Atorvastatin and Fluoxetine Prevent Oxidative Stress and Mitochondrial Dysfunction Evoked by Glutamate Toxicity in Hippocampal Slices

Abstract

Atorvastatin has been shown to exert a neuroprotective action by counteracting glutamatergic toxicity. Recently, we have shown atorvastatin also exerts an antidepressant-like effect that depends on both glutamatergic and serotonergic systems modulation. Excitotoxicity is involved in several brain disorders including depression; thus, it is suggested that antidepressants may target glutamatergic system as a final common pathway. In this study, a comparison of the mechanisms involved in the putative neuroprotective effect of a repetitive atorvastatin or fluoxetine treatment against glutamate toxicity in hippocampal slices was performed. Adult Swiss mice were treated with atorvastatin (10 mg/kg, p.o.) or fluoxetine (10 mg/kg, p.o.), once a day during seven consecutive days. On the eighth day, animals were killed and hippocampal slices were obtained and subjected to an in vitro protocol of glutamate toxicity. An acute treatment of atorvastatin or fluoxetine was not neuroprotective; however, the repeated atorvastatin or fluoxetine treatment prevented the decrease in cellular viability induced by glutamate in hippocampal slices. The loss of cellular viability induced by glutamate was accompanied by increased D-aspartate release, increased reactive oxygen species (ROS) and nitric oxide (NO) production, and impaired mitochondrial membrane potential. Atorvastatin or fluoxetine repeated treatment also presented an antidepressant-like effect in the tail suspension test. Atorvastatin or fluoxetine treatment was effective in protecting mice hippocampal slices from glutamate toxicity by preventing the oxidative stress and mitochondrial dysfunction.

Statins for major depressive disorder: A systematic review and meta-analysis of randomized controlled trials

“…Moreover, statins reduce depressive-like behaviors in rats by counteracting microglial and astrocyte activation as well as cytokine release in the central nervous system via inhibition of the nuclear factor-kB pathway and subsequent interleukin (IL)-1B, IL-6, and tumor necrosis factor-α secretion [18][19][20]; similarly, they offset the peripheral effects of IL-6 and IL-18 in humans [21]. The depressogenic effect of oxidative stress in the brain appears reduced both directly [22] and via peroxisome proliferator-activated receptor-γ activity and decreased nitrous oxide levels [23] by statins. Statins also normalize high fat dietmediated changes in the endocannabinoid system whilst improving depressive-like behaviors Oxford Health NIHR Biomedical Research Centre, or the NHS.…”

A comprehensive metabolomics investigation of hippocampus, serum, and feces affected by chronic fluoxetine treatment using the chronic unpredictable mild stress mouse model of depression

“…It is also a precursor to L-glutamic acid, which was down-regulated by fluoxetine in the hippocampus in our previous study 6 . Its increase in the hippocampus by fluoxetine treatment, shown in Table 1, implies that fluoxetine treatment effects might be associated with the histaminergic neuron 43 and glutamatergic systems 44 or with the stimulated energy metabolism in hippocampus, of which non-synaptic mitochondria exhibited enhanced enzymatic activities including glutamate dehydrogenase 45,46 .Inosinic acid or ionosine monophosphate is formed by deamination of adenosine monophosphate and can be hydrolyzed to produce inosine. Inosine had an antidepressant-like effect in mice, as observed by FST 47 and TST 48 , which is related to our results that inosinic acid in the hippocampus was significantly decreased by the CUMS treatment, and that fluoxetine treatment induced its up-regulation in both the model and control mice.…”

Oxidative Stress Assessment in Alzheimer’s Disease: A Clinic Setting Study

“…34,50,51 We did not evaluate use of antidepressants for which a possible antioxidant effect was recently reported. [52][53][54] The result of lower OS in patients with AD having stable antidementia treatments we found should be interpreted with caution, as OS levels were not assessed in these patients before antidementia therapy.…”

“…34,50,51 We did not evaluate use of antidepressants for which a possible antioxidant effect was recently reported. 52 -54…”