Targeting 5-HT1A receptors in astrocytes to protect dopaminergic neurons in parkinsonian models

Miyazaki, Ikuko; Asanuma, Masato; Murakami, Shinki; Takeshima, Mika; Torigoe, Nao; Kitamura, Yoshihisa; Miyoshi, Katsuhiko

doi:10.1016/j.nbd.2013.08.003

Cited by 64 publications

(68 citation statements)

References 28 publications

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“…Several studies pointed at the therapeutic potential of astrocytic 5‐HT1A receptors. Stimulation of 5‐HT1A receptors on astrocytes promotes astrocyte proliferation and neuroprotection both in vitro and in PD model mice (Miyazaki et al, 2013). The 8‐OH‐DPAT [(R)‐(+)−8‐hydroxy‐2‐(di‐n‐propylamino)tetralin hydrobromide], a full 5‐HT1A agonist, enhances astrocyte proliferation in mouse striatum.…”

Section: Potential Therapeutic Targets In Astrocytesmentioning

confidence: 99%

“…The 8‐OH‐DPAT [(R)‐(+)−8‐hydroxy‐2‐(di‐n‐propylamino)tetralin hydrobromide], a full 5‐HT1A agonist, enhances astrocyte proliferation in mouse striatum. The 8‐OH‐DPAT significantly up‐regulates astrocytic antioxidant pathways by increasing the expression of erythroid 2‐related factor 2 (Nrf2) (Miyazaki et al, 2013) which activates genes involved in anti‐oxidant defense (see below). Nrf2‐regulated genes are preferentially activated in astrocytes, boosting their detoxification and antioxidant functions (Vargas and Johnson, 2009).…”

Section: Potential Therapeutic Targets In Astrocytesmentioning

confidence: 99%

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Astroglia as a cellular target for neuroprotection and treatment of neuro‐psychiatric disorders

Liu

Teschemacher

Kasparov

2017

Glia

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Astrocytes are key homeostatic cells of the central nervous system. They cooperate with neurons at several levels, including ion and water homeostasis, chemical signal transmission, blood flow regulation, immune and oxidative stress defense, supply of metabolites and neurogenesis. Astroglia is also important for viability and maturation of stem‐cell derived neurons. Neurons critically depend on intrinsic protective and supportive properties of astrocytes. Conversely, all forms of pathogenic stimuli which disturb astrocytic functions compromise neuronal functionality and viability. Support of neuroprotective functions of astrocytes is thus an important strategy for enhancing neuronal survival and improving outcomes in disease states. In this review, we first briefly examine how astrocytic dysfunction contributes to major neurological disorders, which are traditionally associated with malfunctioning of processes residing in neurons. Possible molecular entities within astrocytes that could underpin the cause, initiation and/or progression of various disorders are outlined. In the second section, we explore opportunities enhancing neuroprotective function of astroglia. We consider targeting astrocyte‐specific molecular pathways which are involved in neuroprotection or could be expected to have a therapeutic value. Examples of those are oxidative stress defense mechanisms, glutamate uptake, purinergic signaling, water and ion homeostasis, connexin gap junctions, neurotrophic factors and the Nrf2‐ARE pathway. We propose that enhancing the neuroprotective capacity of astrocytes is a viable strategy for improving brain resilience and developing new therapeutic approaches.

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Section: Potential Therapeutic Targets In Astrocytesmentioning

confidence: 99%

Section: Potential Therapeutic Targets In Astrocytesmentioning

confidence: 99%

Astroglia as a cellular target for neuroprotection and treatment of neuro‐psychiatric disorders

Liu

Teschemacher

Kasparov

2017

Glia

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“…Indeed, Nrf2-induced molecules, such as GSH-related enzyme and MTs, are higher in astrocytes than neurons. A number of investigators, including our group, have reported that activation of Nrf2 in astrocytes has a major role in protecting dopaminergic neurons from oxidative stress [9, 10, 18, 75, 78]. For example, it is reported that administration of MPTP resulted in dramatic reduction of dopaminergic nerve terminal in the striatum of Nrf2-knockout mice [83].…”

Section: Neuroprotective Properties Of Astrocytes In Parkinson's Diseasementioning

confidence: 99%

“…Taken together with previous reports, increasing the number of healthy astrocytes containing various antioxidative molecules could be a potential therapeutic approach to prevent the degenerative process of PD. We have recently shown that stimulation of serotonin 1A (5-HT 1A ) receptors on astrocytes promotes astrocyte proliferation and upregulates antioxidative molecules to act as a neuroprotectant in PD model mice [18]. In this article, we review the neuroprotective role of astrocytes in the brain and neuroprotective approaches targeting astrocytes for PD models, especially stimulation of 5-HT 1A receptors on astrocytes.…”

Section: Introductionmentioning

confidence: 99%

Serotonin 1A Receptors on Astrocytes as a Potential Target for the Treatment of Parkinson’s Disease

Miyazaki

Asanuma²

2016

CMC

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Astrocytes are the most abundant neuron-supporting glial cells in the central nervous system. The neuroprotective role of astrocytes has been demonstrated in various neurological disorders such as amyotrophic lateral sclerosis, spinal cord injury, stroke and Parkinson’s disease (PD). Astrocyte dysfunction or loss-of-astrocytes increases the susceptibility of neurons to cell death, while astrocyte transplantation in animal studies has therapeutic advantage. We reported recently that stimulation of serotonin 1A (5-HT1A) receptors on astrocytes promoted astrocyte proliferation and upregulated antioxidative molecules to act as a neuroprotectant in parkinsonian mice. PD is a progressive neurodegenerative disease with motor symptoms such as tremor, bradykinesia, rigidity and postural instability, that are based on selective loss of nigrostriatal dopaminergic neurons, and with non-motor symptoms such as orthostatic hypotension and constipation based on peripheral neurodegeneration. Although dopaminergic therapy for managing the motor disability associated with PD is being assessed at present, the main challenge remains the development of neuroprotective or disease-modifying treatments. Therefore, it is desirable to find treatments that can reduce the progression of dopaminergic cell death. In this article, we summarize first the neuroprotective properties of astrocytes targeting certain molecules related to PD. Next, we review neuroprotective effects induced by stimulation of 5-HT1A receptors on astrocytes. The review discusses new promising therapeutic strategies based on neuroprotection against oxidative stress and prevention of dopaminergic neurodegeneration.

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“…Astrocytes most likely improve dopaminergic neuronal survival by uptake of toxic molecules, such as glutamate and α-synuclein (Hazell et al 1997; Lee et al 2010; Miyazaki et al 2013). Numerous studies have demonstrated that astrocytes play an important role in neurodegenerative disorders and exert a protective function against oxidative stress because of their effects on the metabolism of the antioxidant glutathione (GSH) and the defense against reactive oxygen species (ROS) (Wilson, 1997).…”

Section: Introductionmentioning

confidence: 99%

Glia Maturation Factor Deficiency Suppresses 1-Methyl-4-Phenylpyridinium-Induced Oxidative Stress in Astrocytes

et al. 2014

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Inflammation is closely intertwined with pathogenesis of Parkinson's disease (PD). Increasing evidence suggests that inhibition of glia-mediated inflammation might represent a promising therapeutic target for PD. Glia maturation factor (GMF), an inflammatory protein, predominantly localized in astrocytes is previously isolated, sequenced and cloned in our laboratory. In the present investigation, we demonstrate that GMF-deficiency in astrocytes upregulates the antioxidant status and limit the extent of lipid peroxidation and production of reactive oxygen species (ROS) along with diminished nuclear factor-κB-mediated inflammatory responses in 1-methyl-4-phenylpyridinium (MPP+)-induced toxicity. Primary astrocytes obtained from wild-type (Wt) and GMF-deficient (GMF-KO) mice were treated with 5, 10, and 20 μM MPP+ for 24, 48, and 72 h in vitro. Our results show decreased release of ROS and increased level of glutathione in astrocytes obtained from GMF-KO mice when compared to astrocytes derived from Wt mice following MPP+ treatment. Additionally, we found decreased activity of NF-κB, and reduced levels of proinflammatory tumor necrosis factor- α, interleukin-1β (IL-1β), IL-17, IL-33, and chemokine (C–C motif) ligand 2 (CCL2) in GMF-KO astrocytes when compared to Wt astrocytes. Our overall results suggest that GMF-KO astrocytes are significantly resistant to MPP+ toxicity when compared to Wt astrocytes.

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Targeting 5-HT1A receptors in astrocytes to protect dopaminergic neurons in parkinsonian models

Cited by 64 publications

References 28 publications

Astroglia as a cellular target for neuroprotection and treatment of neuro‐psychiatric disorders

Astroglia as a cellular target for neuroprotection and treatment of neuro‐psychiatric disorders

Serotonin 1A Receptors on Astrocytes as a Potential Target for the Treatment of Parkinson’s Disease

Glia Maturation Factor Deficiency Suppresses 1-Methyl-4-Phenylpyridinium-Induced Oxidative Stress in Astrocytes

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