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

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ABSTRACT

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.

No MeSH data available.


Related in: MedlinePlus

Serotonin 1A (5-HT1A) receptors on astrocytes as a novel target of neuroprotection. Stimulation of 5-HT1A receptors on astrocytes promotes S100β secretion followed by astrocyte proliferation and Nrf2 activation to up-regulate expression of antioxidative molecules, such as glutathione (GSH) and metallothionein (MT). Therefore, the strategy of increasing the number of intrinsically healthy astrocytes through stimulation of 5-HT1A receptors on astrocytes is conceivable and could help design new therapies that provide neuroprotection against oxidative stress and neurodegenerative disorders.
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Figure 3: Serotonin 1A (5-HT1A) receptors on astrocytes as a novel target of neuroprotection. Stimulation of 5-HT1A receptors on astrocytes promotes S100β secretion followed by astrocyte proliferation and Nrf2 activation to up-regulate expression of antioxidative molecules, such as glutathione (GSH) and metallothionein (MT). Therefore, the strategy of increasing the number of intrinsically healthy astrocytes through stimulation of 5-HT1A receptors on astrocytes is conceivable and could help design new therapies that provide neuroprotection against oxidative stress and neurodegenerative disorders.

Mentions: In these days, various approaches using 5-HT1A agonists target mainly motor fluctuation in PD [138-142, 161-167] (Table 1). Eltoprazine, a selective 5-HT1A and 5-HT1B agonist, is currently being tested in clinical trials for motor complications derived from dopaminergic therapy in PD [140, 141]. The dopamine D2 and 5-HT1A dual-agonist, N-propylnoraporphin-11-yl 5-(1,2-dithiolan-3-yl)pentanoate, significantly reduced L-dopa-induced dyskinesia in parkinsonian rats [142]. In addition, previous studies demonstrated that 8-OH-DPAT also reduced dyskinesia and improved movement in parkinsonian animals [138, 139]. Almost all 5-HT1A agonists are thought to affect on neurons, and it is unclear whether these drugs affect on 5-HT1A receptors on astrocytes. Nevertheless, the treatment with 5-HT1A agonists is useful for L-dopa-induced side effects in PD (Fig. 3). On the other hand, neuroprotective or disease-modifying treatments are clinically required to prevent or delay disease progression in PD. Based on the neuroprotective property of astrocytes, many researchers have focused to astrocytes as a target for therapy in neurodegenerative diseases. Some recent studies have demonstrated that astrocyte transplantation produces neuronal repair in amyotrophic lateral


Serotonin 1A Receptors on Astrocytes as a Potential Target for the Treatment of Parkinson ’ s Disease
Serotonin 1A (5-HT1A) receptors on astrocytes as a novel target of neuroprotection. Stimulation of 5-HT1A receptors on astrocytes promotes S100β secretion followed by astrocyte proliferation and Nrf2 activation to up-regulate expression of antioxidative molecules, such as glutathione (GSH) and metallothionein (MT). Therefore, the strategy of increasing the number of intrinsically healthy astrocytes through stimulation of 5-HT1A receptors on astrocytes is conceivable and could help design new therapies that provide neuroprotection against oxidative stress and neurodegenerative disorders.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4997990&req=5

Figure 3: Serotonin 1A (5-HT1A) receptors on astrocytes as a novel target of neuroprotection. Stimulation of 5-HT1A receptors on astrocytes promotes S100β secretion followed by astrocyte proliferation and Nrf2 activation to up-regulate expression of antioxidative molecules, such as glutathione (GSH) and metallothionein (MT). Therefore, the strategy of increasing the number of intrinsically healthy astrocytes through stimulation of 5-HT1A receptors on astrocytes is conceivable and could help design new therapies that provide neuroprotection against oxidative stress and neurodegenerative disorders.
Mentions: In these days, various approaches using 5-HT1A agonists target mainly motor fluctuation in PD [138-142, 161-167] (Table 1). Eltoprazine, a selective 5-HT1A and 5-HT1B agonist, is currently being tested in clinical trials for motor complications derived from dopaminergic therapy in PD [140, 141]. The dopamine D2 and 5-HT1A dual-agonist, N-propylnoraporphin-11-yl 5-(1,2-dithiolan-3-yl)pentanoate, significantly reduced L-dopa-induced dyskinesia in parkinsonian rats [142]. In addition, previous studies demonstrated that 8-OH-DPAT also reduced dyskinesia and improved movement in parkinsonian animals [138, 139]. Almost all 5-HT1A agonists are thought to affect on neurons, and it is unclear whether these drugs affect on 5-HT1A receptors on astrocytes. Nevertheless, the treatment with 5-HT1A agonists is useful for L-dopa-induced side effects in PD (Fig. 3). On the other hand, neuroprotective or disease-modifying treatments are clinically required to prevent or delay disease progression in PD. Based on the neuroprotective property of astrocytes, many researchers have focused to astrocytes as a target for therapy in neurodegenerative diseases. Some recent studies have demonstrated that astrocyte transplantation produces neuronal repair in amyotrophic lateral

View Article: PubMed Central - PubMed

ABSTRACT

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.

No MeSH data available.


Related in: MedlinePlus