Sigesbeckia orientalis L. Derived Active Fraction Ameliorates Perioperative Neurocognitive Disorders Through Alleviating Hippocampal Neuroinflammation.

Neuroinflammation is closely related to the pathogenesis of perioperative neurocognitive disorders (PNDs), which is characterized by the activation of microglia, inflammatory pathways and the release of inflammatory mediators. Sigesbeckia orientalis L. (SO) is a traditional Chinese medicine which demonstrates anti-inflammatory activities in different models. In this study, we aim to isolate the active fraction from the extract of SO with higher anti-inflammatory potential and confirm if the selected fraction exerts neuroprotection against the development of PND in an animal model. Moreover, the components in the selected fraction would be determined by UPLC-PDA analysis. Three fractions were prepared by column chromatography packed with three different macroporous resins. Anti-inflammatory activities of prepared fractions were accessed in microglial BV2 cultures by nitric oxide release, gene expression of inflammatory cytokines and activation of inflammatory JNK and NF-kB pathway molecules. Our results demonstrated that the fraction prepared from D101 macroporous resin (D101 fraction) exhibited a more potent anti-neuroinflammatory effect. The neuroprotective effect of D101 fraction was further examined in postoperative mice. Our results showed that surgery-induced cognitive dysfunction was attenuated by the D101 fraction treatment. This fraction also reduced microglial activation, inflammatory cytokines and inhibiting JNK and NF-kB pathway molecules in the hippocampus. In addition, surgery induced dendritic spine loss while D101 fraction ameliorated the spine loss in the hippocampus. For safety concerns, anti-thrombotic effect was examined by tail bleeding assay and no significant change of the bleeding pattern was found. UPLC-PDA analysis indicated that flavonoids (rutin, isochlorogenic acid A, isochlorogenic acid C) and terpenoid (darutoside) were the most important components in the D101 fraction. Our results support a therapeutic, as well as the translational potential for D101 fraction in ameliorating postoperative neuroinflammation and subsequent PND in the clinical setting without increasing bleeding tendencies.

Applications of adeno-associated virus vector-mediated gene delivery for neurodegenerative diseases and psychiatric diseases: Progress, advances, and challenges.

Neurodegeneration is the most common disease in the elderly population due to its slowly progressive nature of neuronal deterioration, eventually leading to executive dysfunction. The pathological markers of neurological disorders are relatively well-established, however, detailed molecular mechanisms of progression and therapeutic targets are needed to develop novel treatments in human patients. Treating known therapeutic targets of neurological diseases has been aided by recent advancements in adeno-associated virus (AAV) technology. AAVs are known for their low-immunogenicity, blood-brain barrier (BBB) penetrating ability, selective neuronal tropism, stable transgene expression, and pleiotropy. In addition, the usage of AAVs has enormous potential to be optimized. Therefore, AAV can be a powerful tool used to uncover the underlying pathophysiology of neurological disorders and to increase the success in human gene therapy. This review summarizes different optimization approaches of AAV vectors with their current applications in disease modeling, neural tracing and gene therapy, hence exploring progressive mechanisms of neurodegenerative diseases as well as effective therapy. Lastly, this review discusses the limitations and future perspectives of the AAV-mediated transgene delivery system.