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

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.

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

“…Stimulation of 5‐HT1A receptors on astrocytes leads to secretion of S100β which seems to be protective at nanomolar concentrations although deleterious at micromolar concentrations. It is therefore conceivable that pharmacological modulation of 5‐HT1A receptors on astrocytes could be astro‐ and neuroprotective [for more detail see (Miyazaki and Asanuma, 2016)].…”

The Migraine Attack as a Homeostatic, Neuroprotective Response to Brain Oxidative Stress: Preliminary Evidence for a Theory

“…Thus, via the 5‐HT 1A receptor, serotonin appears to trigger the release of a protein, S100B, from astrocytes. S100B resembles a neurotrophic factor in that it prevents apoptosis, facilitates the outgrowth of neurites, and modulates long‐term synaptic plasticity . Moreover, serotonin causes astrocytes to raise their antioxidant support for neurons, by stimulating the release of metallothioneins, a class of antioxidant enzymes, and cysteine, which is taken up by neurons and used to produce the antioxidant glutathione …”

“…S100B resembles a neurotrophic factor in that it prevents apoptosis, facilitates the outgrowth of neurites, and modulates long-term synaptic plasticity. 141 Moreover, serotonin causes astrocytes to raise their antioxidant support for neurons, by stimulating the release of metallothioneins, a class of antioxidant enzymes, and cysteine, which is taken up by neurons and used to produce the antioxidant glutathione. 141 It appears that serotonin can also induce the production of BDNF, which as we have seen promotes neurogenesis, dendritic branching, synaptic plasticity, and neuronal survival (suppression of apoptosis) during ischemia, physical trauma, and psychosocial stress.…”

“…141 Moreover, serotonin causes astrocytes to raise their antioxidant support for neurons, by stimulating the release of metallothioneins, a class of antioxidant enzymes, and cysteine, which is taken up by neurons and used to produce the antioxidant glutathione. 141 It appears that serotonin can also induce the production of BDNF, which as we have seen promotes neurogenesis, dendritic branching, synaptic plasticity, and neuronal survival (suppression of apoptosis) during ischemia, physical trauma, and psychosocial stress. 89,91,92 Further, serotonin can stimulate neurogenesis via insulin-like growth factor-1 (IGF-1) 142,143 and limit glutamatergic neurotransmission through the release of VEGF and fractalkine.…”

Lipopolysaccharide-Induced Matrix Metalloproteinase-9 Expression Associated with Cell Migration in Rat Brain Astrocytes

“…However, in contrast, their character is also like immune cells. Serval lines of evidence have shown that astrocytes can release inflammatory mediators such as tumor necrosis factor-alpha (TNFα), interleukin-1 beta (IL-1β), and matrix metalloproteinase-9 (MMP-9) [3] to participate in pathological processes of brain insults, such as Alzheimer s disease and other age-associated dementias [4], multiple sclerosis [5], major depressive disorder [6], and Parkinson s disease [7]. Thus, astrocytes play an important role in several neuroinflammatory and neurodegenerative processes.MMPs are a series of zinc-dependent endopeptidases that consist of more than twenty MMPs in human and other species.…”