Glucagon-Like Peptide-1 Receptor Agonist Ameliorates 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine (MPTP) Neurotoxicity Through Enhancing Mitophagy Flux and Reducing α-Synuclein and Oxidative Stress

Lin, Tsu-Kung; Lin, Kai-Jung; Lin, Hung‐Yu; Lin, Kai-Lieh; Lan, Min‐Yu; Wang, Pei‐Wen; Wang, Tzu‐Jou; Wang, Feng‐Sheng; Tsai, Po-Chin; Liou, Chia‐Wei; Chuang, Jiin‐Haur

doi:10.3389/fnmol.2021.697440

Cited by 33 publications

(27 citation statements)

References 67 publications

(84 reference statements)

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“…In this disease, antioxidants were found to decrease ROS levels and their harmful consequences [ 48 ]. Later, when investigating the neuroprotective effects of GLP-1R agonists on PD, researchers found that this is related to its function of antioxidative stress and reduction of mitochondrial dysfunction [ 7 , 23 ]. Consistent with this, our work demonstrates that both semaglutide and liraglutide can reduce ROS levels and increase mitochondrial membrane potential in SH-SY5Y cells exposed to 6-OHDA.…”

Section: Discussionmentioning

confidence: 99%

“…Studies have demonstrated that raising autophagy critically allows the GLP-1 analog to exert a wide range of effects, including neuroprotection [ 20 , 21 ]. In addition, through continuous research, oxidative stress and mitochondrial dysfunction were found to be involved in the pathogenesis of PD by mediating apoptosis [ 22 , 23 ]. Therefore, we suggest that the enhancement of autophagy and antioxidative stress, together with a reduction in mitochondrial dysfunction, are pivotal molecular mechanisms underlying the beneficial outcomes of semaglutide against 6-OHDA-mediated toxicity.…”

Section: Introductionmentioning

confidence: 99%

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Semaglutide Protects against 6-OHDA Toxicity by Enhancing Autophagy and Inhibiting Oxidative Stress

Liu

Zhao

Wang

et al. 2022

Parkinson's Disease

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Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder for which no effective treatment is available. Studies have demonstrated that improving insulin resistance in type 2 diabetes mellitus (T2DM) can benefit patients with PD. In addition, a neuroprotective effect of glucagon-like peptide-1 (GLP-1) receptor agonists was demonstrated in experimental models of PD. In addition, there are some clinical trials to study the neuroprotective effect of GLP-1 analog on PD patients. Semaglutide is a long-acting, once-a-week injection treatment and the only available oral form of GLP-1 analog. In the present study, we treated the human neuroblastoma SH-SY5Y cell line with 6-hydroxydopamine (6-OHDA) as a PD in vitro model to explore the neuroprotective effects and potential mechanisms of semaglutide to protect against PD. Moreover, we compared the effect of semaglutide with liraglutide given at the same dose. We demonstrated that both semaglutide and liraglutide protect against 6-OHDA cytotoxicity by increasing autophagy flux and decreasing oxidative stress as well as mitochondrial dysfunction in SH-SY5Y cells. Moreover, by comparing the neuroprotective effects of semaglutide and liraglutide on PD cell models at the same dose, we found that semaglutide was superior to liraglutide for most parameters measured. Our results indicate that semaglutide, the new long-acting and only oral GLP-1 analog, may be represent a promising treatment for PD.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Semaglutide Protects against 6-OHDA Toxicity by Enhancing Autophagy and Inhibiting Oxidative Stress

Liu

Zhao

Wang

et al. 2022

Parkinson's Disease

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“…The other oral hypoglycemics, DPP-4 inhibitors (or gliptins) can enhance the bioavailability of GLP-1 for the purpose of increasing incretin levels. For example, the DPP4 inhibitor sitagliptin could ameliorate rotenone-induced decrease of dopamine production and improve motor function in a rotenone PD rat model, as discussed above [ 137 ]. Supporting this, treatment with DPP4 inhibitors confer beneficial effects on the baseline nigrostriatal dopamine degeneration and long-term motor outcomes in diabetic patients with PD and may extend its role into non-diabetic patients with PD [ 138 ].…”

Section: The Linkage Between Dm and Pdmentioning

confidence: 99%

Two Birds One Stone: The Neuroprotective Effect of Antidiabetic Agents on Parkinson Disease—Focus on Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors

et al. 2021

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Parkinson’s disease (PD) is the second most common neurodegenerative disease after Alzheimer’s disease affecting more than 1% of the population over 65 years old. The etiology of the disease is unknown and there are only symptomatic managements available with no known disease-modifying treatment. Aging, genes, and environmental factors contribute to PD development and key players involved in the pathophysiology of the disease include oxidative stress, mitochondrial dysfunction, autophagic–lysosomal imbalance, and neuroinflammation. Recent epidemiology studies have shown that type-2 diabetes (T2DM) not only increased the risk for PD, but also is associated with PD clinical severity. A higher rate of insulin resistance has been reported in PD patients and is suggested to be a pathologic driver in this disease. Oral diabetic drugs including sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and dipeptidyl peptidase-4 (DPP-4) inhibitors have been shown to provide neuroprotective effects in both PD patients and experimental models; additionally, antidiabetic drugs have been demonstrated to lower incidence rates of PD in DM patients. Among these, the most recently developed drugs, SGLT2 inhibitors may provide neuroprotective effects through improving mitochondrial function and antioxidative effects. In this article, we will discuss the involvement of mitochondrial-related oxidative stress in the development of PD and potential benefits provided by antidiabetic agents especially focusing on sglt2 inhibitors.

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“…Aberrant mitochondrial accumulation occurs in neuronal autophagosomes of PD patients [ 19 – 21 ]. Defective mitophagy flux and mitochondrial damage have also been demonstrated in PD models in vivo and in vitro [ 22 , 23 ]. Therefore, enhancing mitophagy may be a potential strategy for the treatment of PD [ 24 , 25 ].…”

Section: Introductionmentioning

confidence: 99%

Dexmedetomidine Can Enhance PINK1/Parkin-Mediated Mitophagy in MPTP-Induced PD Mice Model by Activating AMPK

Chen

Liu

et al. 2022

Oxidative Medicine and Cellular Longevity

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Parkinson’s disease (PD) is a common neurodegenerative disease characterized by the degeneration of dopaminergic (DA) neurons in the substantia nigra (SN). Our previous study has shown that dexmedetomidine (Dex) can protect mitochondrial function and reduce apoptosis in MPP+-induced SH-SY5Y cells. Evidences have shown that mitophagy is related to the development of PD. In this study, we investigated whether Dex can enhance mitophagy in MPTP-induced mice to play a neuroprotective effect. In our experiment, mice were injected with MPTP 30 mg/kg intraperitoneally for 5 consecutive days to establish a PD subacute model. Dex (30, 50, and 100 μg/kg) was injected intraperitoneally 30 minutes before each injection of MPTP, respectively. Our results showed that Dex (50 μg/kg) most significantly attenuated MPTP-induced motor dysfunction and restored TH-positive neurons in the SN, increased the expression of the antiapoptotic protein Bcl-2, and decreased the expression of apoptotic proteins cleaved casepase3, cleaved casepase9, and Bax. Moreover, Dex increased the activity of mitochondrial Complexes I-IV and decreased the level of oxidative stress, manifesting as decreased MDA levels and increased SOD and GSH-PX levels. Besides, under transmission electron microscopy, Dex increased the mitophagosome which is an autophagosome with a mitochondrion-like structure inside under the electron microscope. In addition, Dex could also increase the expression of mitophagy-related proteins p-AMPK, LC3II/I, PINK1, and Parkin and decrease P62. However, after using Compound C (CC, 10 mg/kg, AMPK inhibitor), the effects of Dex on increasing PINK1/Parkin-induced mitophagy and neuroprotection were attenuated. In conclusion, Dex may improve mitochondrial function by activating AMPK to enhance PINK1/Parkin-induced mitophagy, thereby protecting dopaminergic neurons.

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Glucagon-Like Peptide-1 Receptor Agonist Ameliorates 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine (MPTP) Neurotoxicity Through Enhancing Mitophagy Flux and Reducing α-Synuclein and Oxidative Stress

Cited by 33 publications

References 67 publications

Semaglutide Protects against 6-OHDA Toxicity by Enhancing Autophagy and Inhibiting Oxidative Stress

Semaglutide Protects against 6-OHDA Toxicity by Enhancing Autophagy and Inhibiting Oxidative Stress

Two Birds One Stone: The Neuroprotective Effect of Antidiabetic Agents on Parkinson Disease—Focus on Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors

Dexmedetomidine Can Enhance PINK1/Parkin-Mediated Mitophagy in MPTP-Induced PD Mice Model by Activating AMPK

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