PI3K/AKT/JNK/p38 signalling pathway‐mediated neural apoptosis in the prefrontal cortex of mice is involved in the antidepressant‐like effect of pioglitazone

Abstract

Summary Numerous studies have reported that inflammation is involved in the pathophysiology of depression. Pioglitazone, a PPAR‐γ agonist, has potential anti‐inflammatory and antidepressive effects. However, the underlying molecular mechanisms of the antidepressant‐like effect of pioglitazone on an inflammation‐related mouse model of depression remain to be fully elucidated. Herein, we aimed to explore the effects of pioglitazone on depressive‐like behaviours of mice exposed to lipopolysaccharides (LPS), and elucidate the underlying mechanisms. We assessed behaviour changes of mice pretreated with pioglitazone exposed to LPS. Additionally, neural apoptosis, and the expression of apoptosis‐related (cleaved caspase‐3, Bax, Bcl‐2, cyt c) and signalling proteins (AKT, JNK, p38) were assessed in the prefrontal cortex (PFC) of these mice. Furthermore, we assessed the influence of anisomycin, a JNK/p38 agonist, and LY294002, a PI3K/AKT inhibitor, on the antidepressant‐like effect of pioglitazone in mice. We show that pioglitazone pretreatment (20 mg/kg, intragastrically) attenuated LPS‐induced (10 ng/μL per site) depressive‐like behaviours. GW9662, a PPAR‐γ antagonist, significantly blocked the antidepressant‐like effect of pioglitazone. Furthermore, at the molecular level, pioglitazone significantly reversed, via PPAR‐γ‐dependent increase in neural apoptosis in the PFC of mice, accompanied by upregulation of the PI3K/AKT pathway and down‐regulation of the JNK/p38 pathway. Moreover, both anisomycin and LY294002 abrogated the antidepressant‐like effect of pioglitazone.; In conclusion, our results showed that PI3K/AKT/JNK/p38 signalling pathway‐mediated neural apoptosis in the PFC of mice may be involved in the antidepressant‐like effect of pioglitazone. This provides novel insights into and therapeutic targets for inflammation‐related depression.

Hesperetin, a Citrus Flavonoid, Attenuates LPS-Induced Neuroinflammation, Apoptosis and Memory Impairments by Modulating TLR4/NF-κB Signaling

“…JNK, a stress kinase, has been found to be associated with apoptotic processes. Inflammatory mediators, UV radiation, and oxidative stress trigger the JNK cascades [63]. Similarly, the anti- and pro-apoptotic protein markers Bcl-2 and Bax play an important role in the regulation of apoptotic cell death pathways at the mitochondrial level [64,65].…”

Perturbation of Ephrin Receptor Signaling and Glutamatergic Transmission in the Hypothalamus in Depression Using Proteomics Integrated With Metabolomics

“…Our integrated network analysis also predicted that the EPHB2 and EFNB1 interactions play an important role in regulating NMDARs (Figure 5). Although studies emphasized the role of the GluN2A and AKT signaling cascade in LPS-induced depression (Francija et al, 2018;Li et al, 2018), it remains open how Ephrin receptor signaling acts on NMDARs and AKT signaling contributes to decreased neuroplasticity and aberrant behavior upon LPS treatment. To probe into possible mechanisms, we also selected an additional three proteins involved in this biological process (PSD-95, p-AKT, and BDNF) for immunoblotting.…”

Pioglitazone, a PPAR-γ Activator, Stimulates BKCa but Suppresses IKM in Hippocampal Neurons

“…They are also type II diabetes drugs approved by U.S. Food and Drug Administration. There is growing evidence that the agonist of PPAR-γ might have neuroprotective potential in CNS diseases such as stroke, Parkinson’s disease and depression (Kapadia et al, 2008; Schlachetzki and Winkler, 2015; Li et al, 2018). …”