Faculty Opinions recommendation of Induction of functional dopamine neurons from human astrocytes in vitro and mouse astrocytes in a Parkinson's disease model.

Cytokinins are adenine-based phytohormones that regulate key processes in plants, such as cell division and differentiation, root and shoot growth, apical dominance, branching, and seed germination. In preliminary studies, they have also shown protective activities against human neurodegenerative diseases. To extend knowledge of the protection (protective activity) they offer, we investigated activities of natural cytokinins against salsolinol (SAL)-induced toxicity (a Parkinson’s disease model) and glutamate (Glu)-induced death of neuron-like dopaminergic SH-SY5Y cells. We found that kinetin-3-glucoside, cis-zeatin riboside, and N6-isopentenyladenosine were active in the SAL-induced PD model. In addition, trans-, cis-zeatin, and kinetin along with the iron chelator deferoxamine (DFO) and the necroptosis inhibitor necrostatin 1 (NEC-1) significantly reduced cell death rates in the Glu-induced model. Lactate dehydrogenase assays revealed that the cytokinins provided lower neuroprotective activity than DFO and NEC-1. Moreover, they reduced apoptotic caspase-3/7 activities less strongly than DFO. However, the cytokinins had very similar effects to DFO and NEC-1 on superoxide radical production. Overall, they showed protective activity in the SAL-induced model of parkinsonian neuronal cell death and Glu-induced model of oxidative damage mainly by reduction of oxidative stress.

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Simvastatin Prevents Neurodegeneration in the MPTP Mouse Model of Parkinson’s Disease via Inhibition of A1 Reactive Astrocytes

NeuroImmunoModulation ◽

10.1159/000513678 ◽

2021 ◽

pp. 1-8

Author(s):

Ren-Wei Du ◽

Wen-Guang Bu

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Mouse Model ◽

Underlying Mechanism ◽

Reactive Astrocytes ◽

Dopamine Neurons ◽

Neuron Death ◽

Neurologic Disorders

Emerging evidence indicates that A1 reactive astrocytes play crucial roles in the pathogenesis of Parkinson’s disease (PD). Thus, development of agents that could inhibit the formation of A1 reactive astrocytes could be used to treat PD. Simvastatin has been touted as a potential neuroprotective agent for neurologic disorders such as PD, but the specific underlying mechanism remains unclear. The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD and primary astrocytes/neurons were prepared to investigate the effects of simvastatin on PD and its underlying mechanisms in vitro and in vivo. We show that simvastatin protects against the loss of dopamine neurons and behavioral deficits in the MPTP mouse model of PD. We also found that simvastatin suppressed the expression of A1 astrocytic specific markers in vivo and in vitro. In addition, simvastatin alleviated neuron death induced by A1 astrocytes. Our findings reveal that simvastatin is neuroprotective via the prevention of conversion of astrocytes to an A1 neurotoxic phenotype. In light of simvastatin favorable properties, it should be evaluated in the treatment of PD and related neurologic disorders characterized by A1 reactive astrocytes.

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Loss of SATB1 Induces a p21 Dependent Cellular Senescence Phenotype in Dopaminergic Neurons

10.1101/452243 ◽

2018 ◽

Cited By ~ 1

Author(s):

Markus Riessland ◽

Benjamin Kolisnyk ◽

Tae Wan Kim ◽

Jia Cheng ◽

Jason Ni ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cellular Senescence ◽

Dopaminergic Neurons ◽

Dna Binding Protein ◽

Dopamine Neurons ◽

Human Stem Cell ◽

Transcriptional Program

AbstractCellular senescence is a mechanism used by mitotic cells to prevent uncontrolled cell division. As senescent cells persist in tissues, they cause local inflammation and are harmful to surrounding cells, contributing to aging. Generally, neurodegenerative diseases, such as Parkinson‘s, are disorders of aging. The contribution of cellular senescence to neurodegeneration is still unclear. SATB1 is a DNA binding protein associated with Parkinson’s disease. We report that SATB1 prevents cellular senescence in post-mitotic dopaminergic neurons. Loss of SATB1 causes activation of a cellular senescence transcriptional program in dopamine neurons, both in human stem cell-derived dopaminergic neurons and in mice. We observed phenotypes which are central to cellular senescence in SATB1 knockout dopamine neurons in vitro and in vivo. Moreover, we found that SATB1 directly represses expression of the pro-senescence factor, p21, in dopaminergic neurons. Our data implicate senescence of dopamine neurons as a contributing factor to the pathology of Parkinson’s disease.

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Peptide TFP5/TP5 derived from Cdk5 activator P35 provides neuroprotection in the MPTP model of Parkinson’s disease

Molecular Biology of the Cell ◽

10.1091/mbc.e15-06-0415 ◽

2015 ◽

Vol 26 (24) ◽

pp. 4478-4491 ◽

Cited By ~ 19

Author(s):

BK. Binukumar ◽

Varsha Shukla ◽

Niranjana D. Amin ◽

Philip Grant ◽

M. Bhaskar ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Neurodegenerative Disorder ◽

Neuroprotective Effect ◽

Selective Inhibition ◽

Motor Dysfunction ◽

Dopamine Neurons ◽

Dopamine Depletion ◽

Neuroprotective Effects

Parkinson’s disease (PD) is a chronic neurodegenerative disorder characterized by the loss of dopamine neurons in the substantia nigra, decreased striatal dopamine levels, and consequent extrapyramidal motor dysfunction. Recent evidence indicates that cyclin-dependent kinase 5 (Cdk5) is inappropriately activated in several neurodegenerative conditions, including PD. To date, strategies to specifically inhibit Cdk5 hyperactivity have not been successful without affecting normal Cdk5 activity. Previously we reported that TFP5 peptide has neuroprotective effects in animal models of Alzheimer’s disease. Here we show that TFP5/TP5 selective inhibition of Cdk5/p25 hyperactivation in vivo and in vitro rescues nigrostriatal dopaminergic neurodegeneration induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP/MPP+) in a mouse model of PD. TP5 peptide treatment also blocked dopamine depletion in the striatum and improved gait dysfunction after MPTP administration. The neuroprotective effect of TFP5/TP5 peptide is also associated with marked reduction in neuroinflammation and apoptosis. Here we show selective inhibition of Cdk5/p25 hyperactivation by TFP5/TP5 peptide, which identifies the kinase as a potential therapeutic target to reduce neurodegeneration in Parkinson’s disease.

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Neuroregeneration in Parkinson’s Disease: From Proteins to Small Molecules

Current Neuropharmacology ◽

10.2174/1570159x16666180905094123 ◽

2019 ◽

Vol 17 (3) ◽

pp. 268-287 ◽

Cited By ~ 11

Author(s):

Yulia A. Sidorova ◽

Konstantin P. Volcho ◽

Nariman F. Salakhutdinov

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Small Molecules ◽

Neurodegenerative Disorder ◽

Dopamine Neurons ◽

Current Therapy ◽

Small Molecular Weight ◽

Diagnostic Symptoms ◽

Nigrostriatal Dopamine Neurons

Background: Parkinson’s disease (PD) is the second most common neurodegenerative disorder worldwide, the lifetime risk of developing this disease is 1.5%. Motor diagnostic symptoms of PD are caused by degeneration of nigrostriatal dopamine neurons. There is no cure for PD and current therapy is limited to supportive care that partially alleviates disease signs and symptoms. As diagnostic symptoms of PD result from progressive degeneration of dopamine neurons, drugs restoring these neurons may significantly improve treatment of PD. Method: A literature search was performed using the PubMed, Web of Science and Scopus databases to discuss the progress achieved in the development of neuroregenerative agents for PD. Papers published before early 2018 were taken into account. Results: Here, we review several groups of potential agents capable of protecting and restoring dopamine neurons in cultures or animal models of PD including neurotrophic factors and small molecular weight compounds. Conclusion: Despite the promising results of in vitro and in vivo experiments, none of the found agents have yet shown conclusive neurorestorative properties in PD patients. Meanwhile, a few promising biologicals and small molecules have been identified. Their further clinical development can eventually give rise to disease-modifying drugs for PD. Thus, intensive research in the field is justified.

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