Old and new challenges in Parkinson's disease therapeutics

Pires, Ana O.; Teixeira, Fábio G.; Mendes-Pinheiro, Bárbara; Serra, S.; Sousa, Nuno; Salgado, António J.

doi:10.1016/j.pneurobio.2017.04.006

Cited by 70 publications

(61 citation statements)

References 302 publications

(436 reference statements)

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“…MSC-based therapies have shown promising results for the treatment of CNS-related diseases such as SCI [21][22][23], TBI [24,25], IS [26][27][28], and PD [20]. Although the mechanism of action remains to be completely understood.…”

Section: Cell Secretome-based Therapymentioning

confidence: 99%

“…PD is a neurodegenerative disorder characterized by the progressive degeneration of dopaminergic neurons. As a result, patients develop motor complications such as rigidity, bradykinesia, and postural instability [20]. In PD, cell replacement therapies could be an attractive strategy for replacing the progressive loss of nigral dopaminergic neurons.…”

Section: Parkinson's Disease (Pd)mentioning

confidence: 99%

“…Currently, a growing body of evidence points to the importance of the paracrine signaling as a mechanism to support recovery by the transplanted cells. For instance, it has been demonstrated that the beneficial effects observed upon mesenchymal stem cell (MSC) grafts on the injured CNS were mainly due to secreted factors rather than cellular engraftment, in models of spinal cord injury [14] and Parkinson's disease [17], as reviewed elsewhere [18][19][20]. This new paradigm regarding the paracrine action instead of cellular replacement or cell-cell interrelation has originated a new possible therapeutic opportunity, using the cellular secretome to tackle diverse pathologies.…”

Section: Introductionmentioning

confidence: 99%

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Cell Secretome: Basic Insights and Therapeutic Opportunities for CNS Disorders

et al. 2020

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Transplantation of stem cells, in particular mesenchymal stem cells (MSCs), stands as a promising therapy for trauma, stroke or neurodegenerative conditions such as spinal cord or traumatic brain injuries (SCI or TBI), ischemic stroke (IS), or Parkinson’s disease (PD). Over the last few years, cell transplantation-based approaches have started to focus on the use of cell byproducts, with a strong emphasis on cell secretome. Having this in mind, the present review discusses the current state of the art of secretome-based therapy applications in different central nervous system (CNS) pathologies. For this purpose, the following topics are discussed: (1) What are the main cell secretome sources, composition, and associated collection techniques; (2) Possible differences of the therapeutic potential of the protein and vesicular fraction of the secretome; and (3) Impact of the cell secretome on CNS-related problems such as SCI, TBI, IS, and PD. With this, we aim to clarify some of the main questions that currently exist in the field of secretome-based therapies and consequently gain new knowledge that may help in the clinical application of secretome in CNS disorders.

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Section: Cell Secretome-based Therapymentioning

confidence: 99%

Section: Parkinson's Disease (Pd)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cell Secretome: Basic Insights and Therapeutic Opportunities for CNS Disorders

et al. 2020

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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%

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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“…44,45 To date, out of these gene therapy clinical trials, only the vector with the gene encoding for increased production of glutamic acid decarboxylase has demonstrated beneficial motor function. 46 Therefore, although gene therapy might be a promising strategy, development of an effective treatment requires more research.…”

Section: Historic and Current Treatments For Pd Evolution Of Care: Phmentioning

confidence: 99%

Emerging regenerative medicine and tissue engineering strategies for Parkinson’s disease

Harris

Burrell

Struzyna

et al. 2020

npj Parkinsons Dis.

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Parkinson’s disease (PD) is the second most common progressive neurodegenerative disease, affecting 1–2% of people over 65. The classic motor symptoms of PD result from selective degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc), resulting in a loss of their long axonal projections to the striatum. Current treatment strategies such as dopamine replacement and deep brain stimulation (DBS) can only minimize the symptoms of nigrostriatal degeneration, not directly replace the lost pathway. Regenerative medicine-based solutions are being aggressively pursued with the goal of restoring dopamine levels in the striatum, with several emerging techniques attempting to reconstruct the entire nigrostriatal pathway—a key goal to recreate feedback pathways to ensure proper dopamine regulation. Although many pharmacological, genetic, and optogenetic treatments are being developed, this article focuses on the evolution of transplant therapies for the treatment of PD, including fetal grafts, cell-based implants, and more recent tissue-engineered constructs. Attention is given to cell/tissue sources, efficacy to date, and future challenges that must be overcome to enable robust translation into clinical use. Emerging regenerative medicine therapies are being developed using neurons derived from autologous stem cells, enabling the construction of patient-specific constructs tailored to their particular extent of degeneration. In the upcoming era of restorative neurosurgery, such constructs may directly replace SNpc neurons, restore axon-based dopaminergic inputs to the striatum, and ameliorate motor deficits. These solutions may provide a transformative and scalable solution to permanently replace lost neuroanatomy and improve the lives of millions of people afflicted by PD.

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Old and new challenges in Parkinson's disease therapeutics

Cited by 70 publications

References 302 publications

Cell Secretome: Basic Insights and Therapeutic Opportunities for CNS Disorders

Cell Secretome: Basic Insights and Therapeutic Opportunities for CNS Disorders

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

Emerging regenerative medicine and tissue engineering strategies for Parkinson’s disease

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