Phytic acid attenuates upregulation of GSK-3β and disturbance of synaptic vesicle recycling in MPTP-induced Parkinson's disease models

Wang, Liping; Zhang, Zheng; Hou, Lin; Wang, YueHua; Zuo, JinHui; Xue, Mei‐lan; Li, Xianghong; Liu, YongChao; Song, Jin Yeong; Pan, Fengyu; Pu, TingWei

doi:10.1016/j.neuint.2019.104507

Cited by 11 publications

(5 citation statements)

References 37 publications

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“…The prime objective of drug therapy is to improve motor dysfunction in PD. The motor features of MPTP/Pro-induced mice are similar to the signs and symptoms of PD, suggesting that these are suitable models for discovering new drug candidates for PD [50]. Furthermore, long time administration of MPTP/Pro induces a large loss of dopaminergic neurons and significant motor dysfunction in chronic PD mouse models [20,26,27,55].…”

Section: Discussionmentioning

confidence: 81%

Targeting the Nrf2-dependent mechanism of b-Ecdysterone in attenuating the motor dysfunction in the MPTP/Pro-induced Parkinson’s disease mice model

Rong,

Li,

et al. 2024

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Oxidative stress is a pivotal stimulating factor in neurocyte apoptosis and has been involved in the pathogenesis of Parkinson's disease (PD). In this study, we have demonstrated that the improvement in the motor disorder of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)/Pro-induced mice caused by β-Ecdysterone (β-Ecd) treatment is due to its antioxidant properties. Using open field, rotarod, and pole climbing tests, we have found that β-Ecd alleviates motor disorder in MPTP/ Pro-induced mice and ultimately reduces the impairment of tyrosine hydroxylase (TH)-positive dopaminergic neurons in the substantia nigra (SN). Notably, these effects of β-Ecd were not observed in Nrf2-KO mice. In addition, β-Ecd significantly reduced the formation of ROS and the level of MDA, blocked the increase of LPO, and partially reversed the GSH/GSSG ratio in MPTP/Pro-induced WT mice; however, these results were also not observed in MPTP/Pro-induced Nrf2-KO mice. Mechanistically, β-Ecd enhanced the expression levels of heme oxygenase 1 (HO-1) and GCLc, but not NQO1 (NAD(P)H quinone dehydrogenase 1) and GCLm expression. Interestingly, β-Ecd failed to increase the protein and mRNA levels of HO-1 and GCLc in Nrf2-KO mice, suggesting that β-Ecd attenuates oxidative stress through an Nrf2-dependent mechanism. Furthermore, β-Ecd promoted the expressions of PI3K/Akt phosphorylation (activity) and . Conversely, administration of β-Ecd markedly decreased Fyn phosphorylation levels. Collectively, our findings suggest that β-Ecd focuses on Nrf2 in reducing MPTP/Pro-induced oxidative stress and subsequent motor deficits by inhibiting its nuclear export through PI3K/Akt/GSK-3β/Fyn pathway regulation. These further indicate that β-Ecd may be an absorbing therapeutic agent for PD.

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Section: Discussionmentioning

confidence: 81%

Targeting the Nrf2-dependent mechanism of b-Ecdysterone in attenuating the motor dysfunction in the MPTP/Pro-induced Parkinson’s disease mice model

Rong,

Li,

et al. 2024

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“…Accumulation of DA in the dopaminergic neuronal cytosol can trigger oxidative stress and neurotoxicity, suggesting that the proper compartmentalization of DA is critical for dopaminergic neuronal function and risk of PD . Previous data clearly show that MPTP administration to mice results in a dramatic reduction in striatal DA levels and the decreased expression levels of DAT and VMAT2 in vivo and in vitro models of MPTP/MPP + injury. , RES, a VMAT2 inhibitor, can lead to the depletion of DA and reduce the level of intracellular and extracellular DA in the STR . NOM, a DA reuptake inhibitor, increases the level of DA in the STR and is used to determine whether DAT activity is related to the increase of extracellular DA level .…”

Section: Discussionmentioning

confidence: 99%

“…6,7 The expression levels of DAT and VMAT2 are also decreased in vivo and in vitro models of MPTP/MPP + injury. 8,9 Based on the depletion of dopamine in the striatum, most of the current drugs focus on clinical symptom relief to improve the quality of life in PD patients. However, there is not any neuroprotective therapy available, although significant development has been made in the treatment of symptomatic PD, since the discovery of L-dopa in the middle of the 20th century (1960s).…”

Section: ■ Introductionmentioning

confidence: 99%

“…Dopamine transporter (DAT) and vesicular monoamine transporter 2 (VMAT2) are both DA carriers that are used to transport DA from the synaptic gap and cytoplasm and determine the amount of DA released from synaptic vesicles . DAT and VMAT2 are important reference indexes for exploring the pathogenesis of PD, which is supported by that the reduced expression levels of DAT and VMAT2 are obtained in the nigrostriatal pathway of PD patients. , Previous studies have reported that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration to mice results in a severe loss of dopaminergic neurons and a dramatic reduction in striatal DA levels, which is similar to those in PD patients. , The expression levels of DAT and VMAT2 are also decreased in vivo and in vitro models of MPTP/MPP + injury. , Based on the depletion of dopamine in the striatum, most of the current drugs focus on clinical symptom relief to improve the quality of life in PD patients. However, there is not any neuroprotective therapy available, although significant development has been made in the treatment of symptomatic PD, since the discovery of l -dopa in the middle of the 20th century (1960s) .…”

Section: Introductionmentioning

confidence: 99%

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(+)-Borneol Protects Dopaminergic Neuronal Loss in Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-Induced Parkinson’s Disease Mice: A Study of Dopamine Level using In Vivo Brain Microdialysis

Ding,

Wang,

Yang

et al. 2024

ACS Chem. Neurosci.

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Considerable research efforts have been directed toward the symptom relief of Parkinson’s disease (PD) by attenuating dopamine (DA) depletion. One common feature of these existing therapies is their unavailability of preventing the neurodegenerative process of dopaminergic neurons. (+)-Borneol, a natural highly lipid-soluble bicyclic monoterpene, has been reported to regulate the levels of monoamine neurotransmitters in the central nervous system and exhibit neuroprotective effects. However, the effect of (+)-borneol on the dopaminergic neuronal loss of methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice is not defined. Herein, we first report that 30 mg/kg (+)-borneol significantly attenuated the motor deficits of PD mice, which benefits from markedly increasing the level of DA and decreasing the metabolic rate of DA in the striatum of conscious and freely moving mouse detected by ultraperformance liquid chromatography tandem mass spectrometry online combined with in vivo brain microdialysis sampling. It is worth noting that the enhanced level of DA by (+)-borneol was enabled by the reduction in loss of tyrosine hydroxylase-immunoreactive dopaminergic neurons in the substantia nigra and striatum and promotion of reserpine- or nomifensine-induced DA release in PD mice. Interestingly, (+)-borneol evidently inhibited the decreased expression levels of DA transporter (DAT) and vesicular monoamine transporter 2 (VMAT2) on the MPTP mouse model of PD. Moreover, (+)-borneol suppressed the neuroinflammation by inhibiting the production of IL-1β, IL-6, and TNF-α and attenuated oxidative stress by decreasing the level of MDA and increasing the activities of SOD and GSH-px in PD mice. These findings demonstrate that (+)-borneol protects DA neurons by inhibiting neuroinflammation and oxidative stress. Further research work for the neuroprotection mechanism of (+)-borneol will focus on reactive oxygen species-mediated apoptosis. Therefore, (+)-borneol is a potential therapeutic candidate for retarding the neurodegenerative process of PD.

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“…Many environmental toxins, such as MPTP, can also cause the dysfunction of DA homeostasis and the loss of VMAT2 [10]. Interestingly, VMAT2 overexpressed mice can increase vesicle capacity, improve the prognosis of anxiety-like and depression-like behavior, and reduce MPTP toxic damage to mice [11,12], which indicated VMAT2 is a potentially effective target for the treatment of PD.…”

Section: Introductionmentioning

confidence: 99%

Gastrodin ameliorated features of MPTP-induced Parkinson's disease via activating VMAT2 maintained dopamine homeostasis

Zhao

Xia

Wang

et al. 2022

Preprint

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The vesicular monoamine transporter (VMAT2) plays a crucial role in maintaining dopamine (DA) homeostasis through packaged DA into vesicles, which has been suggested to being an excellent marker for presynaptic dopaminergic nerve terminals in the nigrostriatal of Parkinson's disease. Gastrodin (GTD), the major bioactive compound of Gastrodia elata, has shown neuroprotective in animal models for many neurological disorders. However, it is unclear whether GTD confers neuroprotection via activating VMAT2 to maintain DA homeostasis in an animal model of Parkinson's disease (PD) using the DA neuron-specific toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Here, we first identified that GTD could ameliorate cell damage and the dysfunction of DA homeostasis in PC12 cells induced by MPTP via up-regulating VMAT2 expression. Moreover, GTD could enhance VMAT2 protein expression, increase striatal vesicle volume, and ameliorate DA dysregulation in MPTP-induced PD mice. Furthermore, we found that the DA homeostasis and therapeutic effect of GTD could be reversed by the VMAT2 inhibitor in vitro and in vivo. Finally, we confirmed that GTD could increase VMAT2 expression by activating MEK/ERK pathway. In summary, our data showed that GTD attenuated MPTP neurotoxicity through activating of the MEK/ERK/VMAT2 signaling pathway maintained DA homeostasis, suggesting that the manipulation of VMAT2 by GTD may provide a potential therapeutic strategy for PD.

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Phytic acid attenuates upregulation of GSK-3β and disturbance of synaptic vesicle recycling in MPTP-induced Parkinson's disease models

Cited by 11 publications

References 37 publications

Targeting the Nrf2-dependent mechanism of b-Ecdysterone in attenuating the motor dysfunction in the MPTP/Pro-induced Parkinson’s disease mice model

Targeting the Nrf2-dependent mechanism of b-Ecdysterone in attenuating the motor dysfunction in the MPTP/Pro-induced Parkinson’s disease mice model

(+)-Borneol Protects Dopaminergic Neuronal Loss in Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-Induced Parkinson’s Disease Mice: A Study of Dopamine Level using In Vivo Brain Microdialysis

Gastrodin ameliorated features of MPTP-induced Parkinson's disease via activating VMAT2 maintained dopamine homeostasis

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