Dimethyl fumarate ameliorates parkinsonian pathology by modulating autophagy and apoptosis via Nrf2-TIGAR-LAMP2/Cathepsin D axis

Khot, Mayuri; Sood, Anika; Tryphena, Kamatham Pushpa; Pinjala, Poojitha; Srivastava, Saurabh; Singh, Shashi Bala; Khatri, Dharmendra Kumar

doi:10.1016/j.brainres.2023.148462

Cited by 8 publications

(5 citation statements)

References 74 publications

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“…The membrane was blocked using 3% BSA for 1-2 h, followed by overnight incubation in the following primary antibodies at 4°C: Anti-NRF2 (Sigma Aldrich, 1 : 1000), Anti-BNIP3 (Sigma Aldrich, 1 : 1000), TH (Santa Cruz, 1 : 2500), β-actin (Santa Cruz, 1 : 1000), α-synuclein (Santa Cruz, 1 : 500), NRF1 (Santa Cruz, 1 : 2500), PINK1 (Santa Cruz, 1 : 500), PARKIN (Santa Cruz, 1 : 500), LC3 (CST, 1 : 1000), BECLIN-1 (Santa Cruz, 1 : 1000), BCL2 (Santa Cruz, 1 : 500). Then, blots were incubated with HRP-conjugated anti-mouse (CST) and anti-rabbit (Santa Cruz) secondary antibody (1 : 10000 dilution) before visualizing using ECL reagent through chemiluminescence [ 39 ]. The relative band densities were quantified by densitometry using Image J analyzing software (Image J 1.53 k, National Institute of Health, Bethesda, MD, USA).…”

Section: Methodsmentioning

confidence: 99%

“…The sections were incubated in TH primary antibody (Santa Cruz, 1 : 200 dilution using 1% BSA in PBST) overnight at 4°C followed incubation in Alexa Fluor 488 secondary antibody (Invitrogen, 1 : 2000 dilution using 1% BSA in PBST) for 2 h in the dark at room temperature. The sections were counterstained with fluoroshield DAPI and visualized under the fluorescent microscope (Olympus, BX53) [ 39 ].…”

Section: Methodsmentioning

confidence: 99%

“…The robust bioavailability and therapeutic efficacy of DMF is mediated by its potent metabolite MMF through the activation of NRF2 pathway, a key transcription factor involved in antioxidant response [ 38 ]. In our previous study, we have shown that DMF modulates autophagy via NRF2-TIGAR-LAMP2/Cathepsin D pathway in rotenone induced PD model [ 39 ]. Similarly, inducing NRF2 through the administration of DMF can be used to directly induce BNIP3, PINK1/PARKIN expression in the PD disease model and promote mitophagy.…”

Section: Introductionmentioning

confidence: 99%

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Dimethyl Fumarate Exerts a Neuroprotective Effect by Enhancing Mitophagy via the NRF2/BNIP3/PINK1 Axis in the MPP+ Iodide-Induced Parkinson’s Disease Mice Model

Pinjala,

Tryphena,

Kulkarni

et al. 2024

ADR

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Background: Parkinson’s disease (PD) is a progressive neurodegenerative disorder linked to the loss of dopaminergic neurons in the substantia nigra. Mitophagy, mitochondrial selective autophagy, is critical in maintaining mitochondrial and subsequently neuronal homeostasis. Its impairment is strongly implicated in PD and is associated with accelerated neurodegeneration. Objective: To study the positive effect of dimethyl fumarate (DMF) on mitophagy via the NRF2/BNIP3/PINK1 axis activation in PD disease models. Methods: The neuroprotective effect of DMF was explored in in vitro and in vivo PD models. MTT assay was performed to determine the DMF dose followed by JC-1 assay to study its mitoprotective effect in MPP+ exposed SHSY5Y cells. For the in vivo study, C57BL/6 mice were divided into six groups: Normal Control (NC), Disease Control (DC), Sham (Saline i.c.v.), Low Dose (MPP+ iodide+DMF 15 mg/kg), Mid Dose (MPP+ iodide+DMF 30 mg/kg), and High Dose (MPP+ iodide+DMF 60 mg/kg). The neuroprotective effect of DMF was assessed by performing rotarod, open field test, and pole test, and biochemical parameter analysis using immunofluorescence, western blot, and RT-PCR. Results: DMF treatment significantly alleviated the loss of TH positive dopaminergic neurons and enhanced mitophagy by increasing PINK1, Parkin, BNIP3, and LC3 levels in the MPP+ iodide-induced PD mice model. DMF treatment groups showed good locomotor activity and rearing time when compared to the DC group. Conclusions: DMF confers neuroprotection by activating the BNIP3/PINK1/Parkin pathway, enhancing the autophagosome formation via LC3, and improving mitophagy in PD models, and could be a potential therapeutic option in PD.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Dimethyl Fumarate Exerts a Neuroprotective Effect by Enhancing Mitophagy via the NRF2/BNIP3/PINK1 Axis in the MPP+ Iodide-Induced Parkinson’s Disease Mice Model

Pinjala,

Tryphena,

Kulkarni

et al. 2024

ADR

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“…DMF treatments prevent MPTP-induced loss of dopaminergic neurons and striatal dopamine, depletion of tyrosine hydroxylase, GSH and dopamine transporter, and reduce cellular levels of nitrative stress marker 3-nitrotyrosine (3-NT), TNF-α, monocyte chemoattractant protein-1 (MCP-1), α-synuclein oligomers, NF-κB and other oxidative stress or inflammatory markers. More recently, DMF (15–30–60 mg/kg) has been administered to a rotenone-induced mouse model of PD, leading to improvements in the rotenone-induced motor deficits and to decreases in the levels of α-synuclein in brain sections ( Khot et al, 2023 ). Results from this study also remarked a DMF-induced activation of the autophagic pathway, and an inhibition of apoptosis and inflammatory cytokines.…”

Section: Novel Potential Pharmacological Applicationsmentioning

confidence: 99%

Novel potential pharmacological applications of dimethyl fumarate—an overview and update

Bresciani,

Manai,

Davinelli

et al. 2023

Front. Pharmacol.

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Dimethyl fumarate (DMF) is an FDA-approved drug for the treatment of psoriasis and multiple sclerosis. DMF is known to stabilize the transcription factor Nrf2, which in turn induces the expression of antioxidant response element genes. It has also been shown that DMF influences autophagy and participates in the transcriptional control of inflammatory factors by inhibiting NF-κB and its downstream targets. DMF is receiving increasing attention for its potential to be repurposed for several diseases. This versatile molecule is indeed able to exert beneficial effects on different medical conditions through a pleiotropic mechanism, in virtue of its antioxidant, immunomodulatory, neuroprotective, anti-inflammatory, and anti-proliferative effects. A growing number of preclinical and clinical studies show that DMF may have important therapeutic implications for chronic diseases, such as cardiovascular and respiratory pathologies, cancer, eye disorders, neurodegenerative conditions, and systemic or organ specific inflammatory and immune-mediated diseases. This comprehensive review summarizes and highlights the plethora of DMF’s beneficial effects and underlines its repurposing opportunities in a variety of clinical conditions.

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“…[24,25] Activating the Nrf2 antioxidant signaling pathway has been demonstrated to exert beneficial effects on hindering the progression of PD. [26,27] Vincamine (chemical structure shown in Figure 1A) is an indole alkaloid obtained from the leaves of Vinca minor, a flowering plant that has been used as a nutritional supplement or antiaging drug for thousands of years. [28] Modern pharmacological studies have revealed that vincamine has antiapoptotic, anti-inflammatory, and antioxidant properties against a variety of central and/or peripheral diseases.…”

Section: Introductionmentioning

confidence: 99%

Vincamine alleviates brain injury by attenuating neuroinflammation and oxidative damage in a mouse model of Parkinson's disease through the NF‐κB and Nrf2/HO‐1 signaling pathways

Wang,

Chen,

Shan

2024

J Biochem & Molecular Tox

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Parkinson's disease (PD) is a neurodegenerative disease featured by progressive loss of nigrostriatal dopaminergic neurons, the etiology of which is associated with the existence of neuroinflammatory response and oxidative stress. Vincamine is an indole alkaloid that was reported to exhibit potent anti‐inflammatory and antioxidant properties in many central and/or peripheral diseases. Nevertheless, the specific role of vincamine in PD development remains unknown. In our study, dopaminergic neuron loss was determined through immunohistochemistry staining and western blot analysis of tyrosine hydroxylase (TH) expression in the substantia nigra (SN) of PD mice. Reactive oxygen species (ROS) production and malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH) levels were detected through DHE staining and commercially available kits to assess oxidative stress. Pro‐inflammatory cytokine (TNF‐α, IL‐1β, and IL‐6) levels in the SN were measured via RT‐qPCR and western blot analysis. Microglial and astrocyte activation was examined through immunofluorescence staining of Iba‐1 (microglia marker) and GFAP (astrocyte marker) in the SN. The regulation of vincamine on the NF‐κB and Nrf2/HO‐1 pathway was estimated through western blot analysis. Our results showed that vincamine treatment decreased TNF‐α, IL‐1β, and IL‐6 mRNA and protein levels, reduced GFAP and Iba‐1 expression, decreased ROS production and MDA level, and increased SOD activity and GSH level in the SN of PD mice. Mechanically, vincamine repressed the phosphorylation levels of p65, IKKβ, and IκBα but enhanced the protein levels of Nrf2 and HO‐1 in PD mice. Collectively, vincamine plays a neuroprotective role in PD mouse models by alleviating neuroinflammation and oxidative damage via suppressing the NF‐κB pathway and activating the Nrf2/HO‐1 pathway.

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Dimethyl fumarate ameliorates parkinsonian pathology by modulating autophagy and apoptosis via Nrf2-TIGAR-LAMP2/Cathepsin D axis

Cited by 8 publications

References 74 publications

Dimethyl Fumarate Exerts a Neuroprotective Effect by Enhancing Mitophagy via the NRF2/BNIP3/PINK1 Axis in the MPP+ Iodide-Induced Parkinson’s Disease Mice Model

Dimethyl Fumarate Exerts a Neuroprotective Effect by Enhancing Mitophagy via the NRF2/BNIP3/PINK1 Axis in the MPP+ Iodide-Induced Parkinson’s Disease Mice Model

Novel potential pharmacological applications of dimethyl fumarate—an overview and update

Vincamine alleviates brain injury by attenuating neuroinflammation and oxidative damage in a mouse model of Parkinson's disease through the NF‐κB and Nrf2/HO‐1 signaling pathways

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