Neurogenesis in Substantia Nigra of Parkinsonian Brains?

Arias-Carrión, Óscar; Yamada, Elizabeth Sumi; Freundlieb, Nils; Djufri, Miriam; Maurer, Lukas; Hermanns, Guido; Ipach, Bastian; Chiu, Wei‐Hua; Steiner, Corinna; Oertel, Wolfgang H.; Höglinger, Günter U.

doi:10.1007/978-3-211-92660-4_23

Cited by 23 publications

(21 citation statements)

References 49 publications

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“…Recent studies have suggested that NSC proliferation and neuronal differentiation are diminished in neurodegenerative diseases such as PD and that impaired neurogenesis contributes to disease progression [16,18,[34][35][36]. In various animal PD models, lesions of the SN stimulate the proliferation of NSCs or progenitor cells in the Fig.…”

Section: Discussionmentioning

confidence: 97%

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1,25-dyhydroxyvitamin D3 Attenuates l-DOPA-Induced Neurotoxicity in Neural Stem Cells

et al. 2014

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The neurotoxicity of levodopa (L-DOPA) on neural stem cells (NSCs) and treatment strategies to protect NSCs from this neurotoxicity remain to be elucidated. Recently, an active form of vitamin D3 has been reported to display neuroprotective properties. Therefore, we investigated the protective effect of 1,25-dyhydroxyvitamin D3 (calcitriol) on L-DOPA-induced NSC injury. We measured cell viability via the cell counting kit-8 (CCK-8) and lactate dehydrogenase (LDH) assays and Annexin V/PI staining followed by flow cytometry, cell proliferation using the BrdU and colony-forming unit (CFU) assays, cell differentiation via immunocytochemistry, the levels of free radicals via 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) staining, apoptosis via DAPI and TUNEL staining, and intracellular signaling protein expression via Western blot. Antibody microarrays were also employed to detect changes in the expression of prosurvival- and death-related proteins. Treatment of NSCs with L-DOPA reduced their viability and proliferation. This treatment also increased the levels of free radicals and decreased the expression levels of intracellular signaling proteins that are associated with cell survival. However, simultaneous exposure to calcitriol significantly reduced these effects. The calcitriol-mediated protection against L-DOPA toxicity was blocked by the phosphoinositide 3-kinase (PI3K) inhibitor LY294004. L-DOPA also inhibited the expression of Nestin and Ki-67, and co-treatment with calcitriol alleviated these effects. The expression levels of GFAP, DCX, and Tuj1 were not significantly affected by treatment with L-DOPA or calcitriol. Calcitriol protects against L-DOPA-induced NSC injury by promoting prosurvival signaling, including activation of the PI3K pathway, and reducing oxidative stress.

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Section: Discussionmentioning

confidence: 97%

“…Many recent studies have focused on neurogenesis in PD [16,17]. It has been suggested that the substantia nigra (SN) contains a population of neural stem cells (NSCs) and exhibits a basal level of neurogenesis [18].…”

Section: Introductionmentioning

confidence: 99%

1,25-dyhydroxyvitamin D3 Attenuates l-DOPA-Induced Neurotoxicity in Neural Stem Cells

et al. 2014

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“…Attempts have been made to monitor adult DA neurogenesis in the SN directly using various cell lineage tracing methods with conflicting results [13-15]. Lack of compelling evidence for DA neurogenesis has reinforced the prevailing notion that the presence of a toxic stimulus or trophic factor withdrawal induces mature DA neurons to undergo death in a slow and progressive manner.…”

Section: Introductionmentioning

confidence: 99%

“…Lack of compelling evidence for DA neurogenesis has reinforced the prevailing notion that the presence of a toxic stimulus or trophic factor withdrawal induces mature DA neurons to undergo death in a slow and progressive manner. Therefore, while still controversial, the predominate viewpoint is that stem cell replacement of adult DA neurons in the SN does not occur at appreciable levels [13]. The most prevalent method of DA neuron lineage tracing utilizes DNA incorporation of the thymidine analog bromodeoxyuridine (Brd-U) or similar reagent to monitor for cell division of SCs.…”

Section: Introductionmentioning

confidence: 99%

Nestin-positive/SOX2−negative cells mediate adult neurogenesis of nigral dopaminergic neurons in mice

Albright

Stojkovska

Rahman

et al. 2016

Neuroscience Letters

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The primary clinical motor symptoms of Parkinson’s disease (PD) result from loss of dopaminergic (DA) neurons in the substantia nigra (SN). Consequently, neurogenesis of this group of neurons in the adult brain has drawn considerable interest for the purpose of harnessing endogenous neurogenerative potential as well as devising better strategies for stem cell therapy for PD. However, the existence of adult neurogenesis for DA neurons within the SN remains controversial. To overcome technical and design limitations associated with previous studies, our group has developed a novel genetic mouse model for assessing adult nigral DA neurogenesis. This system utilizes transgenic mice that express a tamoxifen-activatable Cre recombinase (CreERT2) under the control of the neuronal progenitor cell promoters nestin or Sox2 leading to suppression of the DA neuron marker tyrosine hydroxylase (TH) via excision of exon 1 by flanking loxP sites in adult animals. This study reports that six months following initiation of a six week treatment with tamoxifen mice with nestin-mediated Th excision displayed a significant reduction in TH+ neurons in the SN. This finding indicates that nestin-expressing cells regenerate DA neurons within the SN of adult animals. Interestingly, no reduction was observed in TH+ cells following Sox2-mediated Th excision suggesting that a nestin+/SOX2- precursor cell population drives DA neurogenesis in the adult SN. This information represents a substantial leap in current knowledge of adult DA neurogenesis, will enable improved in vitro and in vivo modeling, as well as facilitate the harnessing of this process for therapeutic intervention for PD.

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“…They are either presently at a very early phase of clinical trial, with no clear outcome or they have yielded mixed results after trial. 30 These treatments vary greatly in approach, for example, changing the phenotype of neurons (gene therapy, introduction of viral vectors), 31 introducing trophic factors that increase neuronal survival (eg, glial cell line-derived neurotrophic factor), 32 stimulating neurogenesis, 33 increasing patient exercise programs, 34 and finally, changing dietary intake, for instance, using antioxidants (eg, coenzyme Q10), fish oil, and vitamin E. 35 Light therapy, specifically low-level laser therapy of red to infrared light, is an emerging, putative neuroprotective treatment that, as with the aforementioned treatments, is showing promise at the basic science level. It awaits rigorous exploration at the clinical level for Parkinson's disease, but given its novel mode of application (see below; "What is light therapy and how does it offer neuroprotection"), we are very hopeful of positive outcomes for many patients.…”

Section: Putative Neuroprotective Treatmentsmentioning

confidence: 99%

The potential of light therapy in Parkinson's disease

Johnstone¹,

Coleman²,

Moro³

et al. 2014

CPT

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Parkinson's disease is a movement disorder with cardinal signs of resting tremor, akinesia, and rigidity. These manifest after a progressive death of many dopaminergic neurons of the midbrain. Unfortunately, the progression of this neuronal death has proved difficult to slow and impossible to reverse despite an intense search for the specific causes and for treatments that address the causes. There is a corresponding need to develop approaches that regulate the self-repair mechanisms of neurons, independent of the specific causes of the damage that leads to their death. Red to infrared light therapy (λ=600-1,070 nm) is emerging as an effective, repair-oriented therapy that is capable of stabilizing dying neurons. Initially a space-age anecdote, light therapy has become a treatment for tissue stressed by the known causes of age-related diseases: hypoxia, toxic environments, and mitochondrial dysfunction. Here we focus on several issues relating to the use of light therapy for Parkinson's disease: 1) What is the evidence that it is neuroprotective? We consider the basic science and clinical evidence; 2) What are the mechanisms of neuroprotection? We suggest a primary mechanism acting directly on the neuron's mitochondria (direct effect) as well as a secondary, supportive mechanism acting indirectly through systemic systems (indirect effect); 3) Could this be effective in humans? We discuss the pros and cons of this treatment in humans, including the development of a new surgical method of delivery; and 4) What are the advantages of using light therapy? We explore the features that make this therapy a promising potential treatment. In summary, early evidence indicates that light regulates specific neuronal functions and is neuroprotective in animal models of Parkinson's disease. The stage is set for detailed and rigorous explorations into its use on Parkinson's disease patients, in particular, whether light slows the disease progression rather than simply mitigating signs.

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Neurogenesis in Substantia Nigra of Parkinsonian Brains?

Cited by 23 publications

References 49 publications

1,25-dyhydroxyvitamin D3 Attenuates l-DOPA-Induced Neurotoxicity in Neural Stem Cells

1,25-dyhydroxyvitamin D3 Attenuates l-DOPA-Induced Neurotoxicity in Neural Stem Cells

Nestin-positive/SOX2−negative cells mediate adult neurogenesis of nigral dopaminergic neurons in mice

The potential of light therapy in Parkinson's disease

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Neurogenesis in Substantia Nigra of Parkinsonian Brains?

Cited by 23 publications

References 49 publications

1,25-dyhydroxyvitamin D3 Attenuates l-DOPA-Induced Neurotoxicity in Neural Stem Cells

1,25-dyhydroxyvitamin D3 Attenuates l-DOPA-Induced Neurotoxicity in Neural Stem Cells

Nestin-positive/SOX2−negative cells mediate adult neurogenesis of nigral dopaminergic neurons in mice

The potential of light therapy in Parkinson&#39;s disease

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The potential of light therapy in Parkinson's disease