Objective: In this study, we examined neuroprotective effects of mirtazapine and involvement of astrocytes in the effects using primary cultured cells and parkinsonian mice.

Background: We previously reported that 8-OH-DPAT, a full serotonin 1A (5-HT1A) agonist, upregulated an antioxidative molecule metallothionein (MT) in the striatal astrocytes and protected dopaminergic neurons in parkinsonian mice. Mirtazapine, a noradrenergic and specific serotonergic antidepressant (NaSSA), shows multiple pharmacological actions such as inhibiting presynaptic α2 noradrenergic receptors and activating indirectly 5-HT1A receptors.

Methods: Primary cultured neurons and astrocytes were prepared from the mesencephalon and striata of Sprague-Dawley rat embryos at 15 days of gestation. Mesencephalic neurons or neuron-astrocyte co-cultures were treated with mirtazapine (10 µM) for 24 h, followed by exposed to 6-hydroxydopamine (6-OHDA). Changes in the number of dopaminergic neurons and MT expression in astrocytes were evaluated. The hemi-parkinsonian mice unilaterally lesioned by intrastriatal injections of 6-OHDA were treated with mirtazapine (5 or 16 mg/kg, i.p.) for 8 days, and immunohistochemical analyses were performed using brain slices.

Results: Pretreatment with mirtazapine significantly prevented 6-OHDA-induced dopaminergic neurotoxicity in neuron-astrocyte cocultures, but not in enriched neuronal cultures. Mirtazapine did not affect MT expression in cultured astrocytes directly, but conditioned medium from mirtazapine-treated mesencephalic neurons upregulated MT expression in astrocytes. The neuroprotective effects of mirtazapine in neuron-astrocyte cocultures were annulled by 5-HT1A antagonist. The treatment with mirtazapine (16 mg/kg) reduced neurodegeneration of nigrostriatal dopaminergic neurons in parkinsonian mice, with increasing striatal MT expression.

Conclusions: These results suggest that mirtazapine upregulates MT expression in astrocytes via secreted molecules from mesencephalic neurons and the drug exerts neuroprotective effects against dopaminergic neurodegeneration possibly by targeting astrocytes. (The part of this paper was presented at 46th Annual Meeting of the Japanese Society of Neuropsychopharmacology on July 2-3, 2016. )

« Back to 2017 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/neuroprotective-effects-of-antidepressant-mirtazapine-against-dopaminergic-neurodegeneration-in-cultured-cells-and-in-parkinsonian-mice-possibly-by-targeting-astrocytes/