Promising disease-modifying therapies for Parkinson’s disease

Dawson, Valina L.; Dawson, Ted M.

doi:10.1126/scitranslmed.aba1659

Cited by 52 publications

(55 citation statements)

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“…The major ndings of this paper are the observation that celastrol protects against the loss of dopaminergic neurons and maintains the nigro-striatal system function, and attenuates the motor de cit in both MPTP-induced and human α-synuclein overexpression-induced PD mouse model. It's well established that the hallmark of PD is the loss of dopaminergic neurons [6,8,39,62,63]. Recently, the glia (astrocyte and microglia) mediated neuroin ammation has been found to play critical roles in the pathologies of PD [38][39][40].…”

Section: Discussionmentioning

confidence: 99%

“…Recently, the glia (astrocyte and microglia) mediated neuroin ammation has been found to play critical roles in the pathologies of PD [38][39][40]. It's recently reported that GLP-1 receptor agonists (exenatide, NLY01) may prevent pathological microglial activation and secretion of the proin ammatory cytokines (TNFα, IL1) to prevents the conversion of resting astrocytes to the toxic and reactive A1 phenotype; and Amylin Pharmaceuticals' and AstraZeneca's GLP-1 receptor agonist exenatide and Novo Nordisk's Liraglutide, Sano 's Lixisenatide, and Neuraly's NLY-01 are in placebo-controlled phase 2 trial in patients with moderate PD [8,48,64]. These reports show that both the dopaminergic and neuroin ammation-targeting therapies may contribute to the development of PD treatments.…”

Section: Discussionmentioning

confidence: 99%

“…To date, there's no disease-modifying agents for the treatment of PD [8], and recent genetic gene therapies failed to show favorable anti-neurodegenerative effect [9]. Therefore, development of the neuroprotective agents to halt, delay or prevent the progression of PD remains a high priority.…”

Section: Discussionmentioning

confidence: 99%

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The Nrf2-NLRP3-Caspase1 axis mediates the neuroprotective effects of Celastrol in Parkinson's disease

Zhang

Zhao

Wang

et al. 2020

Preprint

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Background: Parkinson’s disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNc), accompanied by chronic neuroinflammation, oxidative stress, and widespread accumulation of α-synuclein. Celastrol (Cel), a potent anti-inflammatory and anti-oxidative pentacyclic triterpene, has emerged as a neuroprotective agent. However, the mechanisms by which celastrol is neuroprotective in PD has not yet been elucidated. Methods: The MPTP and AAV-mediated human wild-type α-syn overexpression within SNc induced PD mouse models were employed in this study. By using multiple genetically modified mice (Nrf2-KO, NLRP3-KO and Caspase1-KO), we identified that celastrol effectively inhibited the NLRP3 inflammasome activation, mitigated motor deficits and nigrostriatal dopaminergic degeneration through Nrf2-NLRP3-Caspase1 pathway. Results: Here we show that celastrol protected against the loss of dopaminergic neurons, mitigated the neuroinflammation and motor deficits in both MPTP-induced PD mouse model and AAV-mediated human α-syn overexpression PD model. Whole-genome deep sequencing analysis reveals that Nrf2, NLRP3 and Caspase1 in SNc may be associated with the neuroprotective actions of celastrol in PD. Conclusions: These findings suggest that Nrf2-NLRP3-Caspase1 axis may be a key target of celastrol in PD treatment, and highlight the favorable properties linked to neuroprotection of celastrol, making celastrol as a promising disease-modifying agent for PD.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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The Nrf2-NLRP3-Caspase1 axis mediates the neuroprotective effects of Celastrol in Parkinson's disease

Zhang

Zhao

Wang

et al. 2020

Preprint

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“…Although mechanistic studies have made some important discoveries, there is still no cure for PD. However, breaking through a therapeutic approach that can modify disease progression is very limited to pilot clinical studies or animal experiments [6,7]. In this context, dopamine replacement remains the gold standard to relieve motor symptoms [6].…”

mentioning

confidence: 99%

“…However, breaking through a therapeutic approach that can modify disease progression is very limited to pilot clinical studies or animal experiments [6,7]. In this context, dopamine replacement remains the gold standard to relieve motor symptoms [6]. In the past few years, a non-dopaminergic drug that targets the adenosine A2A receptor has been approved as an adjunct therapy for PD [8,9].…”

mentioning

confidence: 99%

Emerging novel approaches to drug research and diagnosis of Parkinson’s disease

Zhen

Chu

2020

Acta Pharmacol Sin

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Speech Biomarkers in Rapid Eye Movement Sleep Behavior Disorder and Parkinson Disease

Rusz

Hlavnička

Novotný

et al. 2021

Annals of Neurology

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This multilanguage study used simple speech recording and high-end pattern analysis to provide sensitive and reliable noninvasive biomarkers of prodromal versus manifest α-synucleinopathy in patients with idiopathic rapid eye movement sleep behavior disorder (iRBD) and early-stage Parkinson disease (PD). Methods: We performed a multicenter study across the Czech, English, German, French, and Italian languages at 7 centers in Europe and North America. A total of 448 participants (337 males), including 150 with iRBD (mean duration of iRBD across language groups 0.5-3.4 years), 149 with PD (mean duration of disease across language groups 1.7-2.5 years), and 149 healthy controls were recorded; 350 of the participants completed the 12-month follow-up. We developed a fully automated acoustic quantitative assessment approach for the 7 distinctive patterns of hypokinetic dysarthria. Results: No differences in language that impacted clinical parkinsonian phenotypes were found. Compared with the controls, we found significant abnormalities of an overall acoustic speech severity measure via composite dysarthria index for both iRBD (p = 0.002) and PD (p < 0.001). However, only PD (p < 0.001) was perceptually distinct in a blinded subjective analysis. We found significant group differences between PD and controls for monopitch (p < 0.001), prolonged pauses (p < 0.001), and imprecise consonants (p = 0.03); only monopitch was able to differentiate iRBD patients from controls (p = 0.004). At the 12-month follow-up, a slight progression of overall acoustic speech impairment was noted for the iRBD (p = 0.04) and PD (p = 0.03) groups. Interpretation: Automated speech analysis might provide a useful additional biomarker of parkinsonism for the assessment of disease progression and therapeutic interventions.

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Promising disease-modifying therapies for Parkinson’s disease

Abstract: To date, there is no disease-modifying therapy for Parkinson’s disease; however, promising new agents have advanced into clinical trials.

Cited by 52 publications

References 10 publications

The Nrf2-NLRP3-Caspase1 axis mediates the neuroprotective effects of Celastrol in Parkinson's disease

The Nrf2-NLRP3-Caspase1 axis mediates the neuroprotective effects of Celastrol in Parkinson's disease

Emerging novel approaches to drug research and diagnosis of Parkinson’s disease

Speech Biomarkers in Rapid Eye Movement Sleep Behavior Disorder and Parkinson Disease

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