Multiple sclerosis (MS) is a chronic disease in the central nervous system (CNS), characterized by inflammatory cells invade into the brain and the spinal cord. Among a bulk of different MS models, the rodent model of experimental autoimmune encephalomyelitis (EAE) is the most widely used and best understood. Arctigenin, a botanical extract from Arctium lappa, is reported to exhibit pharmacological properties including anti-inflammation and neuroprotection. However, the effects of Arctigenin on neural activity attacked by inflammation in MS are still unclear.Methods Female C57BL/6 mice were expressed by an ultra-sensitive protein calcium sensor GCamp6f in somatosensory cortex neurons through stereotaxic virus injection. Then we induced EAE model in mice with myelin oligodendrocyte glycoprotein (MOG) peptide (35-55) and used two-photon calcium imaging to chronically observe cortical activity in vivo throughout the disease progression. Besides, we performed whole-cell electrophysiological recording to determine the frequency of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated spontaneous excitatory postsynaptic current (sEPSC) in cortical brain slices of preclinical EAE mice.ResultsHere we found added hyperactive cells, calcium influx, network connectivity and synchronization, mainly at preclinical stage of EAE model. Besides, more silent cells and decreased calcium influx and reduced network synchronization accompanied by a compensatory rise in functional connectivity were found at the remission stage. Arctigenin treatment not only restricted inordinate individually neural spiking, calcium influx and network activity at preclinical stage, but also restored neuronal activity and communication at remission stage. In addition, we confirmed that the frequency of AMPA receptor-sEPSC was also increased at preclinical stage and can be blunted by Arctigenin. Conclusions Our findings suggest that excitotoxicity resulted from calcium influx is involved in EAE at preclinical stage. Moreover, Arctigenin exerts neuroprotective effect by limiting hyperactivity at preclinical stage and ameliorates EAE symptoms, indicating Arctigenin could be a potential therapeutic drug for neuroprotection in MS-related neuropsychological disorders.

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Effect of sildenafil on neuroinflammation and synaptic plasticity pathways in experimental autoimmune encephalomyelitis

Cited by 10 publications

References 61 publications

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

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

Arctigenin Exerts Neuroprotective Effect by Ameliorating Cortical Activities in Experimental Autoimmune Encephalomyelitis In Vivo

Arctigenin Exerts Neuroprotective Effect By Ameliorating Cortical Activities in Experimental Autoimmune Encephalomyelitis in Vivo

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