Antidepressants reduce neuroinflammatory responses and astroglial alpha‐synuclein accumulation in a transgenic mouse model of multiple system atrophy

Abstract

Multiple system atrophy (MSA) is a neurodegenerative disease characterized by the pathological accumulation of alpha-synuclein (α-syn) within oligodendroglial cells. This accumulation is accompanied by neuroinflammation with astrogliosis and microgliosis, that leads to neuronal death and subsequent parkinsonism and dysautonomia. Antidepressants have been explored as neuroprotective agents as they normalize neurotrophic factor levels, increase neurogenesis and reduce neurodegeneration, but their anti-inflammatory properties have not been fully characterized. We analyzed the anti-inflammatory profiles of three different antidepressants (fluoxetine, olanzapine and amitriptyline) in the MBP1-hα-syn transgenic (tg) mouse model of MSA. We observed that antidepressant treatment decreased the number of α-syn-positive cells in the basal ganglia of 11-month old tg animals. This reduction was accompanied with a similar decrease in the colocalization of α-syn with astrocyte markers in this brain structure. Consistent with these results, antidepressants reduced astrogliosis in the hippocampus and basal ganglia of the MBP1-hα-syn tg mice, and modulated the expression levels of key cytokines that were dysregulated in the tg mouse model, such as IL-1β. In vitro experiments in the astroglial cell line C6 confirmed that antidepressants inhibited NF-κB translocation to the nucleus and reduced IL-1β protein levels. We conclude that the anti-inflammatory properties of antidepressants in the MBP1-hα-syn tg mouse model of MSA might be related to their ability to inhibit α-syn propagation from oligodendrocytes to astroglia and to regulate transcription factors involved in cytokine expression. Our results suggest that antidepressants might be of interest as anti-inflammatory and α-syn-reducing agents for MSA and other α-synucleinopathies.

Imipramine and amitriptyline ameliorate the rotenone model of Parkinson’s disease in rats

“…In agreement, recent studies reported that AMI increased the expression of BDNF in the nigrostriatal system and retarded the progression of its dopaminergic neuronal loss in the 6-hydroxydopamine rat model of PD (Paumier et al, 2015). In addition, AMI augmented hippocampal and striatal BDNF levels in mouse models of multiple systems atrophy and Huntington's disease, respectively (Valera et al, 2014;Cong et al, 2015). While treatment of maternally deprived rats with IMI increased BDNF level in the amygdala (Réus et al, 2013).…”

Effects of olanzapine on LPS-induced inflammation in rat primary glia cells

“…These findings are in line with previous reports in which OLZ was found to exert both anti-and pro-inflammatory effects. 10,26,32,[38][39][40]73 In this study we used two concentrations of OLZ: 1 and 50 mM. Unlike most of the drugs used for prophylactic treatment in schizophrenia and bipolar disorder, OLZ is a drug whose plasma concentration is not routinely monitored in treated patients.…”

“…73 Moreover, OLZ inhibited translocation of the transcription factor NF-kB to the nucleus and decreased IL-1b protein levels in astrocytes. 32 In contrast, other studies have shown contrasting results, i.e. that OLZ has prominent proinflammatory effects.…”

“…[14][15][16][17][18][19] Moreover, a large body of data implies that inhibition of inflammation may contribute to the therapeutic effects of psychotropic drugs. [20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] However, it is important to emphasize that many studies reported opposite findings; namely, that psychotropic drugs also exhibit pro-inflammatory effects. 10,31,[38][39][40][41] Furthermore, the mechanism underlying the anti-inflammatory properties of psychotropic drugs is not fully understood and it is not known whether their influence on inflammation contributes to their therapeutic and toxic effects.…”

Chronic Amitriptyline Treatment Attenuates Nigrostriatal Degeneration and Significantly Alters Trophic Support in a Rat Model of Parkinsonism

“…AMI also elicits neuroprotection by binding directly to neurotrophic factor receptors TrkA and TrkB (Jang et al, 2009). More recently, AMI was shown to mediate changes in hippocampal BDNF and GDNF, resulting in reduced neuroinflammation and alpha-synuclein accumulation in a mouse model of multiple systems atrophy (Valera et al, 2014). Finally, nortriptyline (a metabolite of AMI), was shown to delay the onset of neurodegeneration in mouse models of ALS and Huntington's disease (Wang et al, 2007).…”