Melatonin Attenuates Neuroinflammation by Down-Regulating NLRP3 Inflammasome via a SIRT1-Dependent Pathway in MPTP-Induced Models of Parkinson’s Disease

Zheng, Ran; Ruan, Yang; Yan, Yiqun; Lin, Zhi‐Hao; Xue, Nai‐Jia; Yan, Yaping; Tian, Jun; Yin, Xinzhen; Pu, Jiali; Zhang, Baorong

doi:10.2147/jir.s317672

Cited by 34 publications

(22 citation statements)

References 34 publications

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“…In 6-OHDA-induced rats, Dex could improve motor symptoms, inhibit inflammation, and increase the level of DA in the striatum [ 12 ]. In our study, we found that after 5 days of continuous intraperitoneal injection of MPTP 30 mg/kg, which is consistent with previous models of PD [ 39 ], the behavioral disorders were most obvious on the 3rd day, so we chose the 3rd day as the time point for subsequent observation of various indicators. We found that Dex pretreatment could significantly improve movement disorders in PD which is also consistent with previous research [ 12 ].…”

Section: Discussionsupporting

confidence: 88%

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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Section: Discussionsupporting

confidence: 88%

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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“…To identify the role of SIRT1 in baicalein-mediated mitochondrial autophagy, we silenced SIRT1 in PD rats and treated PD rats with baicalein and discovered that SIRT1 knockdown partially averted the function of baicalein on improving mitochondrial function, elevating LC3-II/LC3-I, and lowering p62. Consistently, knockdown of SIRT1 averted melatonin-mediated attenuation of the NLRP3 inflammasome activation and aggravated PD ( 58 ). In brief, SIRT1 silencing averted the property of baicalein on promoting mitochondrial autophagy and improving mitochondrial disorder.…”

Section: Discussionmentioning

confidence: 83%

Baicalein Induces Mitochondrial Autophagy to Prevent Parkinson's Disease in Rats via miR-30b and the SIRT1/AMPK/mTOR Pathway

et al. 2022

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Parkinson's disease (PD) is a prevailing neurodegenerative disorder. Baicalein has neuroprotective effects on PD animals, but its mechanism is not clarified. We explored baicalein effects on PD rats. PD rat models were established by injecting 6-hydroxydopamine into the striatum of substantia nigra on the left side of the rat brain and treated with baicalein. Dopamine (DA) content, neuronal apoptosis, neuronal injury, neuronal mitochondria, and autophagy were assessed. Baicalein-treated PD rats were treated with autophagy inhibitor 3-methyladenine to identify the role of autophagy in PD. PD rats were injected with AgomiR-30b-5p or sh-SIRT1 plasmids and treated with baicalein. PD rats elicited decreased neurological score and DA secretion of the striatum, increased neuronal apoptosis, and injury, and reduced number of mitochondria and autophagy, whereas baicalein alleviated neuronal injury and partly recovered mitochondrial dysfunction, 3-methyladenine inhibited the protection of baicalein. miR-30b-5p was elevated and SIRT1 was diminished in PD rats and inhibited by baicalein. miR-30b-5p targeted SIRT1. miR-30b-5p overexpression or SIRT1 silencing annulled the protection of baicalein. The phosphorylation level of AMPK in the substantia nigra of PD rats was decreased and mTOR was increased, whereas baicalein annulled these trends. Briefly, baicalein activated mitochondrial autophagy via miR-30b-5p and the SIRT1/AMPK/mTOR pathway, thus protecting PD rats.

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“…As a cocktail, EPO and MLT may additively and/or synergistically drive pathways to augment sustained neuro-immunomodulation and promote microenvironmental homeostasis. Notably, levels of the nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylase sirtuin 1 (silent mating-type information regulation 2 homolog 1 [SIR], SIRT1) are elevated by both EPO [75,76] and MLT [77][78][79] (Fig. 5).…”

Section: Discussionmentioning

confidence: 99%

Infantile Cocktail of Erythropoietin and Melatonin Restores Gait in Adult Rats with Preterm Brain Injury

et al. 2022

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Cerebral palsy (CP) is the most common cause of physical disability for children worldwide. Many infants and toddlers are not diagnosed with CP until they fail to achieve obvious motor milestones. Currently, there are no effective pharmacologic interventions available for infants and toddlers to substantially improve their trajectory of neurodevelopment. Because children with CP from preterm birth also exhibit a sustained immune system hyper-reactivity, we hypothesized that neuro-immunomodulation with a regimen of repurposed endogenous neurorestorative medications, erythropoietin (EPO) and melatonin (MLT) could improve this trajectory. Thus, we administered EPO+MLT to rats with CP during human infant-toddler equivalency to determine whether we could influence gait patterns in mature animals. After a prenatal injury on embryonic day 18 (E18) that mimics chorioamnionitis at ~25 weeks human gestation, rat pups were born and raised with their dam. Beginning on postnatal day 15 (P15), equivalent to human infant ~1 year, rats were randomized to receive either a regimen of EPO+MLT or vehicle (sterile saline) through P20. Gait was assessed in young adult rats at P30 using computerized digital gait analyses including videography on a treadmill. Results indicate that gait metrics of young adult rats treated with an infantile cocktail of EPO+MLT were restored compared to vehicle-treated rats (p<0.05), and similar to sham controls. These results provide reassuring evidence that pharmacological interventions may be beneficial to infants and toddlers who are diagnosed with CP well after the traditional neonatal window of intervention.

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Melatonin Attenuates Neuroinflammation by Down-Regulating NLRP3 Inflammasome via a SIRT1-Dependent Pathway in MPTP-Induced Models of Parkinson’s Disease

Cited by 34 publications

References 34 publications

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

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

Baicalein Induces Mitochondrial Autophagy to Prevent Parkinson's Disease in Rats via miR-30b and the SIRT1/AMPK/mTOR Pathway

Infantile Cocktail of Erythropoietin and Melatonin Restores Gait in Adult Rats with Preterm Brain Injury

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