Luteolin protects microglia against rotenone-induced toxicity in a hormetic manner through targeting oxidative stress response, genes associated with Parkinson’s disease and inflammatory pathways

Elmazoğlu, Zübeyir; Sağlam, Atiye Seda Yar; Sonmez, Can; Karasu, Çi̇men

doi:10.1080/01480545.2018.1504961

Cited by 39 publications

(20 citation statements)

References 45 publications

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“…Mn also increased LRRK2 expression in both macrophages and microglia, indicating that Mn may enhance LRRK2 at the transcriptional level. Interestingly, another toxicant, rotenone, also increased LRRK2 expression in microglia [62].…”

Section: Discussionmentioning

confidence: 99%

LRRK2 kinase plays a critical role in manganese-induced inflammation and apoptosis in microglia

et al. 2019

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Long-term exposure to elevated levels of manganese (Mn) causes manganism, a neurodegenerative disorder with Parkinson’s disease (PD)-like symptoms. Increasing evidence suggests that leucine-rich repeat kinase 2 (LRRK2), which is highly expressed in microglia and macrophages, contributes to the inflammation and neurotoxicity seen in autosomal dominant and sporadic PD. As gene-environment interactions have emerged as important modulators of PD-associated toxicity, LRRK2 may also mediate Mn-induced inflammation and pathogenesis. In this study, we investigated the role of LRRK2 in Mn-induced toxicity using human microglial cells (HMC3), LRRK2-wild-type (WT) and LRRK2-knockout (KO) RAW264.7 macrophage cells. Results showed that Mn activated LRRK2 kinase by phosphorylation of its serine residue at the 1292 position (S1292) as a marker of its kinase activity in macrophage and microglia, while inhibition with GSK2578215A (GSK) and MLi-2 abolished Mn-induced LRRK2 activation. LRRK2 deletion and its pharmacological inhibition attenuated Mn-induced apoptosis in macrophages and microglia, along with concomitant decreases in the pro-apoptotic Bcl-2-associated X (Bax) protein. LRRK2 deletion also attenuated Mn-induced production of reactive oxygen species (ROS) and the pro-inflammatory cytokine TNF-α. Mn-induced phosphorylation of mitogen-activated protein kinase (MAPK) p38 and ERK signaling proteins was significantly attenuated in LRRK2 KO cells and GSK-treated cells. Moreover, inhibition of MAPK p38 and ERK as well as LRRK2 attenuated Mn-induced oxidative stress and cytotoxicity. These findings suggest that LRRK2 kinase activity plays a critical role in Mn-induced toxicity via downstream activation of MAPK signaling in macrophage and microglia. Collectively, these results suggest that LRRK2 could be a potential molecular target for developing therapeutics to treat Mn-related neurodegenerative disorders.

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Section: Discussionmentioning

confidence: 99%

LRRK2 kinase plays a critical role in manganese-induced inflammation and apoptosis in microglia

et al. 2019

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“…However, neobaicalein pre-treatment survived the rotenone treated cells significantly and decreased the rate of early apoptosis, as well as late apoptosis/necrosis. Other flavonoids with a similar structure as neobaicalein have also been shown the potential against rotenone toxicity, suggesting the neuroprotective effects of flavonoids [9,60,61]. In addition to cell death, another reason, which can explain the symptoms of PD, is the disability of neurons in recruiting transmitters, synaptic communication with neighbor neurons, and glial cells.…”

Section: Discussionmentioning

confidence: 99%

Multiple neuroprotective features of Scutellaria pinnatifida–derived small molecule

Parsafar

Nayeri

Aliakbari

et al. 2020

Heliyon

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Parkinson's disease (PD) is one of the most prevalent neurodegenerative disorders with no precise etiology. Multiple lines of evidence support that environmental factors, either neurotoxins or neuroinflammation, can induce Parkinsonism. In this study, we purified an active compound, neobaicalein (Skullcapflavone II), from the roots of Scutellaria pinnatifida (S. pinnatifida). Neobaicalein not only had protective impacts on rotenone-induced neurotoxicity but in glial cultures, it dampened the inflammatory response when stimulated with lipopolysaccharide (LPS). Neobaicalein had high antioxidant activity without any obvious toxicity. In addition, it could raise the cell viability, decrease early apoptosis, reduce the generation of reactive oxygen species (ROS), and keep the neurite's length normal in the treated SH-SY5Y cells. Pathway enrichment analysis (PEA) and target prediction provided insights into the PD related genes, protein-protein interaction (PPI) network, and the key proteins enriched in the signaling pathways. Furthermore, docking simulation (DS) on the proteins of the PD-PPI network revealed that neobaicalein might interact with the key proteins involved in PD pathology, including MAPK14, MAPK8, and CASP3. It also blocks the destructive processes, such as cell death, inflammation, and oxidative stress pathways. Our results demonstrate that neobaicalein alleviates pathological effects of factors related to PD, and may provide new insight into PD therapy.

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“…In this regard, Wen et al reported that the overexpression of miR-185 gene can lead to the inhibition on apoptosis of dopaminergic neurons through regulating the mTOR-dependent autophagy pathway [25]. Furthermore, Elmazoglu et al reported a decrease in the PARK2 gene expression level in an in vitro model of PD induced by rotenone [26]. The increase in the PARK2 gene expression level was also observed in clinical cases of PD or PD models occurred through certain epigenetic processes.…”

Section: Discussionmentioning

confidence: 99%

miR-185 and SEPT5 Genes May Contribute to Parkinson’s Disease Pathophysiology

Rahimmi

Peluso²,

Rajabi

et al. 2019

Oxidative Medicine and Cellular Longevity

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There are still unknown mechanisms involved in the development of Parkinson's disease (PD), which elucidating them can assist in developing efficient therapies. Recently, studies showed that genes located on the human chromosomal location 22q11.2 might be involved in the development of PD. Therefore, the present study was designed to evaluate the role of two genes located on the chromosomal location (miR-185 and SEPT5), which were the most probable candidates based on our bibliography. In vivo and in vitro models of PD were developed using male Wistar rats and SHSY-5Y cell line, respectively. The expression levels of miR-185, SEPT5, LRRK2, and PARK2 genes were measured at a mRNA level in dopaminergic areas of rats' brains and SHSY-5Y cells using the SYBR Green Real-Time PCR Method. Additionally, the effect of inhibition on the genes or their products on cell viability and gene expression pattern in SHSY-5Y cells was investigated. The level of miR-185 gene expression was significantly decreased in the substantia nigra (SN) and striatum (ST) of the rotenone-treated group (control group) compared to the healthy normal group (P < 0.05). In addition, there was a significant difference in the expression of SEPT5 gene (P < 0.05) in the substantia nigra between two studied groups. The results of an in vitro study showed no significant change in the expression of the genes; however, the inhibition on miR-185 gene expression led to the increase in LRRK2 gene expression in SHSY-5Y cells. The inhibition on LRRK2 protein also decreased the cellular toxicity effect of rotenone on SHSY-5Y cells. The results suggested the protective role of miR-185 gene in preventing the development of PD.

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Luteolin protects microglia against rotenone-induced toxicity in a hormetic manner through targeting oxidative stress response, genes associated with Parkinson’s disease and inflammatory pathways

Cited by 39 publications

References 45 publications

LRRK2 kinase plays a critical role in manganese-induced inflammation and apoptosis in microglia

LRRK2 kinase plays a critical role in manganese-induced inflammation and apoptosis in microglia

Multiple neuroprotective features of Scutellaria pinnatifida–derived small molecule

miR-185 and SEPT5 Genes May Contribute to Parkinson’s Disease Pathophysiology

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