Nilotinib inhibits microglia-mediated neuroinflammation to protect against dopaminergic neuronal death in Parkinson’s disease models

Wu, Jiayuan; Xu, Xinqin; Li, Zheng; Mo, Juanfen; Jin, Xiuhui; Bao, Yi

doi:10.1016/j.intimp.2021.108025

Cited by 20 publications

(16 citation statements)

References 34 publications

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“…Nilotinib has been shown to mitigate Alzheimer’s disease (AD) and Parkinson’s disease (PD) pathologies [ 23 , 24 ], but its effects on LPS-induced proinflammatory cytokine levels and the corresponding mechanism of action have not been studied. Before proceeding with in vitro experiments, we first confirmed that nilotinib had no cytotoxicity in BV2 microglial cells at concentrations up to 50 μM, as assessed by MTT assays (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…In BV2 microglial and RAW 264.7 cells, nilotinib reduces LPS-induced increases in c-Abl mRNA and protein levels [ 34 , 35 ]. Moreover, nilotinib suppresses LPS-mediated increases in COX-2, IL-1β, IL-6, and TNF-α proinflammatory cytokines in BV2 microglial cells [ 24 ]. Transfection of c-Abl siRNA significantly reduces levels of the transcription co-factor p-IκB in primary microglia and astrocytes [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

“…Given the effects of nilotinib on LPS-mediated proinflammatory cytokine expression in vitro (microglia and astrocytes), we investigated whether nilotinib modulates neuroinflammation in vivo and its underlying mechanism. Previous work has shown that administration of 25 mg/kg nilotinib (p.o., 7 days) significantly decreases LPS-induced increases in proinflammatory cytokine COX-2 and IL-1β levels as well as Iba-1 immunoreactivity in the substantia nigra part compacta (SNpc) in a mouse model of PD [ 24 ]. Similarly, treatment with 30 mg/kg nilotinib (p.o., 5 months) reduces α-synuclein preformed fibril (PFF)-induced activation of Iba-1 and GFAP immunoreactivity in the SNpc in a PD mouse model [ 41 ].…”

Section: Discussionmentioning

confidence: 99%

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Nilotinib modulates LPS-induced cognitive impairment and neuroinflammatory responses by regulating P38/STAT3 signaling

Kim

Lee

Park

et al. 2022

J Neuroinflammation

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Background In chronic myelogenous leukemia, reciprocal translocation between chromosome 9 and chromosome 22 generates a chimeric protein, Bcr-Abl, that leads to hyperactivity of tyrosine kinase-linked signaling transduction. The therapeutic agent nilotinib inhibits Bcr-Abl/DDR1 and can cross the blood–brain barrier, but its potential impact on neuroinflammatory responses and cognitive function has not been studied in detail. Methods The effects of nilotinib in vitro and in vivo were assessed by a combination of RT-PCR, real-time PCR, western blotting, ELISA, immunostaining, and/or subcellular fractionation. In the in vitro experiments, the effects of 200 ng/mL LPS or PBS on BV2 microglial cells, primary microglia or primary astrocytes pre- or post-treated with 5 µM nilotinib or vehicle were evaluated. The in vivo experiments involved wild-type mice administered a 7-day course of daily injections with 20 mg/kg nilotinib (i.p.) or vehicle before injection with 10 mg/kg LPS (i.p.) or PBS. Results In BV2 microglial cells, pre- and post-treatment with nilotinib altered LPS-induced proinflammatory/anti-inflammatory cytokine mRNA levels by suppressing AKT/P38/SOD2 signaling. Nilotinib treatment also significantly downregulated LPS-stimulated proinflammatory cytokine levels in primary microglia and primary astrocytes by altering P38/STAT3 signaling. Experiments in wild-type mice showed that nilotinib administration affected LPS-mediated microglial/astroglial activation in a brain region-specific manner in vivo. In addition, nilotinib significantly reduced proinflammatory cytokine IL-1β, IL-6 and COX-2 levels and P38/STAT3 signaling in the brain in LPS-treated wild-type mice. Importantly, nilotinib treatment rescued LPS-mediated spatial working memory impairment and cortical dendritic spine number in wild-type mice. Conclusions Our results indicate that nilotinib can modulate neuroinflammatory responses and cognitive function in LPS-stimulated wild-type mice.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Nilotinib modulates LPS-induced cognitive impairment and neuroinflammatory responses by regulating P38/STAT3 signaling

Kim

Lee

Park

et al. 2022

J Neuroinflammation

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“…suggesting that c-Abl might be associated with PD progression and that its inhibitor nillotinib might have a potential benefit in treating PD. Subsequent studies found that nilotinib (1–10 mg/kg) could protect animal models of PD from neurodegeneration in the brain via inhibiting c-Abl, degrading α-synuclein and blocking inactivation of parkin (Hebron et al, 2013a , 2014 ; Karuppagounder et al, 2014 ; Lonskaya et al, 2014 ; Wu et al, 2021 ; Werner and Olanow, 2022 ). Researchers also found that nilotinib could improve motor behavior in PD models (Hebron et al, 2013a ).…”

Section: Introductionmentioning

confidence: 99%

Nilotinib in Parkinson's disease: A systematic review and meta-analysis

Xie

Yuan

Kou

et al. 2022

Front. Aging Neurosci.

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BackgroundNilotinib, which inhibits cellular Abelson tyrosine kinase, may be an effective treatment for patients with Parkinson's disease (PD). The purpose of this study is to evaluate the outcomes of different doses of nilotinib in patients with PD.MethodsWe searched PubMed, Embase, Web of Science, and Cochrane Central Register of Controlled Clinical Trials from inception to 7 March 2022 to identify all randomized controlled trials (RCTs) of nilotinib reporting outcomes of interest in patients with PD. Outcomes included tolerability, efficacy, safety, and CSF biomarker levels. Review manager 5.4 software was used to analyze all data.ResultsThree RCTs with a total of 163 patients were included. No significant difference was found between 150 mg nilotinib or 300 mg nilotinib and placebo in terms of tolerability, adverse events, or HVA levels. 300 mg nilotinib showed significantly higher Movement Disorder Society Unified Parkinson's Disease Rating Scale III (MDS-UPDRS III) scores [SMD = 0.52, 95%CI = (0.12, 0.92), P = 0.01] and 3,4-dihydroxyphenylacetic acid (DOPAC) levels [SMD = 0.52, 95%CI = (0.12, 0.92), P = 0.01], and lower α-synuclein levels [SMD = −2.16, 95%CI = (−3.38, −1.84), P < 0.00001] compared with placebo. And compared with 150 mg nilotinib, 300 mg nilotinib showed significantly lower α-synuclein levels [SMD = −1.16, 95%CI = (−1.70, −0.61), P < 0.0001].ConclusionsAlthough our study demonstrated favorable tolerability and safety of different doses of nilotinib, and improvement in part of CSF biomarker levels of 300 mg nilotinib, the poor efficacy on motor outcomes indicated that nilotinib had no advantages in the clinic.

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“…Microglia, the major cellular elements of neuroinflammation, influence brain development and maintain the neural environment and responses to brain injury [ 2 ]. Activated microglia are characterized by the increased release of neurotoxic proinflammatory mediators, such as nitric oxide (NO), interleukin-6 (IL-6) and tumor necrosis factor- α (TNF- α ) [ 3 , 4 ]. Thus, inhibiting neuroinflammation by suppressing the activation of microglia is a promising therapeutic strategy for the treatment of neuroinflammation-associated diseases [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Anti-Neuroinflammatory Activity of 1,7-diphenyl-1,4-heptadien-3-ones in LPS-Stimulated BV2 Microglia Via Inhibiting NF-κB/MAPK Signaling Pathways

et al. 2022

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A series of 1,7-diphenyl-1,4-heptadien-3-ones with various substituents (HO-, CH3O-, CH3-, Cl-) on the phenyl rings were synthesized and evaluated for anti-neuroinflammatory effects in LPS-stimulated BV2 microglia. The pharmacological results showed that the target compounds bearing methoxy groups greatly inhibited LPS-induced NO release, and that the active compounds CU-19 and CU-21 reduced the level of NO, TNF-α, IL-6 and PGE-2, downregulated the expression of COX-2 and iNOS in LPS-stimulated BV2 cells. A study of the mechanism of action revealed that CU-19 and CU-21 inhibited the nuclear translocation of NF-κB and phosphorylation of MAPKs (ERK, JNK, and p38). A preliminary pharmacokinetic study in rats revealed that the pharmacokinetic properties of CU-19 and CU-21 were dramatically ameliorated in comparison with the pharmacokinetic properties of curcumin.

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Nilotinib inhibits microglia-mediated neuroinflammation to protect against dopaminergic neuronal death in Parkinson’s disease models

Cited by 20 publications

References 34 publications

Nilotinib modulates LPS-induced cognitive impairment and neuroinflammatory responses by regulating P38/STAT3 signaling

Nilotinib modulates LPS-induced cognitive impairment and neuroinflammatory responses by regulating P38/STAT3 signaling

Nilotinib in Parkinson's disease: A systematic review and meta-analysis

Synthesis and Anti-Neuroinflammatory Activity of 1,7-diphenyl-1,4-heptadien-3-ones in LPS-Stimulated BV2 Microglia Via Inhibiting NF-κB/MAPK Signaling Pathways

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