SF-6 attenuates 6-hydroxydopamine-induced neurotoxicity: An in vitro and in vivo investigation in experimental models of Parkinson's disease

The movement disorder Parkinson’s disease (PD) is the second most frequently diagnosed neurodegenerative disease, and is associated with aging, the environment, and genetic factors. The intracellular aggregation of α-synuclein and the loss of dopaminergic neurons in the substantia nigra pars compacta are the pathological hallmark of PD. At present, there is no successful treatment for PD. Maackiain (MK) is a flavonoid extracted from dried roots of Sophora flavescens Aiton. MK has emerged as a novel agent for PD treatment that acts by inhibiting monoamine oxidase B. In this study, we assessed the neuroprotective potential of MK in Caenorhabditis elegans and investigated possible mechanism of this neuroprotection in the human SH-SY5Y cell line. We found that MK significantly reduced dopaminergic neuron damage in 6-hydroxydopamine (6-OHDA)-exposed worms of the BZ555 strain, with corresponding improvements in food-sensing behavior and life-span. In transgenic worms of strain NL5901 treated with 0.25 mM MK, the accumulation of α-synuclein was diminished by 27% (p < 0.01) compared with that in untreated worms. Moreover, in worms and the SH-SY5Y cell line, we confirmed that the mechanism of MK-mediated protection against PD pathology may include blocking apoptosis, enhancing the ubiquitin-proteasome system, and augmenting autophagy by increasing PINK1/parkin expression. The use of small interfering RNA to downregulate parkin expression in vivo and in vitro could reverse the benefits of MK in PD models. MK may have considerable therapeutic applications in PD.

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Cannabinoids provide neuroprotection against 6-hydroxydopamine toxicity in vivo and in vitro: Relevance to Parkinson's disease

Neurobiology of Disease ◽

10.1016/j.nbd.2004.11.009 ◽

2005 ◽

Vol 19 (1-2) ◽

pp. 96-107 ◽

Cited By ~ 213

Author(s):

Isabel Lastres-Becker ◽

Francisco Molina-Holgado ◽

José A. Ramos ◽

Raphael Mechoulam ◽

Javier Fernández-Ruiz

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

6 Hydroxydopamine

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Disruption of the Circadian Clock Alters Antioxidative Defense via the SIRT1-BMAL1 Pathway in 6-OHDA-Induced Models of Parkinson’s Disease

Oxidative Medicine and Cellular Longevity ◽

10.1155/2018/4854732 ◽

2018 ◽

Vol 2018 ◽

pp. 1-11 ◽

Cited By ~ 14

Author(s):

Yali Wang ◽

Dongjun Lv ◽

Wenwen Liu ◽

Siyue Li ◽

Jing Chen ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Circadian Clock ◽

Antioxidative Activity ◽

Expression Patterns ◽

Antioxidative Defense ◽

Real Time Quantitative Pcr ◽

6 Hydroxydopamine

Parkinson’s disease (PD) is the second most common neurodegenerative disease and is known to involve circadian dysfunction and oxidative stress. Although antioxidative defense is regulated by the molecular circadian clock, few studies have examined their function in PD and their regulation by silent information regulator 1 (SIRT1). We hypothesize that reduced antioxidative activity in models of PD results from dysfunction of the molecular circadian clock via the SIRT1 pathway. We treated rats and SH-SY5Y cells with 6-hydroxydopamine (6-OHDA) and measured the expression of core circadian clock and associated nuclear receptor genes using real-time quantitative PCR as well as levels of SIRT1, brain and muscle Arnt-like protein 1 (BMAL1), and acetylated BMAL1 using Western blotting. We found that 6-OHDA treatment altered the expression patterns of clock and antioxidative molecules in vivo and in vitro. We also detected an increased ratio of acetylated BMAL1:BMAL1 and a decreased level of SIRT1. Furthermore, resveratrol, an activator of SIRT1, decreased the acetylation of BMAL1 and inhibited its binding with CRY1, thereby reversing the impaired antioxidative activity induced by 6-OHDA. These results suggest that a dysfunctional circadian clock contributes to an abnormal antioxidative response in PD via a SIRT1-dependent BMAL1 pathway.

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Carvacrol Protects Against 6-Hydroxydopamine-Induced Neurotoxicity in In Vivo and In Vitro Models of Parkinson’s Disease

Neurotoxicity Research ◽

10.1007/s12640-019-00088-w ◽

2019 ◽

Vol 37 (1) ◽

pp. 156-170 ◽

Cited By ~ 4

Author(s):

Mahboubeh Manouchehrabadi ◽

Mona Farhadi ◽

Zahra Azizi ◽

Anahita Torkaman-Boutorabi

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

In Vitro Models ◽

6 Hydroxydopamine

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Neuroprotective Effects of Resveratrol in In vivo and In vitro Experimental Models of Parkinson’s Disease: a Systematic Review

Neurotoxicity Research ◽

10.1007/s12640-021-00450-x ◽

2022 ◽

Author(s):

Michele Goulart dos Santos ◽

Lucia Emanueli Schimith ◽

Corinne André-Miral ◽

Ana Luiza Muccillo-Baisch ◽

Bruno Dutra Arbo ◽

...

Keyword(s):

Systematic Review ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Experimental Models ◽

Neuroprotective Effects

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Tetramethylpyrazine Analogue T-006 Exerts Neuroprotective Effects against 6-Hydroxydopamine-Induced Parkinson’s Disease In Vitro and In Vivo

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/8169125 ◽

2019 ◽

Vol 2019 ◽

pp. 1-14 ◽

Cited By ~ 3

Author(s):

Hefeng Zhou ◽

Min Shao ◽

Xuanjun Yang ◽

Chuwen Li ◽

Guozhen Cui ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Motor Coordination ◽

Neurodegenerative Disorder ◽

Nerve Fibers ◽

Substantia Nigra Pars Compacta ◽

Neuroprotective Effects ◽

6 Hydroxydopamine

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), and there is no cure for it at present. We have previously reported that the tetramethylpyrazine (TMP) derivative T-006 exhibited beneficial effects in Alzheimer’s disease (AD) models. However, its effect on PD remains unclear. In the present study, we investigated the neuroprotective effects and underlying mechanisms of T-006 against 6-hydroxydopamine- (6-OHDA-) induced lesions in in vivo and in vitro PD models. Our results demonstrated that T-006 alleviated mitochondrial membrane potential loss and restored the energy metabolism and mitochondrial biogenesis that were induced by 6-OHDA in PC12 cells. In addition, animal experiments showed that administration of T-006 significantly attenuated the 6-OHDA-induced loss of tyrosine hydroxylase- (TH-) positive neurons in the SNpc, as well as dopaminergic nerve fibers in the striatum, and also increased the concentration of dopamine and its metabolites (DOPAC, HVA) in the striatum. Functional deficits were restored following T-006 treatment in 6-OHDA-lesioned mice, as demonstrated by improved motor coordination and rotational behavior. In addition, we found that the neuroprotective effects of T-006 were mediated, at least in part, by the activation of both the PKA/Akt/GSK-3β and CREB/PGC-1α/NRF-1/TFAM pathways. In summary, our findings demonstrate that T-006 could be developed as a novel neuroprotective agent for PD, and the two pathways might be promising therapeutic targets for PD.

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4R-Cembranoid Improves Outcomes after 6-Hydroxydopamine Challenge in Both In vitro and In vivo Models of Parkinson's Disease

Frontiers in Neuroscience ◽

10.3389/fnins.2017.00272 ◽

2017 ◽

Vol 11 ◽

Cited By ~ 4

Author(s):

Jing Hu ◽

P. A. Ferchmin ◽

Ann M. Hemmerle ◽

Kim B. Seroogy ◽

Vesna A. Eterovic ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

In Vivo Models ◽

6 Hydroxydopamine

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Neuroprotection with the Cannabidiol Quinone Derivative VCE-004.8 (EHP-101) against 6-Hydroxydopamine in Cell and Murine Models of Parkinson’s Disease

Molecules ◽

10.3390/molecules26113245 ◽

2021 ◽

Vol 26 (11) ◽

pp. 3245

Author(s):

Sonia Burgaz ◽

Concepción García ◽

María Gómez-Cañas ◽

Alain Rolland ◽

Eduardo Muñoz ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Peroxisome Proliferator ◽

Cytoprotective Effect ◽

Neuroprotective Effects ◽

Ppar Γ ◽

Cb2 Receptors ◽

6 Hydroxydopamine

The 3-hydroxyquinone derivative of the non-psychotrophic phytocannabinoid cannabigerol, so-called VCE-003.2, and some other derivatives have been recently investigated for neuroprotective properties in experimental models of Parkinson’s disease (PD) in mice. The pharmacological effects in those models were related to the activity on the peroxisome proliferator-activated receptor-γ (PPAR-γ) and possibly other pathways. In the present study, we investigated VCE-004.8 (formulated as EHP-101 for oral administration), the 3-hydroxyquinone derivative of cannabidiol (CBD), with agonist activity at the cannabinoid receptor type-2 (CB2) receptor in addition to its activity at the PPAR-γ receptor. Studies were conducted in both in vivo (lesioned-mice) and in vitro (SH-SY5Y cells) models using the classic parkinsonian neurotoxin 6-hydroxydopamine (6-OHDA). Our data confirmed that the treatment with VCE-004.8 partially reduced the loss of tyrosine hydroxylase (TH)-positive neurons measured in the substantia nigra of 6-OHDA-lesioned mice, in parallel with an almost complete reversal of the astroglial (GFAP) and microglial (CD68) reactivity occurring in this structure. Such neuroprotective effects attenuated the motor deficiencies shown by 6-OHDA-lesioned mice in the cylinder rearing test, but not in the pole test. Next, we explored the mechanism involved in the beneficial effect of VCE-004.8 in vivo, by analyzing cell survival in cultured SH-SY5Y cells exposed to 6-OHDA. We found an important cytoprotective effect of VCE-004.8 at a concentration of 10 µM, which was completely reversed by the addition of antagonists, T0070907 and SR144528, aimed at blocking PPAR-γ and CB2 receptors, respectively. The treatment with T0070907 alone only caused a partial reversal, whereas SR144528 alone had no effect, indicating a major contribution of PPAR-γ receptors in the cytoprotective effect of VCE-004.8 at 10 µM. In summary, our data confirmed the neuroprotective potential of VCE-004.8 in 6-OHDA-lesioned mice, and in vitro studies confirmed a greater relevance for PPAR-γ receptors rather than CB2 receptors in these effects.

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Peiminine Reduces ARTS-Mediated Degradation of XIAP by Modulating the PINK1/Parkin Pathway to Ameliorate 6-Hydroxydopamine Toxicity and α-Synuclein Accumulation in Parkinson’s Disease Models In Vivo and In Vitro

International Journal of Molecular Sciences ◽

10.3390/ijms221910240 ◽

2021 ◽

Vol 22 (19) ◽

pp. 10240

Author(s):

Yu-Ling Hsu ◽

Huey-Shan Hung ◽

Chia-Wen Tsai ◽

Shih-Ping Liu ◽

Yu-Ting Chiang ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Mechanism Of Action ◽

Treatment Strategies ◽

Ubiquitin Proteasome System ◽

Pathologic Features ◽

Induced Apoptosis ◽

6 Hydroxydopamine

Parkinson’s disease (PD) is a degenerative disease that can cause motor, cognitive, and behavioral disorders. The treatment strategies being developed are based on the typical pathologic features of PD, including the death of dopaminergic (DA) neurons in the substantia nigra of the midbrain and the accumulation of α-synuclein in neurons. Peiminine (PMN) is an extract of Fritillaria thunbergii Miq that has antioxidant and anti-neuroinflammatory effects. We used Caenorhabditis elegans and SH-SY5Y cell models of PD to evaluate the neuroprotective potential of PMN and address its corresponding mechanism of action. We found that pretreatment with PMN reduced reactive oxygen species production and DA neuron degeneration caused by exposure to 6-hydroxydopamine (6-OHDA), and therefore significantly improved the DA-mediated food-sensing behavior of 6-OHDA-exposed worms and prolonged their lifespan. PMN also diminished the accumulation of α-synuclein in transgenic worms and transfected cells. In our study of the mechanism of action, we found that PMN lessened ARTS-mediated degradation of X-linked inhibitor of apoptosis (XIAP) by enhancing the expression of PINK1/parkin. This led to reduced 6-OHDA-induced apoptosis, enhanced activity of the ubiquitin–proteasome system, and increased autophagy, which diminished the accumulation of α-synuclein. The use of small interfering RNA to down-regulate parkin reversed the benefits of PMN in the PD models. Our findings suggest PMN as a candidate compound worthy of further evaluation for the treatment of PD.

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