Background: Stroke is one of the leading causes of death and disability worldwide and places a heavy burden on the economy in our society. Current treatments, such as the use of thrombolytic agents, are often limited by a narrow therapeutic time window. However, the regeneration of the brain after damage is still active days, even weeks, after stroke occurs, which might provide a second window for treatment. Emodin, a traditional Chinese medicinal herb widely used to treat acute hepatitis, has been reported to possess antioxidative capabilities and protective effects against myocardial ischemia/reperfusion injury. However, the underlying mechanisms and neuroprotective functions of Emodin in a rat middle cerebral artery occlusion (MCAO) model of ischemic stroke remain unknown. This study investigates neuroprotective effects of Emodin in ischemia both in vitro and in vivo. Methods: PC12 cells were exposed to oxygen-glucose deprivation to simulate hypoxic injury, and the involved signaling pathways and results of Emodin treatment were evaluated. The therapeutic effects of Emodin in ischemia animals were further investigated. Results: Emodin reduced infarct volume and cell death following focal cerebral ischemia injury. Emodin treatment restored PC12 cell viability and reduced reactive oxygen species (ROS) production and glutamate release under conditions of ischemia/hypoxia. Emodin increased Bcl-2 and glutamate transporter-1 (GLT-l) expression but suppressed activated-caspase 3 levels through activating the extracellular signal-regulated kinase (ERK)-1/2 signaling pathway. Conclusion: Emodin induced Bcl-2 and GLT-1 expression to inhibit neuronal apoptosis and ROS generation while reducing glutamate toxicity via the ERK-1/2 signaling pathway. Furthermore, Emodin alleviated nerve cell injury following ischemia/reperfusion in a rat MCAO model. Emodin has neuroprotective effects against ischemia/reperfusion injury both in vitro and in vivo, which may be through activating the ERK-1/2 signaling pathway.

Maternal immune activation (MIA) increases the risk of autism spectrum disorder (ASD) in offspring. Microbial dysbiosis is associated with ASD symptoms. However, the alterations in the brain–gut–microbiota axis in lipopolysaccharide (LPS)-induced MIA offspring remain unclear. Here, we examined the social behavior, anxiety-like and repetitive behavior, microbiota profile, and myelination levels in LPS-induced MIA rat offspring. Compared with control offspring, MIA male rat offspring spent less time in an active social interaction with stranger rats, displayed more anxiety-like and repetitive behavior, and had more hypomyelination in the prefrontal cortex and thalamic nucleus. A fecal microbiota analysis revealed that MIA offspring had a higher abundance of Alistipes, Fusobacterium, and Ruminococcus and a lower abundance of Coprococcus, Erysipelotrichaies, and Actinobacteria than control offspring, which is consistent with that of humans with ASD. The least absolute shrinkage and selection operator (LASSO) method was applied to determine the relative importance of the microbiota, which indicated that the abundance of Alistipes and Actinobacteria was the most relevant for the profile of defective social behavior, whereas Fusobacterium and Coprococcus was associated with anxiety-like and repetitive behavior. In summary, LPS-induced MIA offspring showed an abnormal brain–gut–microbiota axis with social behavior deficits, anxiety-like and repetitive behavior, hypomyelination, and an ASD-like microbiota profile.

Background: Parkinson’s disease (PD) is typically characterized by impairment of motor function. Gait disturbances similar to those observed in patients with PD can be observed in animals after injection of neurotoxin 6-hydroxydopamine (6-OHDA) to induce unilateral nigrostriatal dopamine depletion. Exercise has been shown to be a promising non-pharmacological approach to reduce the risk of neurodegenerative disease. Methods: In this study, we investigated the long-term effects of voluntary running wheel exercise on gait phenotypes, depression, cognitive, rotational behaviors as well as histology in a 6-OHDA-lesioned rat model of PD. Results: We observed that, when compared with the non-exercise controls, five-week voluntary exercise alleviated and postponed the 6-OHDA-induced gait deficits, including a significantly improved walking speed, step/stride length, base of support and print length. In addition, we found that the non-motor functions, such as novel object recognition and forced swim test, were also ameliorated by voluntary exercise. However, the rotational behavior of the exercise group did not show significant differences when compared with the non-exercise group. Conclusions: We first analyzed the detailed spatiotemporal changes of gait pattern to investigate the potential benefits after long-term exercise in the rat model of PD, which could be useful for future objective assessment of locomotor function in PD or other neurological animal models. Furthermore, these results suggest that short-term voluntary exercise is sufficient to alleviate cognition deficits and depressive behavior in 6-OHDA lesioned rats and long-term treatment reduces the progression of motor symptoms and elevates tyrosine hydroxylase (TH), Brain-derived neurotrophic factor (BDNF), bone marrow tyrosine kinase in chromosome X (BMX) protein expression level without affecting dopaminergic (DA) neuron loss in this PD rat model.

Stroke is a major cause of death and disability across the world, and its detrimental impact should not be underestimated. Therapies are available and effective for ischemic stroke (e.g., thrombolytic recanalization and mechanical thrombectomy); however, there are limitations to therapeutic interventions. Recanalization therapy has developed dramatically, while the use of adjunct neuroprotective agents as complementary therapies remains deficient. Pathological TAR DNA-binding protein (TDP-43) has been identified as a major component of insoluble aggregates in numerous neurodegenerative pathologies, including ALS, FTLD and Alzheimer’s disease. Here, we show that increased pathological TDP-43 fractions accompanied by impaired mitochondrial function and increased gliosis were observed in an ischemic stroke rat model, suggesting a pathological role of TDP-43 in ischemic stroke. In ischemic rats administered rapamycin, the insoluble TDP-43 fraction was significantly decreased in the ischemic cortex region, accompanied by a recovery of mitochondrial function, the attenuation of cellular apoptosis, a reduction in infarct areas and improvements in motor defects. Accordingly, our results suggest that rapamycin provides neuroprotective benefits not only by ameliorating pathological TDP-43 levels, but also by reversing mitochondrial function and attenuating cell apoptosis in ischemic stroke.

Due to its high oxygen demand and abundance of peroxidation-susceptible lipid cells, the brain is particularly vulnerable to oxidative stress. Induced by a redox state imbalance involving either excessive generation of reactive oxygen species (ROS) or dysfunction of the antioxidant system, oxidative stress plays a central role in a common pathophysiology that underpins neuronal cell death in acute neurological disorders epitomized by stroke and chronic ones such as Alzheimer’s disease. After cerebral ischemia, for example, inflammation bears a key responsibility in the development of permanent neurological damage. ROS are involved in the mechanism of post-ischemic inflammation. The activation of several inflammatory enzymes produces ROS, which subsequently suppress mitochondrial activity, leading to further tissue damage. Pomalidomide (POM) is a clinically available immunomodulatory and anti-inflammatory agent. Using H₂O₂-treated rat primary cortical neuronal cultures, we found POM displayed neuroprotective effects against oxidative stress and cell death that associated with changes in the nuclear factor erythroid derived 2/superoxide dismutase 2/catalase signaling pathway. POM also suppressed nuclear factor kappa-light-chain-enhancer (NF-κB) levels and significantly mitigated cortical neuronal apoptosis by regulating Bax, Cytochrome c and Poly (ADP-ribose) polymerase. In summary, POM exerted neuroprotective effects via its anti-oxidative and anti-inflammatory actions against H₂O₂-induced injury. POM consequently represents a potential therapeutic agent against brain damage and related disorders and warrants further evaluation.

Background: Glioblastoma stem-like cells (GSC) have been shown to promote tumor growth, tumor-associated neovascularization, therapeutic resistance, and metastasis. CXCR4 receptors have been found involved in the proliferation, metastasis, angiogenesis, and drug-resistant characteristics of glioblastoma. However, the role of CXCR4 in modulating the stem-like cell properties of rat glioblastoma remains ambiguous. Methods: To explore the role of the CXCL12/CXCR4 axis in maintaining rat GSC properties, we disrupted the CXCR4 signaling by using small hairpin interfering RNA (shRNA). To investigate the role of the CXCL12/CXCR4 axis in maintaining rat GSC properties, we used a spheroid formation assay to assess the stem cell self-renewal properties. A western blot analysis and PCR arrays were used to examine the genes involved in proliferation, self-renewal, and cancer drug resistance. Finally, DNA content and flow cytometry, an immunohistochemical analysis, and methylcellulose colony formation, in vitro invasive and intracranial injection xenograft assays were employed to examine the disruptive effect of CXCR4 on the characteristics of GSCs of the RG2 cell line. Results: Disrupting CXCR4 inhibited the proliferation of RG2 cells both in vitro and in vivo. The spheroid formation assay indicated that CXCR4 was vital for the self-renewal of RG2 GSCs. Disrupting the CXCL12/CXCR4 pathway also reduced the expression of GSC cell markers, including Nestin, ABCG2, and musashi (Msi), and the expression of genes involved in regulating stem cell properties, including Oct4, Nanog, maternal embryonic leucine zipper kinase (MELK), MGMT, VEGF, MMP2, and MMP9. Conclusion: The chemokine receptor CXCR4 is crucial for maintaining the self-renewal, proliferation, therapeutic resistance, and angiogenesis of GSCs of rat RG2 glioblastoma.