Curcumin Relieves Chronic Unpredictable Mild Stress-Induced Depression-Like Behavior through the PGC-1α/FNDC5/BDNF Pathway

Background and Aim. Increasing evidence suggests that the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α)/fibronectin type III domain-containing 5 (FNDC5)/brain-derived neurotrophic factor (BDNF) pathway might be critical for neuroprotection. Our present study is aimed at investigating the antidepressant-like effects of curcumin (CUR) in a chronic unpredictable mild stress- (CUMS-) induced depression rat model and explore whether the PGC-1α/FNDC5/BDNF pathway is the major driving force behind the therapeutic effects of CUR. Methods. All rats were randomly divided into four groups, namely, control, CUMS, CUMS + CUR , and CUMS + CUR + SR 18292 (PGC-1α inhibitor). Behavioral tests were conducted to assess the antidepressant-like effects of CUR. The expressions of PGC-1α, estrogen-related receptor alpha (ERRα), FNDC5, and BDNF were determined to investigate the regulatory effects of CUR on the PGC-1α/FNDC5/BDNF pathway. The PGC-1α inhibitor SR18292 was used to explore the role of PGC-1α in the induction of BDNF by CUR. Results. Daily gavage of 100 mg/kg CUR successfully attenuated the abnormal behaviors induced by CUMS and effectively prevented CUMS-induced reduction of PGC-1α, ERRα, FNDC5, and BDNF expressions. CUR also enhanced PGC-1α and ERRα translocation from cytoplasm to nucleus. Furthermore, we found that CUR supplementation effectively promoted neurocyte proliferation and suppressed neuronal apoptosis induced by CUMS. Of note, the PGC-1α inhibitor SR18292 remarkably reversed the beneficial effects of CUR on depressed rats, indicating an important role of PGC-1α in the antidepressant-like effects of CUR. Conclusion. Collectively, our data evaluating the neuroprotective action of CUR in the CUMS rats highlights the involvement of the PGC-1α/FNDC5/BDNF pathway in the antidepressant-like effects of CUR.

Coffeeberry Activates the CaMKII/CREB/BDNF Pathway, Normalizes Autophagy and Apoptosis Signaling in Nonalcoholic Fatty Liver Rodent Model

Nonalcoholic fatty liver disease (NAFLD) shows extensive liver cell destruction with lipid accumulation, which is frequently accompanied by metabolic comorbidities and increases mortality. This study aimed to investigate the effects of coffeeberry (CB) on regulating the redox status, the CaMKII/CREB/BDNF pathway, autophagy, and apoptosis signaling by a NAFLD rodent model senescence-accelerated mice prone 8 (SAMP8). Three-month-old male SAMP8 mice were divided into a control group and three CB groups (50, 100, and 200 mg/kg BW), and fed for 12 weeks. The results show that CB reduced hepatic malondialdehyde and carbonyl protein levels. CB significantly enhanced Ca2+/calmodulin-dependent protein kinase II (CaMKII) and brain-derived neurotrophic factor (BDNF) and reduced the phospho-cAMP response element-binding protein (p-CREB)/CREB ratio. In addition, CB increased the silent information regulator T1 level, promoted Beclin 1 and microtubule-associated protein light chain 3 II expressions, and reduced phosphorylated mammalian target of rapamycin and its downstream p-p70s6k levels. CB also inhibited the expressions of apoptosis-related factors poly (ADP-ribose) polymerase-1 and the apoptosis-inducing factor. In conclusion, CB might protect the liver by reducing oxidative stress, activating the CaMKII/CREB/BDNF pathway, and improving autophagic and apoptotic expressions in a dose-dependent manner.

Jie-Yu-He-Huan Capsule Ameliorates Anxiety-Like Behaviours in Rats Exposed to Chronic Restraint Stress via the cAMP/PKA/CREB/BDNF Signalling Pathway

Chronic stress is a critical factor in the aetiology of anxiety disorders; however, in the clinic, enduring and preventive measures are not available, and therapeutic drugs are associated with inevitable side effects. Our study established an anxiety rat model using chronic restraint stress (CRS) and assessed these animals using the open-field test, elevated plus-maze test, and light-dark box test. Jie-Yu-He-Huan capsule (JYHH), a Chinese medicine formula, was used as a preventative drug. The HPA axis-mediated release of corticotropin-releasing hormone, adrenocorticotropic hormone, and corticosterone from the hypothalamus was tested. In the hippocampus and prefrontal cortex, concentrations of 5-HT and its metabolite 5-hydroxyindoleacetic acid, as well as monoamine oxidase A, glucocorticoid receptor, and 5-HT1A receptor expression levels, were measured. Furthermore, we examined protein and mRNA expression of cAMP-PKA-CREB-BDNF pathway components. The results showed that JYHH had a significant preventative effect on the anxiety-like behaviour induced by CRS and prevented abnormal changes in the HPA axis and 5-HT system. Furthermore, CRS inhibited the cAMP-PKA-CREB-BDNF pathway, which returned to normal levels following JYHH treatment. This might be the underlying molecular mechanism of the antianxiety effect of JYHH, which could provide a new clinical target for preventative anxiolytic drugs for chronic stress.

Neuron-Glia Crosstalk Plays a Major Role in the Neurotoxic Effects of Ketamine via Extracellular Vesicles

Background: There is a compelling evidence from animal models that early exposure to clinically relevant general anesthetics (GAs) interferes with brain development, resulting in long-lasting cognitive impairments. Human studies have been inconclusive and are challenging due to numerous confounding factors. Here, we employed primary human neural cells to analyze ketamine neurotoxic effects focusing on the role of glial cells and their activation state. We also explored the roles of astrocyte-derived extracellular vesicles (EVs) and different components of the brain-derived neurotrophic factor (BDNF) pathway.Methods: Ketamine effects on cell death were analyzed using live/dead assay, caspase 3 activity and PARP-1 cleavage. Astrocytic and microglial cell differentiation was determined using RT-PCR, ELISA and phagocytosis assay. The impact of the neuron-glial cell interactions in the neurotoxic effects of ketamine was analyzed using transwell cultures. In addition, the role of isolated and secreted EVs in this cross-talk were studied. The expression and function of different components of the BDNF pathway were analyzed using ELISA, RT-PCR and gene silencing.Results: Ketamine induced neuronal and oligodendrocytic cell apoptosis and promoted pro-inflammatory astrocyte (A1) and microglia (M1) phenotypes. Astrocytes and microglia enhanced the neurotoxic effects of ketamine on neuronal cells, whereas neurons increased oligodendrocyte cell death. Ketamine modulated different components in the BDNF pathway: decreasing BDNF secretion in neurons and astrocytes while increasing the expression of p75 in neurons and that of BDNF-AS and pro-BDNF secretion in both neurons and astrocytes. We demonstrated an important role of EVs secreted by ketamine-treated astrocytes in neuronal cell death and a role for EV-associated BDNF-AS in this effect.Conclusions: Ketamine exerted a neurotoxic effect on neural cells by impacting both neuronal and non-neuronal cells. The BDNF pathway and astrocyte-derived EVs represent important mediators of ketamine effects. These results contribute to a better understanding of ketamine neurotoxic effects in humans and to the development of potential approaches to decrease its neurodevelopmental impact.

Curcumin relieves CUMS-induced depressive-like behaviors through PGC-1α/FNDC5/BDNF pathway

Background Curcumin (CUR), a primary component extracted from the Chinese medicine Curcuma longa, has been suggested to be effective in treating symptoms of a variety of neuropsychiatric disorders including depression. However, the underlying mechanism of CUR’s antidepressant properties remains largely unknown. In this study, the antidepressant effect and its mechanism of CUR were investigated. Methods In this study, the chronic unpredictable mild stress- (CUMS-) induced depression model was employed to investigate the antidepressant effect of CUR. The depressive-like state was evaluated by the behavioral tests. On the day of the sacrifice, blood samples and the hippocampus of Sprague Dawley (SD) rats were collected for the following analysis. The proteins were investigated by Western blotting analysis and immunofluorescence analysis. The mRNA expression was analyzed by quantitative real-time PCR. Cell proliferation and apoptosis was determined with Brdu cell proliferation assay and Nissl staining assay. Results After stress exposure for six weeks, the CUMS rats showed depressive-like behaviors, and the administration of CUR successfully attenuated the depressive-like behaviors in CUMS-treated rats. Additionally, CUR effectively increased the expression of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), fibronectin type III domain-containing 5 (FNDC5), and brain-derived neurotrophic factor (BDNF). The CUR also stimulated the transcription of PGC-1α and estrogen-related receptor alpha (ERRα), enhanced PGC-1α and ERRα translocation from cytoplasm to nucleus, thus activating the PGC-1α/FNDC5/BDNF pathway. Furthermore, we found the supplementation of CUR effectively promoted neurocyte proliferation and suppressed neural apoptosis induced by CUMS. Conclusions Collectively, the study revealed that CUR exerts antidepressant-like effect through the activation of the PGC-1α/FNDC5/BDNF pathway.

History of Atopy Confers Improved Outcomes In IDH Mutant And Wildtype Low-Grade Glioma

Purpose:A history of atopy or allergy has been shown to be protective against the development of glioma, however the effect of atopy on patient outcomes, especially in conjunction with the survival benefit associated with IDH mutation, has not yet been investigated, and is the focus of the study we present here. Methods:Low grade glioma (LGG) data from the TCGA was downloaded, along with IDH, TERT, 1p/19q and ATRX mutational status and genetic alterations. History of asthma, eczema, hay fever, animal, or food allergies, as documented in TCGA, was used to determine patient atopy status. Patients with missing variables were excluded from the study. Results:374 LGG studies were included. Patients with a history of atopy demonstrated longer overall survival (OS) compared to those without (145.3 vs. 81.5 months, p=00.0195). IDH mutant patients with atopy had longer OS compared those without atopy (158.8 vs. 85 months, p=0.035). Multivariate cox regression analysis demonstrated that the effects of atopy on survival were independent of IDH and histological grade, (p=0.002, HR 0.257, 95% 0.109-0.604), (p=<0.001, HR 0.217, 95% 0.107-0.444), and (p=0.004, HR 2.72, 95% 1.373-5.397), respectively. In terms of treatment outcomes, patients with atopy did not differ in treatment response compared to their counterpart. Pathway analysis demonstrated an upstream activation of the BDNF pathway (p=0.00027). Conclusion:A history of atopy confers a survival benefit in patients with diffuse low-grade glioma. Activation of the BDNF pathway may drive the observed differences.