Metformin protects rotenone-induced dopaminergic neurodegeneration by reducing lipid peroxidation

Özbey, Gül; Samur, Dilara Nemutlu; Parlak, Hande; Yıldırım, Sendegül; Aslan, Mutay; Tanrıöver, Gamze; Ağar, Ayşel

doi:10.1007/s43440-020-00095-1

Cited by 20 publications

(5 citation statements)

References 32 publications

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“…Moreover, in order to investigate the effect of Myr on fibril-mediated oxidative stress, we quantified the production of malondialdehyde, an advanced lipo-oxidation end-product implicated in age-related chronic diseases and in PD [ 46 ].…”

Section: Resultsmentioning

confidence: 99%

Inhibition of Ceramide Synthesis Reduces α-Synuclein Proteinopathy in a Cellular Model of Parkinson’s Disease

Mingione

Pivari

Plotegher

et al. 2021

IJMS

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Parkinson’s disease (PD) is a proteinopathy associated with the aggregation of α-synuclein and the formation of lipid–protein cellular inclusions, named Lewy bodies (LBs). LB formation results in impaired neurotransmitter release and uptake, which involve membrane traffic and require lipid synthesis and metabolism. Lipids, particularly ceramides, are accumulated in postmortem PD brains and altered in the plasma of PD patients. Autophagy is impaired in PD, reducing the ability of neurons to clear protein aggregates, thus worsening stress conditions and inducing neuronal death. The inhibition of ceramide synthesis by myriocin (Myr) in SH-SY5Y neuronal cells treated with preformed α-synuclein fibrils reduced intracellular aggregates, favoring their sequestration into lysosomes. This was associated with TFEB activation, increased expression of TFEB and LAMP2, and the cytosolic accumulation of LC3II, indicating that Myr promotes autophagy. Myr significantly reduces the fibril-related production of inflammatory mediators and lipid peroxidation and activates NRF2, which is downregulated in PD. Finally, Myr enhances the expression of genes that control neurotransmitter transport (SNARE complex, VMAT2, and DAT), whose progressive deficiency occurs in PD neurodegeneration. The present study suggests that counteracting the accumulation of inflammatory lipids could represent a possible therapeutic strategy for PD.

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Section: Resultsmentioning

confidence: 99%

Inhibition of Ceramide Synthesis Reduces α-Synuclein Proteinopathy in a Cellular Model of Parkinson’s Disease

Mingione

Pivari

Plotegher

et al. 2021

IJMS

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show abstract

“…In C. elegans, metformin reduced the loss of dopaminergic neurons and decreased α-synuclein aggregation induced by 6-hydroxydopamine (94). Recently, metformin treatment was shown to attenuate dopaminergic cell loss and α-synuclein accumulation in the SN of rotenone-treated mice (95). How metformin alters α-synuclein toxicity is not clear but the drug is able reduce the phosphorylation of the protein that is key to the mediation of its toxicity (96).…”

Section: α-Synuclein Aggregation and Phosphorylationmentioning

confidence: 99%

Metformin as a Potential Neuroprotective Agent in Prodromal Parkinson's Disease—Viewpoint

2020

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“…Hence, we recently speculated that metformin could provide a similar scavenging activity towards MGO by preventing the accumulation of α-syn neurotoxic aggregates, but this could be extended to other aldehydes of neuropathological relevance in PD, i.e., aldehydes derived from oxidative stress and lipid peroxidation (4-hydroxynonenal (4-HNE), malondialdehyde (MDA)) or aldehydic molecules that accumulate from altered monoamine catabolic pathways (3,4-dihydroxyphenylacetaldehyde, 3,4-dihydroxyphenylglycoaldehyde, 5-hydroxyindole-3-acetaldehyde) [ 42 ]. Accordingly, a recent paper investigated the neuroprotective effect of metformin in a PD mouse model based on rotenone-induced dopaminergic neuron death [ 25 ]. The authors demonstrated that metformin co-administration with rotenone significantly reduced the nigral levels of 4-HNE and MDA, together with decreased α-syn accumulation and dopaminergic neuron degeneration in the SNpc [ 25 ].…”

Section: Potential Neuroprotective Mechanisms Of Action Of Metforminmentioning

confidence: 99%

“…Accordingly, a recent paper investigated the neuroprotective effect of metformin in a PD mouse model based on rotenone-induced dopaminergic neuron death [ 25 ]. The authors demonstrated that metformin co-administration with rotenone significantly reduced the nigral levels of 4-HNE and MDA, together with decreased α-syn accumulation and dopaminergic neuron degeneration in the SNpc [ 25 ]. Although the authors did not investigate it directly, the reduced α-syn buildup might derive, at least in part, from a scavenging activity of metformin towards lipid peroxidation products, preventing α-syn modification and oligomerization.…”

Section: Potential Neuroprotective Mechanisms Of Action Of Metforminmentioning

confidence: 99%

Metformin Repurposing for Parkinson Disease Therapy: Opportunities and Challenges

Agostini

Masato

Bubacco

et al. 2021

IJMS

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Parkinson disease (PD) is a severe neurodegenerative disorder that affects around 2% of the population over 65 years old. It is characterized by the progressive loss of nigrostriatal dopaminergic neurons, resulting in motor disabilities of the patients. At present, only symptomatic cures are available, without suppressing disease progression. In this frame, the anti-diabetic drug metformin has been investigated as a potential disease modifier for PD, being a low-cost and generally well-tolerated medication, which has been successfully used for decades in the treatment of type 2 diabetes mellitus. Despite the precise mechanisms of action of metformin being not fully elucidated, the drug has been known to influence many cellular pathways that are associated with PD pathology. In this review, we present the evidence in the literature supporting the neuroprotective role of metformin, i.e., autophagy upregulation, degradation of pathological α-synuclein species, and regulation of mitochondrial functions. The epidemiological studies conducted in diabetic patients under metformin therapy aimed at evaluating the correlation between long-term metformin consumption and the risk of developing PD are also discussed. Finally, we provide an interpretation for the controversial results obtained both in experimental models and in clinical studies, thus providing a possible rationale for future investigations for the repositioning of metformin for PD therapy.

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Metformin protects rotenone-induced dopaminergic neurodegeneration by reducing lipid peroxidation

Cited by 20 publications

References 32 publications

Inhibition of Ceramide Synthesis Reduces α-Synuclein Proteinopathy in a Cellular Model of Parkinson’s Disease

Inhibition of Ceramide Synthesis Reduces α-Synuclein Proteinopathy in a Cellular Model of Parkinson’s Disease

Metformin as a Potential Neuroprotective Agent in Prodromal Parkinson's Disease—Viewpoint

Metformin Repurposing for Parkinson Disease Therapy: Opportunities and Challenges

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