Limits...
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.


Role of antioxidant supply by astrocytes. Astrocytes take up cystine via cystine/glutamate exchange transporter (xCT), reduce it to cysteine to synthesize glutathione (GSH), and consequently release it into the extracellular space. Cysteine is generated from the extracellular thiol/disulfide exchange reaction of cystine and GSH, or generated by a peptidase from the dipeptide cysteinylglycine (CysGly), and then taken up by neighboring neurons for GSH synthesis. Metallothioneins (MTs) are produced by astrocytes in response to oxidative stress, and secreted into extracellular space. MTs secreted specifically by astrocytes protect dopaminergic neurons against oxidative stress.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4997990&req=5

Figure 1: Role of antioxidant supply by astrocytes. Astrocytes take up cystine via cystine/glutamate exchange transporter (xCT), reduce it to cysteine to synthesize glutathione (GSH), and consequently release it into the extracellular space. Cysteine is generated from the extracellular thiol/disulfide exchange reaction of cystine and GSH, or generated by a peptidase from the dipeptide cysteinylglycine (CysGly), and then taken up by neighboring neurons for GSH synthesis. Metallothioneins (MTs) are produced by astrocytes in response to oxidative stress, and secreted into extracellular space. MTs secreted specifically by astrocytes protect dopaminergic neurons against oxidative stress.

Mentions: Glutathione (GSH) is the most potent intrinsic antioxidant against reactive oxygen species (ROS). GSH is a tripeptide comprising the amino acids glutamate, cysteine and glycine. GSH is generated via a two-step reaction catalyzed by γ-glutamyl cysteine ligase (GCL) and GSH synthetase. Because intracellular glutamate and glycine are relatively sufficient, cysteine is the rate-limiting precursor for GSH synthesis. Since extracellular cysteine is readily auto-oxidized to cystine, cystine transport mechanisms are essential to supply a GSH substrate cysteine to cells. Cystine uptake is mediated by cystine/glutamate exchange transporter (xCT), which is expressed primarily on astrocytes, but not on neurons [19-21]. Astrocytes take up cystine via xCT, reduce it to cysteine to synthesize GSH, and consequently release it through the transporter multidrug resistance protein 1 (MRP1). Cysteine is generated from the extracellular thiol/disulfide exchange reaction of GSH and cystine, or generated by a peptidase from the dipeptide cysteinylglycine (CysGly), and then taken up by neighboring neurons for GSH synthesis [22-24]. Therefore, GSH synthesis in neurons is dependent on the expression of xCT and GSH synthesis in astrocytes (Fig. 1).


Serotonin 1A Receptors on Astrocytes as a Potential Target for the Treatment of Parkinson ’ s Disease
Role of antioxidant supply by astrocytes. Astrocytes take up cystine via cystine/glutamate exchange transporter (xCT), reduce it to cysteine to synthesize glutathione (GSH), and consequently release it into the extracellular space. Cysteine is generated from the extracellular thiol/disulfide exchange reaction of cystine and GSH, or generated by a peptidase from the dipeptide cysteinylglycine (CysGly), and then taken up by neighboring neurons for GSH synthesis. Metallothioneins (MTs) are produced by astrocytes in response to oxidative stress, and secreted into extracellular space. MTs secreted specifically by astrocytes protect dopaminergic neurons against oxidative stress.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Role of antioxidant supply by astrocytes. Astrocytes take up cystine via cystine/glutamate exchange transporter (xCT), reduce it to cysteine to synthesize glutathione (GSH), and consequently release it into the extracellular space. Cysteine is generated from the extracellular thiol/disulfide exchange reaction of cystine and GSH, or generated by a peptidase from the dipeptide cysteinylglycine (CysGly), and then taken up by neighboring neurons for GSH synthesis. Metallothioneins (MTs) are produced by astrocytes in response to oxidative stress, and secreted into extracellular space. MTs secreted specifically by astrocytes protect dopaminergic neurons against oxidative stress.
Mentions: Glutathione (GSH) is the most potent intrinsic antioxidant against reactive oxygen species (ROS). GSH is a tripeptide comprising the amino acids glutamate, cysteine and glycine. GSH is generated via a two-step reaction catalyzed by γ-glutamyl cysteine ligase (GCL) and GSH synthetase. Because intracellular glutamate and glycine are relatively sufficient, cysteine is the rate-limiting precursor for GSH synthesis. Since extracellular cysteine is readily auto-oxidized to cystine, cystine transport mechanisms are essential to supply a GSH substrate cysteine to cells. Cystine uptake is mediated by cystine/glutamate exchange transporter (xCT), which is expressed primarily on astrocytes, but not on neurons [19-21]. Astrocytes take up cystine via xCT, reduce it to cysteine to synthesize GSH, and consequently release it through the transporter multidrug resistance protein 1 (MRP1). Cysteine is generated from the extracellular thiol/disulfide exchange reaction of GSH and cystine, or generated by a peptidase from the dipeptide cysteinylglycine (CysGly), and then taken up by neighboring neurons for GSH synthesis [22-24]. Therefore, GSH synthesis in neurons is dependent on the expression of xCT and GSH synthesis in astrocytes (Fig. 1).

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.