Circular RNAs (circRNAs) are a type of noncoding RNAs (ncRNAs), produced in eukaryotic cells during post-transcriptional processes. They are more stable than linear RNAs, and possess spatio-temporal properties. CircRNAs do not distribute equally in the neuronal compartments in the brain, but largely enriched in the synapses. These ncRNA species can be used as potential clinical biomarkers in complex disorders of the central nervous system (CNS), which is supported by recent findings. For example, ciRS-7 was found to be a natural microRNAs sponge for miRNA-7 and regulate Parkinson’s disease (PD)/ Alzheimer’s disease (AD)-related genes; circPAIP2 is an intron-retaining circRNA which upregulates memory-related parental genes PAIP2 to affect memory development through PABP reactivation. The quantity of circRNAs carry important messages, either when they are inside the cells, or in circulation, or in exosomes released from synaptoneurosomes and endothelial. In addition, small molecules such as microRNAs and microvesicles can pass through the blood-brain barrier (BBB) and get into blood. For clinical applications, the study population needs to be phenotypically well-defined. CircRNAs may be combined with other biomarkers and imaging tools to improve the diagnostic power.

Background: Acute ischemic stroke (AIS) is a leading cause of disability and mortality worldwide. Prediction of penumbra existence after AIS is crucial for making decision on reperfusion therapy. Yet a fast, inexpensive, simple, and noninvasive predictive biomarker for the poststroke penumbra with clinical translational potential is still lacking. We aim to investigate whether the CircOGDH (circular RNA derived from oxoglutarate dehydrogenase) is a potential biomarker for penumbra in patients with AIS and its role in ischemic neuronal damage. Methods: CircOGDH was screened from penumbra of middle cerebral artery occlusion mice and was assessed in plasma of patients with AIS by quantitative polymerase chain reaction. Magnetic resonance imaging was used to examine the penumbra volumes. CircOGDH interacted with miR-5112 (microRNA-5112) in primary cortical neurons was detected by fluorescence in situ hybridization, RNA immunoprecipitation, and luciferase reporter assay. Adenovirus-mediated CircOGDH knockdown ameliorated neuronal apoptosis induced by COL4A4 (Gallus collagen, type IV, alpha IV) overexpression. Transmission electron microscope, nanoparticle tracking analysis, and Western blot were performed to confirm exosomes. Results: CircOGDH expression was dramatically and selectively upregulated in the penumbra tissue of middle cerebral artery occlusion mice and in the plasma of 45 patients with AIS showing a 54-fold enhancement versus noncerebrovascular disease controls. Partial regression analysis revealed that CircOGDH expression was positively correlated with the size of penumbra in patients with AIS. Sequestering of miR-5112 by CircOGDH enhanced COL4A4 expression to elevate neuron damage. Additionally, knockdown of CircOGDH significantly enhanced neuronal cell viability under ischemic conditions. Furthermore, the expression of CircOGDH in brain tissue was closely related to that in the serum of middle cerebral artery occlusion mice. Finally, we found that CircOGDH was highly expressed in plasma exosomes of patients with AIS compared with those in noncerebrovascular disease individuals. Conclusions: These results demonstrate that CircOGDH is a potential therapeutic target for regulating ischemic neuronal viability, and is enriched in neuron-derived exosomes in the peripheral blood, serving as a predictive biomarker of penumbra in patients with AIS.

Exosomes contribute to cell–cell communications. Emerging evidence has shown that microglial exosomes may play crucial role in regulation of neuronal functions under ischemic conditions. However, the underlying mechanisms of microglia-derived exosome biosynthesis are largely unknown. Herein, we reported that the microglial PDE1-B expression was progressively elevated in the peri-infarct region after focal middle cerebral artery occlusion. By an oxygen-glucose-deprivation (OGD) ischemic model in cells, we found that inhibition of PDE1-B by vinpocetine in the microglial cells promoted M2 and inhibited M1 phenotype. In addition, knockdown or inhibition of PDE1-B significantly enhanced the autophagic flux in BV2 cells, and vinpocetine-mediated suppression of M1 phenotype was dependent on autophagy in ischemic conditions. Co-culture of BV2 cells and neurons revealed that vinpocetine-treated BV2 cells alleviated OGD-induced neuronal damage, and treatment of BV2 cells with 3-MA abolished the observed effects of vinpocetine. We further demonstrated that ischemia and vinpocetine treatment significantly altered microglial exosome biogenesis and release, which could be taken up by recipient neurons and regulated neuronal damage. Finally, we showed that the isolated exosome per se from conditioned BV2 cells is sufficient to regulate cortical neuronal survival in vivo. Taken together, these results revealed a novel microglia-neuron interaction mediated by microglia-derived exosomes under ischemic conditions. Our findings further suggest that PDE1-B regulates autophagic flux and exosome biogenesis in microglia which plays a crucial role in neuronal survival under cerebral ischemic conditions.

Plant extracellular vesicles (PEVs) have emerged important roles in central nervous system (CNS) disorders. PEVs are nanoscale vesicles (30-150 nm) that mediate intercellular communication and exhibit unique therapeutic potential due to their natural biocompatibility, minimal immunogenicity, and ability to cross the blood-brain barrier (BBB). With increasing interest in neurotherapeutics, PEVs offer promising applications for CNS disorders by overcoming delivery barriers and reducing adverse effects associated with synthetic nanoparticles. This review provides a comprehensive analysis of the role of PEVs in CNS disorders, focusing on their mechanisms of action, therapeutic potential, and advantages over mammalian extracellular vesicles (MEVs) and synthetic delivery systems. It also highlights emerging research, challenges, and future directions for their clinical translation. PEVs, derived from fruits, vegetables, and medicinal plants, contain bioactive molecules such as proteins, lipids, microRNAs (miRNAs) and nucleic acids. These vesicles demonstrate the ability to traverse the BBB through receptor-mediated transport and membrane fusion, delivering therapeutic effects for CNS disorders, including neuroinflammation, ischemic stroke, and gliomas. Their pharmacological benefits stem from active metabolites, such as gingerols, alkaloids, and flavonoids, which modulate immune responses, maintain BBB integrity, and reduce neuronal apoptosis. Despite their advantages, challenges such as efficient extraction methods, standardization, and scalability remain obstacles to clinical application. Addressing these issues through advanced extraction techniques, improved characterization, and optimized drug loading strategies can enhance the clinical utility of PEVs.

Ischemic stroke is usually followed by inflammatory responses mediated by microglia. However, the effect of statins on directly preventing posthypoxia microglia inflammatory factors to prevent injury to surrounding healthy neurons is unclear. Atorvastatin and rosuvastatin, which have different physical properties regarding their lipid and water solubility, are the most common HMG-CoA reductase inhibitors (statins) and might directly block posthypoxia microglia inflammatory factors to prevent injury to surrounding neurons. Neuronal damage and microglial activation of the peri-infarct areas were investigated by Western blotting and immunofluorescence after 24 hours in a middle cerebral artery occlusion (MCAO) rat model. The decrease in neurons was in accordance with the increase in microglia, which could be reversed by both atorvastatin and rosuvastatin. The effects of statins on blocking secretions from posthypoxia microglia and reducing the secondary damage to surrounding normal neurons were studied in a coculture system in vitro. BV2 microglia were cultured under oxygen glucose deprivation (OGD) for 3 hours and then cocultured following reperfusion for 24 hours in the upper wells of transwell plates with primary neurons being cultured in the bottom wells. Inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and cyclooxygenase-2 (COX2), which are activated by the nuclear factor-kappa B (NF-κB) signaling pathway in OGD-induced BV2 microglia, promoted decreased release of the anti-inflammatory cytokine IL-10 and apoptosis of neurons in the coculture systems according to ELISA and Western blotting. However, pretreatment with atorvastatin or rosuvastatin significantly reduced neuronal death, synaptic injury, and amyloid-beta (Aβ) accumulation, which might lead to increased low-density lipoprotein receptors (LDLRs) in BV2 microglia. We concluded that the proinflammatory mediators released from postischemia damage could cause damage to surrounding normal neurons, while HMG-CoA reductase inhibitors prevented neuronal apoptosis and synaptic injury by inactivating microglia through blocking the NF-κB signaling pathway.

Objectives Oxidative stress level takes part in the development of cognitive decline. However, the association between total antioxidant capacity (TAC) from diet and cognitive function is controversial. The aim of this study was to investigate the relationship between TAC and the cognitive function of older adults in the U.S. Design A cross-sectional study. Setting National Health and Nutrition Examination Surveys database. Participants 2712 older adults aged over 60 years. Measurements TAC was calculated from 8 antioxidative vitamins based on the reference values for vitamin C equivalent antioxidant capacity obtained from individuals’ 24 h dietary recall. Four memory-related assessments were employed [Immediate Recall test (IRT), Delayed Recall test (DRT), Animal Fluency test (AFT), and Digit Symbol Substitution test (DSST)]. Results Among the 2712 participants, the median age was 68 years, and 50.4% were women. Participants in the group with higher TAC levels had relatively higher IRT, AFT and DSST scores (P=0.025, P=0.008, P<0.001, respectively). In adjusted weighted linear regression, log-transformed TAC was positively associated with AFT (β=1.10, 95%CI: 0.51, 1.70) and DSST (β=2.81, 95%CI: 1.16, 4.45). Compared with the first quartile, the participants in the second (Q2 vs. Q1, OR=0.66, 95%CI: 0.43,1.02) and fourth quartile (Q4 vs. Q1, OR=0.47, 95%CI:0.28, 0.78) of log-transformed TAC showed a decreased risk of impaired cognitive function (ICF) after adjusting for confounders. The dose-response analysis indicated a gradual descent in the risk of ICF as TAC increases. Diabetes mellitus (DM) mediated part of the effect of TAC on ICF. The relationship between TAC and ICF was more pronounced in subjects with DM (Q4 vs Q1, OR=0.36, 95%CI:0.17, 0.74). Conclusion Our findings support that higher dietary antioxidant potential was related to a decreased risk of cognitive dysfunction, particularly in the subjects with DM who may have oxidative injury. DM was one of the factors mediating the effect of TAC on ICF.