Neuroprotective Effects of Antidepressants via Upregulation of Neurotrophic Factors in the MPTP Model of Parkinson’s Disease

Shadfar, Sina; Kim, Yu-Gyeong; Katila, Nikita; Neupane, Sabita; Ojha, Uttam; Bhurtel, Sunil; Srivastav, Sunil Kumar; Jeong, Gil‐Saeng; Park, Pil-Hoon; Hong, Jin Tae; Choi, Dong‐Young

doi:10.1007/s12035-016-0342-0

Cited by 37 publications

(31 citation statements)

References 40 publications

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“…[40][41][42] In in vivo studies, BDNF potently reduced 6-OHDA-and MPTP-induced death of dopaminergic neurons, 43,44 and BDNFinducing agents protected the nigral dopaminergic neurons. 24,45 In agreement with these findings, we found a role for BDNF in the survival of dopaminergic neurons in the presence of MPTP toxicity.…”

Section: Discussionsupporting

confidence: 90%

“…The number of TH‐positive cells was stereologically counted as described in a previous study . The TH‐fiber density in the striatum was determined using Image J software as described in a previous study …”

Section: Methodsmentioning

confidence: 99%

“…23 The TH-fiber density in the striatum was determined using Image J software as described in a previous study. 24 The extent of gliosis was evaluated as described previously. 23 Briefly, microscopic images of the substantia nigra pars compacta or striatum were captured, and GFAP-or Iba1-immunoreactive cells were analyzed using ImageJ software (http:// rsbweb.nih.gov/ij/).…”

Section: Immunohistochemical Stainingmentioning

confidence: 99%

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Methylene blue protects dopaminergic neurons against MPTP‐induced neurotoxicity by upregulating brain‐derived neurotrophic factor

Bhurtel

Katila

Neupane

et al. 2018

Annals of the New York Academy of Sciences

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The relatively old, yet clinically used, drug methylene blue (MB) is known to possess neuroprotective properties by reducing aggregated proteins, augmenting the antioxidant response, and enhancing mitochondrial function and survival in various models of neurodegenerative diseases. In this study, we aimed to examine the effects of MB in Parkinson's disease (PD) in vivo and in vitro models by using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)/1-methyl-4-phenylpyridinium (MPP ) with a focus on possible effects on induction of neurotrophic factors. Our results indicate that pretreatment with MB significantly attenuated MPTP-induced loss of dopaminergic neurons, glial cell activation, and depletion of dopamine. We also found that MB upregulated brain-derived neurotrophic factor (BDNF) and activated its downstream signaling pathways, suggesting that BDNF might be a contributor to MB-associated neuroprotection. Specific inhibition of the BDNF receptor or extracellular signal-regulated kinase (Erk) reversed the MB-mediated protection against MPP toxicity, thus implying a role for BDNF and the Erk pathway in the neuroprotective effects. Taken together, our data suggest that MB protects neurons from MPTP neurotoxicity via induction of BDNF. Further study to determine whether MB preserves dopaminergic neurons in the brains of PD patients is warranted.

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Section: Discussionsupporting

confidence: 90%

Section: Methodsmentioning

confidence: 99%

Section: Immunohistochemical Stainingmentioning

confidence: 99%

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Methylene blue protects dopaminergic neurons against MPTP‐induced neurotoxicity by upregulating brain‐derived neurotrophic factor

Bhurtel

Katila

Neupane

et al. 2018

Annals of the New York Academy of Sciences

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“…are among the most commonly prescribed pharmacological treatments for FM, and show moderate effectiveness in reducing some FM symptoms (Welsch et al, 2018). While the primary mechanism of action of SNRIs is to normalize concentrations of endogenous monoamine neurotransmitters, which are thought to be imbalanced in FM (Albrecht et al, 2016; Kosek et al, 2016; Russell et al, 1992; Wood, 2008), one potential additional mechanism may be glial modulation, as both duloxetine (Yamashita et al, 2016) and milnacipran (Shadfar et al, 2018) attenuate microglial activation in animal models. Interestingly, among the regions demonstrating neuroimmune activation in our current study were the PCC/precuneus, a core region of the default mode network, where post-treatment changes in pain related activation were specifically related to the degree of positive clinical response to milnacipran treatment in fibromyalgia patients (Jensen et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Brain glial activation in fibromyalgia – A multi-site positron emission tomography investigation

Albrecht

Forsberg

Sandström

et al. 2019

Brain, Behavior, and Immunity

207

170

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Fibromyalgia (FM) is a poorly understood chronic condition characterized by widespread musculoskeletal pain, fatigue, and cognitive difficulties. While mounting evidence suggests a role for neuroinflammation, no study has directly provided evidence of brain glial activation in FM. In this study, we conducted a Positron Emission Tomography (PET) study using [C]PBR28, which binds to the translocator protein (TSPO), a protein upregulated in activated microglia and astrocytes. To enhance statistical power and generalizability, we combined datasets collected independently at two separate institutions (Massachusetts General Hospital [MGH] and Karolinska Institutet [KI]). In an attempt to disentangle the contributions of different glial cell types to FM, a smaller sample was scanned at KI with [C]--deprenyl-D PET, thought to primarily reflect astrocytic (but not microglial) signal. Thirty-one FM patients and 27 healthy controls (HC) were examined using [C]PBR28 PET. 11 FM patients and 11 HC were scanned using [C]--deprenyl-D PET. Standardized uptake values normalized by occipital cortex signal (SUVR) and distribution volume (V) were computed from the [C]PBR28 data. [C]--deprenyl-D was quantified using λ k. PET imaging metrics were compared across groups, and when differing across groups, against clinical variables. Compared to HC, FM patients demonstrated widespread cortical elevations, and no decreases, in [C]PBR28 V and SUVR, most pronounced in the medial and lateral walls of the frontal and parietal lobes. No regions showed significant group differences in [C]--deprenyl-D signal, including those demonstrating elevated [C]PBR28 signal in patients (p's ≥ 0.53, uncorrected). The elevations in [C]PBR28 V and SUVR were correlated both spatially (i.e., were observed in overlapping regions) and, in several areas, also in terms of magnitude. In exploratory, uncorrected analyses, higher subjective ratings of fatigue in FM patients were associated with higher [C]PBR28 SUVR in the anterior and posterior middle cingulate cortices (p's < 0.03). SUVR was not significantly associated with any other clinical variable. Our work provides the first in vivo evidence supporting a role for glial activation in FM pathophysiology. Given that the elevations in [C]PBR28 signal were not also accompanied by increased [C]--deprenyl-D signal, our data suggests that microglia, but not astrocytes, may be driving the TSPO elevation in these regions. Although [C]--deprenyl-D signal was not found to be increased in FM patients, larger studies are needed to further assess the role of possible astrocytic contributions in FM. Overall, our data support glial modulation as a potential therapeutic strategy for FM.

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“…Selective serotonin and noradrenaline reuptake inhibitors (SSNRIs) increase amounts of 5-HT and NA in synaptic clefts by blocking SERT and NET. Members of the SSNRIs group, atomoxetine and milnacipran, induce AKT by increasing its activatory phosphorylation [184,185], whereas duloxetine stimulates expression of AKT and inhibits expression of both GSK3 isozymes [186].…”

Section: Selective Serotonin and Noradrenaline Reuptake Inhibitorsmentioning

confidence: 99%

GSK3β: A Master Player in Depressive Disorder Pathogenesis and Treatment Responsiveness

Duda

Hajka

Wójcicka

et al. 2020

Cells

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Glycogen synthase kinase 3β (GSK3β), originally described as a negative regulator of glycogen synthesis, is a molecular hub linking numerous signaling pathways in a cell. Specific GSK3β inhibitors have anti-depressant effects and reduce depressive-like behavior in animal models of depression. Therefore, GSK3β is suggested to be engaged in the pathogenesis of major depressive disorder, and to be a target and/or modifier of anti-depressants' action. In this review, we discuss abnormalities in the activity of GSK3β and its upstream regulators in different brain regions during depressive episodes. Additionally, putative role(s) of GSK3β in the pathogenesis of depression and the influence of anti-depressants on GSK3β activity are discussed.Cells 2020, 9, 727 2 of 26 any of the groups listed above. Additionally, electroconvulsive therapy, conducted for the first time in 1938, is still widely used in the treatment of MDD, especially in its drug-refractory form [5].Although the monoaminergic hypothesis has led to the invention of many successful therapeutic strategies based on the elevation of levels of NA and 5-HT in the synaptic cleft, it does not explain the anti-depressant effect of lithium and the rapid action of ketamine in the treatment of mood disorders [6]. Therefore, factors other than neurotransmission must be taken into consideration in the context of the MDD pathogenesis. One of them is glycogen synthase kinase 3β (GSK3β) signaling. Glycogen Synthase Kinase 3βGSK3 was isolated in 1980, from rabbit skeletal muscle, and described as a highly specific serine/threonine kinase for glycogen synthase [7]. There are two isozymes of GSK3, α and β, and both are expressed at similar levels in the mouse brain [8]. In the human brain, the β isozyme predominates [9]. Therefore, GSK3β is expected to be crucial for the human central nervous system functioning. The activity of GSK3β is regulated positively and negatively by phosphorylation on Tyr216 and Ser9, respectively [10,11]. Whereas phosphorylation of the residue Tyr216 occurs during the GSK3β translation process and results in a synthesis of the fully activated kinase, Ser9 phosphorylation seems to be the main regulatory modification during the enzyme lifespan [12]. Ser9-phosphorylated GSK3β remains inhibited, and dephosphorylation of the residue results in the disinhibition (activation) of the kinase.GSK3β is part of numerous cellular signaling pathways, and its activity can be regulated, directly or indirectly, by several kinases, phosphatases, and proteases. The wide spectrum of GSK3β substrates, including transcription factors, glycolytic enzymes, pro-and anti-apoptotic factors, mitochondrial channels, membrane receptors, and cytoskeleton-associated proteins, makes GSK3β a central point of the cell homeostasis maintenance [13]. The activity of GSK3β affects energy metabolism, cell survival, proliferation, apoptosis, membrane polarity, internalization of the synaptic receptors, neuroplasticity, neurotransmission, amyloid processing, and many other processes [13].Ex...

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Neuroprotective Effects of Antidepressants via Upregulation of Neurotrophic Factors in the MPTP Model of Parkinson’s Disease

Cited by 37 publications

References 40 publications

Methylene blue protects dopaminergic neurons against MPTP‐induced neurotoxicity by upregulating brain‐derived neurotrophic factor

Methylene blue protects dopaminergic neurons against MPTP‐induced neurotoxicity by upregulating brain‐derived neurotrophic factor

Brain glial activation in fibromyalgia – A multi-site positron emission tomography investigation

GSK3β: A Master Player in Depressive Disorder Pathogenesis and Treatment Responsiveness

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