Abstract
Mirtazapine, a noradrenergic and specific serotonergic antidepressant (NaSSA), is known to activate serotonin (5-HT) 1A receptor. Our recent study demonstrated that stimulation of astrocytic 5-HT1A receptors promoted astrocyte proliferation and upregulated antioxidative property in astrocytes to protect dopaminergic neurons against oxidative stress. Here, we evaluated the neuroprotective effects of mirtazapine against dopaminergic neurodegeneration in models of Parkinson’s disease (PD). Mirtazapine administration attenuated the loss of dopaminergic neurons in the substantia nigra and increased the expression of the antioxidative molecule metallothionein (MT) in the striatal astrocytes of 6-hydroxydopamine (6-OHDA)-injected parkinsonian mice via 5-HT1A receptors. Mirtazapine protected dopaminergic neurons against 6-OHDA-induced neurotoxicity in mesencephalic neuron and striatal astrocyte cocultures, but not in enriched neuronal cultures. Mirtazapine-treated neuron-conditioned medium (Mir-NCM) induced astrocyte proliferation and upregulated MT expression via 5-HT1A receptors on astrocytes. Furthermore, treatment with medium from Mir-NCM-treated astrocytes protected dopaminergic neurons against 6-OHDA neurotoxicity, and these effects were attenuated by treatment with a MT-1/2-specific antibody or 5-HT1A antagonist. Our study suggests that mirtazapine could be an effective disease-modifying drug for PD and highlights that astrocytic 5-HT1A receptors may be a novel target for the treatment of PD.
Highlights
Mirtazapine, a noradrenergic and specific serotonergic antidepressant (NaSSA), is known to activate serotonin (5-HT) 1A receptor
We observed that mirtazapine (10 μM)-treated astrocyte conditioned medium (Mir-ACM) did not protect dopaminergic neurons from 6-OHDA-induced neurotoxicity. These results suggest that Mirtazapine-treated neuronconditioned medium (Mir-neuronal conditioned medium (NCM))-treated astrocytes upregulate MT-1/2 expression through 5-HT1A receptors and secrete it extracellularly, which protects dopaminergic neurons against oxidative stress
The present study demonstrated that mirtazapine upregulated MT-1/2 expression in striatal astrocytes and protected dopaminergic neurons in in vivo and in vitro models of Parkinson’s disease (PD)
Summary
Mirtazapine, a noradrenergic and specific serotonergic antidepressant (NaSSA), is known to activate serotonin (5-HT) 1A receptor. Our recent study demonstrated that stimulation of astrocytic 5-HT1A receptors promoted astrocyte proliferation and upregulated antioxidative property in astrocytes to protect dopaminergic neurons against oxidative stress. Mirtazapine administration attenuated the loss of dopaminergic neurons in the substantia nigra and increased the expression of the antioxidative molecule metallothionein (MT) in the striatal astrocytes of 6-hydroxydopamine (6-OHDA)-injected parkinsonian mice via 5-HT1A receptors. Treatment with medium from Mir-NCM-treated astrocytes protected dopaminergic neurons against 6-OHDA neurotoxicity, and these effects were attenuated by treatment with a MT-1/2-specific antibody or 5-HT1A antagonist. We previously reported that the serotonin (5-HT)1A receptor agonist (R)-(+)-8-hydroxy-2-(di-n-propylamino) tetralin hydrobromide (8-OH-DPAT) exerted neuroprotective effects against dopaminergic neurodegeneration by inducing astrocyte proliferation and upregulating MT-1/2 expression in astrocytes[14]. These results suggest that 5-HT1A receptors on astrocytes could be a potential target for dopaminergic neuroprotection
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