Inflammation and oxidative stress play an important part in the pathogenesis of focal cerebral ischemia/reperfusion (I/R) injury, resulting in neuronal death. The signaling pathways involved and the underlying mechanisms of these events are not fully understood. Chrysin, which is a naturally occurring flavonoid, exhibits various biological activities. In this study, we investigated the neuroprotective properties of chrysin in a mouse model of middle cerebral artery occlusion (MCAO). To this end, male C57/BL6 mice were pretreated with chrysin once a day for seven days and were then subjected to 1 h of middle cerebral artery occlusion followed by reperfusion for 24 h. Our data show that chrysin successfully decreased neurological deficit scores and infarct volumes, compared with the vehicle group. The increases in glial cell numbers and proinflammatory cytokine secretion usually caused by ischemia/reperfusion were significantly ameliorated by chrysin pretreatment. Moreover, chrysin also inhibited the MCAO-induced up-regulation of nuclear factor-kappa B (NF-κB), cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS), compared with the vehicle. These results suggest that chrysin could be a potential prophylactic agent for cerebral ischemia/reperfusion (I/R) injury mediated by its anti-inflammatory and anti-oxidative effects.

Subcortical ischemic vascular dementia (SIVD) is very common among the older people, but has no approved treatment. Preclinical trials show that remote ischemic conditioning (RIC) reduces recurrence of ischemic stroke. We hypothesize that RIC may also be an effective therapy for patients with SIVD. Thirty-seven consecutive SIVD cases were enrolled in this randomized control study. Eighteen RIC patients underwent five brief cycles of conditioning (bilateral upper limb compression at 200 mmHg) followed by reperfusion twice daily over 6 consecutive months. Nineteen control patients underwent the same process, but at a pressure of 60 mmHg which caused no restriction on the blood flow of the upper limb. The primary outcome measures were changes in neuropsychological assessments. The secondary outcomes included the changes in high-sensitive C-reactive protein (hs-CRP) concentration, white matter lesion volume (WMLV), diffusion tension imaging (DTI) metrics of white matter. All data were collected at baseline and follow-up. A significant treatment difference favoring RIC at 6 months was observed on performance of Hopkins Verbal Learning Test-Revised (HVLT-R), Controlled Oral Word Association Test (COWAT), Trail Making Test A and B (TMT-A & TMT-B), and Judgment of Line Orientation (JLO) (p < 0.05). The control group did not show much improvement after the treatment, and only with a slight change in HVLT-R and TMT-R (p < 0.05). Covariance analysis of efficacy between the two groups suggested that RIC patients performed better on JLO than control patients at the 6-month follow-up (RIC 23.10 vs. control 18.56; p = 0.013). Although DTI metrics were comparable, Hs-CRP levels and WMLV in RIC patients showed a declining trend. Over the 6-month treatment period, we found that RIC was safe and effective for improving cognitive function in SIVD patients. Clinical Trial Registration ( http://www.clinicaltrials.gov ), Unique identifier: NCT 03022149; Retrospectively registered; Date of registration: January 16, 2017.

Background: Intracerebral hemorrhage (ICH) is a fatal subtype of stroke that lacks effective therapy. Blood-brain barrier (BBB) damage is a hallmark of ICH-induced brain injury that leads to edema formation, leukocytes infiltration, influx of blood components into the perihematomal (PHE) region, and eventually brain injury. Astrocytes are essential for the formation and maintenance of the BBB by providing secreted molecules that contribute to the association between these cells. Sonic hedgehog (SHH) derived from astrocytes promotes the maturity and integrity of the BBB by upregulating tight junctions (TJs) in brain capillary endothelial cells (ECs). However, the effect of SHH on BBB in ICH has not been investigated.Methods: Cyclopamine (CYC) is a potent, selective inhibitor that specifically blocks the SHH signaling pathway. Here, we used pharmacological inhibitions (CYC and its derivatives) to determine a critical role of the SHH signaling pathway in promoting BBB integrity after ICH by mechanisms of regulating the TJ proteins in vivo and in vitro.Results: The expression of astrocytic SHH was upregulated in mouse brains after ICH. Compared with the vehicle-treated group, inhibition of the SHH signaling pathway with CYC and its derivatives treatments aggravated neurological function deficits, brain edema, hematoma volume, and BBB impairment by downregulating TJs in ECs through the SHH-Gli-1 axis in vivo and in vitro.Conclusions: SHH signaling pathway at the level of the BBB provides a barrier-promoting effect, suggesting that the SHH signaling pathway may function as a potential therapeutic target for restoring BBB function in ICH.

Background: Guillain–Barré syndrome (GBS), a post-infectious, immune-mediated, acute demyelinating disease of the peripheral nerves and nerve roots, represents the most prevalent and severe acute paralyzing neuropathy. Purinergic P2X7 receptors (P2X7R) play a crucial role in central nervous system inflammation. However, little is known about their role in the immune-inflammatory response within the peripheral nervous system. Methods: Initially, we assessed the expression of purinergic P2X7R in the peripheral blood of patients with GBS using flow cytometry and qRT-PCR. Next, we explored the expression of P2 X7R in CD4⁺ T cells, CD8⁺ T cells, and macrophages within the sciatic nerves and spleens of rats using immunofluorescence labeling and flow cytometry. The P2X7R antagonist brilliant blue G (BBG) was employed to examine its therapeutic impact on rats with experimental autoimmune neuritis (EAN) induced by immunization with the P0_{180 − 199} peptide. We analyzed CD4⁺ T cell differentiation in splenic mononuclear cells using flow cytometry, assessed Th17 cell differentiation in the sciatic nerve through immunofluorescence staining, and examined the expression of pro-inflammatory cytokine mRNA using RT-PCR. Additionally, we performed protein blotting to assess the expression of P2X7R and NLRP3-related inflammatory proteins within the sciatic nerve. Lastly, we utilized flow cytometry and immunofluorescence labeling to examine the expression of NLRP3 on CD4⁺ T cells in rats with EAN. Results: P2X7R expression was elevated not only in the peripheral blood of patients with GBS but also in rats with EAN. In rats with EAN, inhibiting P2X7R with BBG alleviated neurological symptoms, reduced demyelination, decreased inflammatory cell infiltration of the peripheral nerves, and improved nerve conduction. BBG also limited the production of pro-inflammatory molecules, down-regulated the expression of P2X7R and NLRP3, and suppressed the differentiation of Th1 and Th17 cells, thus protecting against EAN. These effects collectively contribute to modifying the inflammatory environment and enhancing outcomes in EAN rats. Conclusions: Suppression of P2X7R relieved EAN manifestation by regulating CD4⁺ T cell differentiation and NLRP3 inflammasome activation. This finding underscores the potential significance of P2X7R as a target for anti-inflammatory treatments, advancing research and management of GBS.

Centella asiatica (L.) Urb., a traditional medicinal plant widely distributed in Southeast Asia, has been demonstrated to possess significant neuroprotective effect. However, the pharmacological and molecular mechanisms of C. asiatica (CA) in treating neurological diseases remain to be further explored. This review synthesizes evidence on CA's pharmacokinetics, antioxidant/anti-inflammatory mechanisms, and therapeutic potential in various neurological disorders. Evidence shows CA can mitigate oxidative stress, inflammation, mitochondrial dysfunction, and neuronal apoptosis-key mechanisms underlying these conditions. In epilepsy models, asiatic acid suppresses glutamate release, improves synaptic and mitochondrial function, and reduces neuronal damage. In neurodegenerative diseases, CA extracts enhance memory and cognitive functions by activating antioxidant response pathways and protecting hippocampal mitochondria from oxidative stress. CA extracts also display anticonvulsant effects without major toxicity. Against Bisphenol A-induced neurotoxicity, CA alleviates oxidative stress and inflammation while restoring mitochondrial function. For radiation-induced brain injury, CA improves cognition and memory via antioxidant pathways and anti-inflammatory effects. In cerebral ischemia-reperfusion injury, asiaticoside reduces oxidative stress and neuroinflammation through NOD2/MAPK/NF-κB pathway modulation and microglial regulation. Recent research suggests that CA also plays a significant role in alleviating symptoms of anxiety and depression. The plant's active components have been found to regulate neurotransmitter activity, reduce oxidative stress, and modulate the hypothalamic-pituitary-adrenal (HPA) axis. CA demonstrates broad neuroprotective potential, offering multi-target benefits with relatively low toxicity. These findings support its development as a novel therapeutic agent for neurological disorders. Further clinical research is warranted to confirm safety, optimize dosing, and translate preclinical results into effective human treatments.

Intravenous thrombolysis using recombinant tissue plasminogen activator (tPA) remains the primary treatment for patients with acute ischemic stroke (AIS). However, the mechanism of tPA-related hemorrhagic transformation (HT) remains poorly understood. Elevation of histidine-rich glycoprotein (HRG) expression was detected by nano-liquid chromatography tandem mass spectrometry at 1 h following tPA infusion as compared to baseline prior to tPA infusion (discovery cohort, n = 10), which was subsequently confirmed in a validation cohort ( n = 157) by ELISA. Surprisingly, no elevation of HRG was detected in individuals who subsequently developed HT. During in vitro experiments, HRG reduced neutrophil NETosis, inflammatory cytokine production, and migration across the blood–brain barrier induced by tPA. In a photothrombotic murine AIS model, HRG administration ameliorated HT with delayed thrombolysis, by inhibiting neutrophil immune infiltration and downregulating pro-inflammatory signaling pathways. Neutrophil depletion or NETosis inhibition also alleviated HT, whereas HRG siRNA treatment exacerbated HT. In conclusion, fluctuations in HRG levels may reflect tPA therapy and its associated HT. The inhibitory effect of HRG on neutrophils may counteract tPA-induced immune abnormalities and HT in patients with AIS.