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

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

Function of extracellular S100β. S100β has an effect on neurons depending on its concentration. Nanomolar levels of S100β protect neurons from stress-induced apoptosis, stimulate neurite outgrowth and microtubule associated protein2 (MAP2) expression. Extracellular S100β exerts autocrine effects that promote astrocyte proliferation and glutamate uptake activity of astrocytes.
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Figure 2: Function of extracellular S100β. S100β has an effect on neurons depending on its concentration. Nanomolar levels of S100β protect neurons from stress-induced apoptosis, stimulate neurite outgrowth and microtubule associated protein2 (MAP2) expression. Extracellular S100β exerts autocrine effects that promote astrocyte proliferation and glutamate uptake activity of astrocytes.

Mentions: Astrocyte proliferation is promoted by S100β protein, which is released by astrocytes and affects in the autocrine fashion [143-146]. S100β is a small EF-hand Ca2+-binding protein. This protein is expressed in various cell types such as astrocytes, oligodendrocytes, renal epithelial cells, and neural progenitor cells. The highest level of S100β expression is found in the cytoplasm of astrocytes [145, 146], and astrocytes secret the protein to the extracellular space. Extracellular S100β has various functions and affects on not only astrocytes but also neurons. S100β has opposite effects on neurons depending on its concentration. Nanomolar levels of S100β protect neurons from stress-induced apoptosis [147], stimulate neurite outgrowth and microtubule associated protein2 (MAP2) expression [148, 149] and modulate long-term neuronal plasticity [150] (Fig. 2). On the other hand, exposure to micromolar levels of S100β increases β−amyloid neurotoxicity [151] and causes neuronal apoptosis [152]. In addition, extracellular S100β at low dose enhances glutamate uptake activity of astrocytes, which plays essential roles in regulating extracellular levels of glutamate [153-155] (Fig. 2). Tramontina et al. [154, 155] provided direct evidence for the stimulatory effect of extracellular S100β on glutamate uptake into astrocytes by addition of S100β protein, and that anti-S100β antibody decreased glutamate uptake without affecting cell integrity or viability. It is also reported that epicatechin gallate, which is an abundant polyphenol in green tea, induces glutamate uptake and S100β secretion in astroglial C6 cells [153]. These results suggest that S100β secretion by epicatechin gallate may be associated with the improvement of glutamate uptake. Other studies demonstrated that extracellular S100β could protect hippocampal neurons against glutamate-induced damage [147, 156]. These findings reinforce the importance of astrocytes in the neuroprotective role of S100β against excitotoxic damage. Astrocytes seem to secret S100β to the extracellular space to reduce the excitotoxicity (Fig. 2).


Serotonin 1A Receptors on Astrocytes as a Potential Target for the Treatment of Parkinson ’ s Disease
Function of extracellular S100β. S100β has an effect on neurons depending on its concentration. Nanomolar levels of S100β protect neurons from stress-induced apoptosis, stimulate neurite outgrowth and microtubule associated protein2 (MAP2) expression. Extracellular S100β exerts autocrine effects that promote astrocyte proliferation and glutamate uptake activity of astrocytes.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Function of extracellular S100β. S100β has an effect on neurons depending on its concentration. Nanomolar levels of S100β protect neurons from stress-induced apoptosis, stimulate neurite outgrowth and microtubule associated protein2 (MAP2) expression. Extracellular S100β exerts autocrine effects that promote astrocyte proliferation and glutamate uptake activity of astrocytes.
Mentions: Astrocyte proliferation is promoted by S100β protein, which is released by astrocytes and affects in the autocrine fashion [143-146]. S100β is a small EF-hand Ca2+-binding protein. This protein is expressed in various cell types such as astrocytes, oligodendrocytes, renal epithelial cells, and neural progenitor cells. The highest level of S100β expression is found in the cytoplasm of astrocytes [145, 146], and astrocytes secret the protein to the extracellular space. Extracellular S100β has various functions and affects on not only astrocytes but also neurons. S100β has opposite effects on neurons depending on its concentration. Nanomolar levels of S100β protect neurons from stress-induced apoptosis [147], stimulate neurite outgrowth and microtubule associated protein2 (MAP2) expression [148, 149] and modulate long-term neuronal plasticity [150] (Fig. 2). On the other hand, exposure to micromolar levels of S100β increases β−amyloid neurotoxicity [151] and causes neuronal apoptosis [152]. In addition, extracellular S100β at low dose enhances glutamate uptake activity of astrocytes, which plays essential roles in regulating extracellular levels of glutamate [153-155] (Fig. 2). Tramontina et al. [154, 155] provided direct evidence for the stimulatory effect of extracellular S100β on glutamate uptake into astrocytes by addition of S100β protein, and that anti-S100β antibody decreased glutamate uptake without affecting cell integrity or viability. It is also reported that epicatechin gallate, which is an abundant polyphenol in green tea, induces glutamate uptake and S100β secretion in astroglial C6 cells [153]. These results suggest that S100β secretion by epicatechin gallate may be associated with the improvement of glutamate uptake. Other studies demonstrated that extracellular S100β could protect hippocampal neurons against glutamate-induced damage [147, 156]. These findings reinforce the importance of astrocytes in the neuroprotective role of S100β against excitotoxic damage. Astrocytes seem to secret S100β to the extracellular space to reduce the excitotoxicity (Fig. 2).

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