Axl activation attenuates neuroinflammation by inhibiting the TLR/TRAF/NF-κB pathway after MCAO in rats

Wu, Guangyong; McBride, Devin W.; Zhang, Junyi

doi:10.1016/j.nbd.2017.11.009

Cited by 93 publications

(70 citation statements)

References 43 publications

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“…Accumulating scientific evidence suggests that neuroinflammation and oxidative stress are the main pathological processes responsible for the impairment of neurological function in MCAO [26,29,44,45]. Clinically, Eze, a NPC1L1 inhibitor, is mainly used as a treatment for hypercholesterolemia; however, in addition to its lipid-lowering activity, several studies have reported that Eze may attenuate ischemic-related oxidative stress and inflammation [14,19].…”

Section: Discussionmentioning

confidence: 99%

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Ezetimibe Attenuates Oxidative Stress and Neuroinflammation via the AMPK/Nrf2/TXNIP Pathway after MCAO in Rats

Wang

Matei

et al. 2020

Oxidative Medicine and Cellular Longevity

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122

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Oxidative stress and neuroinflammation play essential roles in ischemic stroke-induced brain injury. Previous studies have reported that Ezetimibe (Eze) exerts antioxidative stress and anti-inflammatory properties in hepatocytes. In the present study, we investigated the effects of Eze on oxidative stress and neuroinflammation in a rat middle cerebral artery occlusion (MCAO) model. One hundred and ninety-eight male Sprague-Dawley rats were used. Animals assigned to MCAO were given either Eze or its control. To explore the downstream signaling of Eze, the following interventions were given: AMPK inhibitor dorsomorphin and nuclear factor erythroid 2-related factor 2 (Nrf2) siRNA. Intranasal administration of Eze, 1 h post-MCAO, further increased the endogenous p-AMPK expression, reducing brain infarction, neurologic deficits, neutrophil infiltration, microglia/macrophage activation, number of dihydroethidium- (DHE-) positive cells, and malonaldehyde (MDA) levels. Specifically, treatment with Eze increased the expression of p-AMPK, Nrf2, and HO-1; Romo-1, thioredoxin-interacting protein (TXNIP), NOD-like receptor protein 3 (NLRP3), Cleaved Caspase-1, and IL-1β were reduced. Dorsomorphin and Nrf2 siRNA reversed the protective effects of Eze. In summary, Eze decreases oxidative stress and subsequent neuroinflammation via activation of the AMPK/Nrf2/TXNIP pathway after MCAO in rats. Therefore, Eze may be a potential therapeutic approach for ischemic stroke patients.

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Section: Discussionmentioning

confidence: 99%

“…Intranasal administration was performed as previously described [29]. Briefly, rats were treated 1 h after MCAO with DMSO or Eze (250 μg/kg, 500 μg/kg, and 1 mg/kg dissolved in 10%DMSO, purity ≥ 98%, SML-1629, Sigma-Aldrich, St. Louis, MO, USA) in a supine position under 2% isoflurane anesthesia.…”

Section: Intranasal Administration Of Ezementioning

confidence: 99%

Ezetimibe Attenuates Oxidative Stress and Neuroinflammation via the AMPK/Nrf2/TXNIP Pathway after MCAO in Rats

Wang

Matei

et al. 2020

Oxidative Medicine and Cellular Longevity

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122

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“…The Morris water maze was performed to assess the spatial learning memory by an independent researcher blinded to the experimental group information as previously described [ 24 , 25 ]. Briefly, rats were placed using a semi-random set of start locations to find a visible platform above the water level in 60 s. After that, the rats were guided to stay on the platform for 5 s. At the last day, the probe trial was performed in which the rats were allowed to swim to search the platform submerged in the water.…”

Section: Methodsmentioning

confidence: 99%

Aggf1 attenuates neuroinflammation and BBB disruption via PI3K/Akt/NF-κB pathway after subarachnoid hemorrhage in rats

Zhu

Enkhjargal

Huang

et al. 2018

J Neuroinflammation

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128

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BackgroundNeuroinflammation and blood-brain barrier (BBB) disruption are two critical mechanisms of subarachnoid hemorrhage (SAH)-induced brain injury, which are closely related to patient prognosis. Recently, angiogenic factor with G-patch and FHA domain 1 (Aggf1) was shown to inhibit inflammatory effect and preserve vascular integrity in non-nervous system diseases. This study aimed to determine whether Aggf1 could attenuate neuroinflammation and preserve BBB integrity after experimental SAH, as well as the underlying mechanisms of its protective roles.MethodsTwo hundred forty-nine male Sprague-Dawley rats were subjected to the endovascular perforation model of SAH. Recombinant human Aggf1 (rh-Aggf1) was administered intravenously via tail vein injection at 1 h after SAH induction. To investigate the underlying neuroprotection mechanism, Aggf1 small interfering RNA (Aggf1 siRNA) and PI3K-specific inhibitor LY294002 were administered through intracerebroventricular (i.c.v.) before SAH induction. SAH grade, neurological score, brain water content, BBB permeability, Western blot, and immunohistochemistry were performed.ResultsExpression of endogenous Aggf1 was markedly increased after SAH. Aggf1 was primarily expressed in endothelial cells and astrocytes, as well as microglia after SAH. Administration of rh-Aggf1 significantly reduced brain water content and BBB permeability, decreased the numbers of infiltrating neutrophils, and activated microglia in the ipsilateral cerebral cortex following SAH. Furthermore, rh-Aggf1 treatment improved both short- and long-term neurological functions after SAH. Meanwhile, exogenous rh-Aggf1 significantly increased the expression of PI3K, p-Akt, VE-cadherin, Occludin, and Claudin-5, as well as decreased the expression of p-NF-κB p65, albumin, myeloperoxidase (MPO), TNF-α, and IL-1β. Conversely, knockdown of endogenous Aggf1 aggravated BBB breakdown, inflammatory response and neurological impairments at 24 h after SAH. Additionally, the protective roles of rh-Aggf1 were abolished by LY294002.ConclusionsTaken together, exogenous Aggf1 treatment attenuated neuroinflammation and BBB disruption, improved neurological deficits after SAH in rats, at least in part through the PI3K/Akt/NF-κB pathway.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1211-8) contains supplementary material, which is available to authorized users.

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“…The upregulation of Gas6 activates its receptor Axl, and Axl activation attenuates inflammation by inhibiting NF-κB pathway in AKI [24]. Since Gas6/Axl pathway could regulate NF-κB pathway, we explored NF-κB pathway in the kidney of IRI rats.…”

Section: The Regulatory Effect Of Melatonin and Paa On Gas6/axlenfeκbmentioning

confidence: 99%

Poricoic acid A enhances melatonin inhibition of AKI-to-CKD transition by regulating Gas6/Axl NF κB/Nrf2 axis

Chen

Feng

Chen

et al. 2019

Free Radical Biology and Medicine

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Renal ischemia-reperfusion injury (IRI) is a complex syndrome, which causes chronic kidney disease (CKD) after recovery from IRI-mediated acute kidney injury (AKI). There is no single therapy that could effectively prevent the renal injury after ischemia. In this study, the effects of melatonin or poricoic acid A (PAA) and their combination were investigated in protecting against AKI-to-CKD transition in rats and hypoxia/reoxygenation (H/R)induced injury in cultured renal NRK-52E cells. Melatonin and PAA significantly reduced the magnitude of rise in serum creatinine and urea levels in IRI rats at days 3 and 14. Our results further showed that treatment with melatonin and PAA ameliorated renal fibrosis and podocyte injury by attenuating oxidative stress and inflammation via regulation of nuclear factor-kappa B (NF-κB) and nuclear factor-erythroid-2-related factor 2 (Nrf2) pathways in IRI rats. Melatonin and PAA protected against AKI-to-CKD transition by regulating growth arrest-specific 6 (Gas6)/AxleNFeκB/Nrf2 signaling cascade. Melatonin and PAA initiallyupregulated Gas6/Axl signaling to reduce oxidative stress and inflammation in AKI and subsequently downregulated Gas6/Axl signaling to attenuate renal fibrosis and progression to CKD. Melatonin and PAA inhibited expression of extracellular matrix proteins. Poricoic acid A enhances melatonin-mediated inhibition of AKI-to-CKD transition by the regulating Gas6/AxleNFeκB/Nrf2 signaling cascade. Notably, our study first identified Axl as a promising therapeutic target for prevention of AKI-to-CKD transition.

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Axl activation attenuates neuroinflammation by inhibiting the TLR/TRAF/NF-κB pathway after MCAO in rats

Abstract: rGas6 reduced the neurological deficits by inhibiting neuroinflammation via the TLR/TRAF/NF-κB signaling pathway. rGas6 can be used as potential treatment to ischemic stroke.

Cited by 93 publications

References 43 publications

Ezetimibe Attenuates Oxidative Stress and Neuroinflammation via the AMPK/Nrf2/TXNIP Pathway after MCAO in Rats

Ezetimibe Attenuates Oxidative Stress and Neuroinflammation via the AMPK/Nrf2/TXNIP Pathway after MCAO in Rats

Aggf1 attenuates neuroinflammation and BBB disruption via PI3K/Akt/NF-κB pathway after subarachnoid hemorrhage in rats

Poricoic acid A enhances melatonin inhibition of AKI-to-CKD transition by regulating Gas6/Axl NF κB/Nrf2 axis

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