Therapeutic activation of autophagy by combined treatment with rapamycin and trehalose in a mouse MPTP-induced model of Parkinson's disease

Пупышев, А. Б.; Tikhonova, Maria A.; Akopyan, Anna A.; Тендитник, М. В.; Дубровина, Н. И.; Короленко, Т. А.

doi:10.1016/j.pbb.2018.12.005

Cited by 74 publications

(42 citation statements)

References 67 publications

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“…In rats overexpressing A53T α‐syn, oral administration of trehalose significantly reduced α‐syn accumulation and aggregation in the nigrostriatal system and mitigated motor asymmetry and dopaminergic neurons neurodegeneration . Similar effects were observed in a neurotoxin MPTP‐induced PD mouse model . Recently, trehalose has been tested in parallel on rat and nonhuman primate PD models overexpressing A53T α‐syn .…”

Section: The Alp As a Possible Therapeutic Target For Pdmentioning

confidence: 62%

“…Interesting results have been obtained by using trehalose, a disaccharide able to activate autophagy processes and regulate the activity of TFEB, the main transcriptional regulator of the coordinated lysosomal expression and regulation network . The therapeutic effects of trehalose have been demonstrated in several in vitro and in vivo models of PD and other neurodegenerative diseases . Hoffman and colleagues showed that exposure of H4 cells and primary neurons to trehalose, before α‐syn exposure, prevents lysosomal enlargement and formation of massive α‐syn aggregates .…”

Section: The Alp As a Possible Therapeutic Target For Pdmentioning

confidence: 99%

“…133,134 The therapeutic effects of trehalose have been demonstrated in several in vitro and in vivo models of PD and other neurodegenerative diseases. 110,133,[135][136][137][138][139][140] Hoffman and colleagues showed that exposure of H4 cells and primary neurons to trehalose, before α-syn exposure, prevents lysosomal enlargement and formation of massive α-syn aggregates. 110,141 In rats overexpressing A53T α-syn, oral administration of trehalose significantly reduced α-syn accumulation and aggregation in the nigrostriatal system and mitigated motor asymmetry 142 and dopaminergic neurons neurodegeneration.…”

Section: The Alp As a Possible Therapeuticmentioning

confidence: 99%

“…139 Similar effects were observed in a neurotoxin MPTP-induced PD mouse model. 140 Recently, trehalose has been tested in parallel on rat and nonhuman primate PD models overexpressing A53T α-syn. 143 In both models, trehalose prevented the development of striatal dopamine loss and behavioral deficits.…”

Section: The Alp As a Possible Therapeuticmentioning

confidence: 99%

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The Vicious Cycle Between α‐Synuclein Aggregation and Autophagic‐Lysosomal Dysfunction

et al. 2019

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The accumulation and misfolding of α‐synuclein (α‐syn) represent the main pathological hallmark of PD. Overexpression of α‐syn and failure of cellular protein degradation systems play a major role in α‐syn aggregation. The discovery of PD‐associated genes related to the autophagic‐lysosomal pathway, such as VPS35, LRRK2, GBA1, SMPD1, GALC, ASAH1, SCARB2, CTSD, CTSB, and GLA, confirms the involvement of cellular clearance systems dysfunction in PD pathogenesis. Of importance, lysosomal enzyme activity is altered both in genetic and sporadic PD. Decreased lysosomal enzymes activities were measured in the same brain regions where α‐syn accumulates, suggesting that a crosstalk between α‐syn aggregation and autophagic‐lysosomal impairment may exist. The understanding of autophagic‐lysosomal pathway dysfunctions’ role in the pathogenesis and progression of synucleinopathies opened new perspectives for novel possible therapeutic strategies. In this article, the evidences and mechanisms of the reciprocal relation between autophagic‐lysosomal pathway impairment and misfolded α‐syn aggregation and propagation are reviewed, together with the most promising compounds targeting autophagic‐lysosomal pathway restoration as a disease‐modifying strategy for PD treatment. © 2019 International Parkinson and Movement Disorder Society

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Section: The Alp As a Possible Therapeutic Target For Pdmentioning

confidence: 62%

Section: The Alp As a Possible Therapeutic Target For Pdmentioning

confidence: 99%

Section: The Alp As a Possible Therapeuticmentioning

confidence: 99%

Section: The Alp As a Possible Therapeuticmentioning

confidence: 99%

See 2 more Smart Citations

The Vicious Cycle Between α‐Synuclein Aggregation and Autophagic‐Lysosomal Dysfunction

et al. 2019

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“…Finally, combined approaches have been developed to enhance MA through both mTOR-dependent and mTOR-independent pathway in order to improve α-syn clearance. A synergistic effect using Rapamycin and Trehalose treatment on dopaminergic neuroprotection was shown in the MPTP mouse model of PD through active enhancement of MA process [359].…”

Section: Activation Of Ma and Lysosomal Functionmentioning

confidence: 96%

Targeting α-Synuclein for PD Therapeutics: A Pursuit on All Fronts

et al. 2020

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Parkinson’s Disease (PD) is characterized both by the loss of dopaminergic neurons in the substantia nigra and the presence of cytoplasmic inclusions called Lewy Bodies. These Lewy Bodies contain the aggregated α-synuclein (α-syn) protein, which has been shown to be able to propagate from cell to cell and throughout different regions in the brain. Due to its central role in the pathology and the lack of a curative treatment for PD, an increasing number of studies have aimed at targeting this protein for therapeutics. Here, we reviewed and discussed the many different approaches that have been studied to inhibit α-syn accumulation via direct and indirect targeting. These analyses have led to the generation of multiple clinical trials that are either completed or currently active. These clinical trials and the current preclinical studies must still face obstacles ahead, but give hope of finding a therapy for PD with time.

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Trehalose alleviates doxorubicin‐induced cardiotoxicity in female Swiss albino mice by suppression of oxidative stress and autophagy

Abu-Khudir

Ibrahim

Shams

et al. 2021

J Biochem & Molecular Tox

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Clinically, the use of doxorubicin (DOX) is limited due to DOX-induced cardiotoxicity (DIC). The current study aimed to evaluate the cardioprotective effect of trehalose (TRE) against DIC in a female Swiss albino mouse model. Mice were divided into five experimental groups: Gp. I: saline control group (200 μl/mouse saline three times per week for 3 weeks day after day), Gp. II: DOX-treated group (2 mg/kg body weight three times per week for 3 weeks day after day), Gp. III: TRE group (200 μg/mouse three times per week for 3 weeks day after day), Gp. IV: DOX + TRE cotreatment group (animals were coadministered with DOX and TRE as in Gp. II and III, respectively), and Gp. V: DOX + TRE posttreatment group (animals were treated with DOX as in Gp. II followed by treatment with TRE as in Gp. III). DOX-treated mice showed significant elevation in cardiac injury biomarkers (lactate dehydrogenase, creatine kinase isoenzyme-MB, and cardiac troponin I), cardiac oxidative stress (OS) markers (malondialdehyde and myeloperoxidase), and cardiac levels of autophagyrelated protein 5. Moreover, DOX significantly reduced the levels of total antioxidant capacity and activities of catalase and glutathione S-transferase.In contrast, TRE treatment of DOX-administered mice significantly improved almost all of the above-mentioned assessed parameters. Furthermore, histopathological changes of cardiac tissues observed in mice treated with TRE in combination with DOX were significantly improved as compared to DOXtreated animals. Taken together, the present study provides evidence that TRE has cardioprotective effects against DIC, which is likely mediated via suppression of OS and autophagy.

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Therapeutic activation of autophagy by combined treatment with rapamycin and trehalose in a mouse MPTP-induced model of Parkinson's disease

Cited by 74 publications

References 67 publications

The Vicious Cycle Between α‐Synuclein Aggregation and Autophagic‐Lysosomal Dysfunction

The Vicious Cycle Between α‐Synuclein Aggregation and Autophagic‐Lysosomal Dysfunction

Targeting α-Synuclein for PD Therapeutics: A Pursuit on All Fronts

Trehalose alleviates doxorubicin‐induced cardiotoxicity in female Swiss albino mice by suppression of oxidative stress and autophagy

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