Effects of Fluoxetine on Hippocampal Neurogenesis and Neuroprotection in the Model of Global Cerebral Ischemia in Rats

Abstract

A selective serotonin reuptake inhibitor, fluoxetine, has recently attracted a significant interest as a neuroprotective therapeutic agent. There is substantial evidence of improved neurogenesis under fluoxetine treatment of brain ischemia in animal stroke models. We studied long-term effects of fluoxetine treatment on hippocampal neurogenesis, neuronal loss, inflammation, and functional recovery in a new model of global cerebral ischemia (GCI). Brain ischemia was induced in adult Wistar male rats by transient occlusion of three main vessels originating from the aortic arch and providing brain blood supply. Fluoxetine was injected intraperitoneally in a dose of 20 mg/kg for 10 days after surgery. To evaluate hippocampal neurogenesis at time points 10 and 30 days, 5-Bromo-2′-deoxyuridine was injected at days 8–10 after GCI. According to our results, 10-day fluoxetine injections decreased neuronal loss and inflammation, improved survival and functional recovery of animals, enhanced neurogenesis, and prevented an early pathological increase in neural stem cell recruitment in the subgranular zone (SGZ) of the hippocampus without reducing the number of mature neurons at day 30 after GCI. In summary, this study suggests that fluoxetine may provide a promising therapy in cerebral ischemia due to its neuroprotective, anti-inflammatory, and neurorestorative effect.

Brain 5-HT Deficiency Prevents Antidepressant-Like Effects of High-Fat-Diet and Blocks High-Fat-Diet-Induced GSK3β Phosphorylation in the Hippocampus

“…Dysregulation of GSK3β (Jope, 2011;Karege et al, 2012;Ren et al, 2013;Ronai et al, 2014;Chen et al, 2015) and inflammation (Syed et al, 2018;Giridharan et al, 2019;Opel et al, 2019;Osimo et al, 2019) have both been identified in clinical studies examining psychiatric patients as well, thus supporting their likely importance in behavioral dysfunction. Given that both brain inflammation (Lu et al, 2017;Khodanovich et al, 2018) and GSK3β activity (Li et al, 2004;Beaulieu et al, 2008) are known to be influenced by brain 5-HT levels, the current work examined whether low 5-HT impacts the effects of HFD on GSK3β phosphorylation or the mRNA expression of several genes involved in inflammation. Although 5-HT could influence HFD responses through both peripheral and central mechanisms, the use of Tph2KI mice limits the present study's focus on central mechanisms.…”

Interaction Between Neurogenic Stimuli and the Gene Network Controlling the Activation of Stem Cells of the Adult Neurogenic Niches, in Physiological and Pathological Conditions

“…Fluoxetine, which belongs to the class of selective serotonin reuptake inhibitors (SSRI), has in fact been thoroughly studied as neurogenic stimulus in SGZ, as in adult dentate gyrus strongly stimulates the proliferation of progenitor cells but is unable to stimulate stem cells; in aged mice, however, it is ineffective in both stem and progenitor cells, but enhances the contextual memory and the density of dendritic spines (Encinas et al, 2006;Couillard-Despres et al, 2009;Li et al, 2015;McAvoy et al, 2015;Micheli et al, 2017Micheli et al, , 2018a. Interestingly, in a mouse model of global ischemia, fluoxetine is able to completely rescue the decrease of stem and progenitor cells (Khodanovich et al, 2018; see below a mechanism of activation of stem cells by focal ischemia in SVZ described by Llorens-Bobadilla et al, 2015) ( Table 1).…”

Preconditioning and Cellular Engineering to Increase the Survival of Transplanted Neural Stem Cells for Motor Neuron Disease Therapy

“…Several strategies to increase neurogenesis after ischemic stroke have been attempted in experimental models. Selective serotonin reuptake inhibitors, statins, and ascorbic acid have been shown to increase NSC proliferation and migration and to improve functional outcome after experimental ischemic stroke in animal models [21][22][23].…”