Treatment Of Cerebral Ischemia Research Articles

Design, Synthesis, and Biological Evaluation of Novel Cinnamide Derivatives as Neuroprotective Agents for the Treatment of Cerebral Ischemia.

Ischemic stroke, the most common type of cerebrovascular accident, is a major cause of severe disability among adults worldwide. Although there has been progress in interventions for ischemic stroke in the past decades, there is no effective treatment to prevent brain damage in acute ischemic stroke. Therefore, it is urgent to develop novel neuroprotective agents with a wide therapeutic time window to provide a better prognosis for ischemic stroke patients. The current study aimed to synthesize novel derivatives with substituent cinnamide scaffolds, evaluate biological activity, and obtain neuroprotective agents. The target compounds were synthesized using classical methods of medicinal chemistry. The neuroprotective effects in vitro against Glu-induced neurotoxicity injury were evaluated in PC12 cells by MTT assay. The cell apoptosis was analyzed by flow cytometer. The proteins were detected by western blotting. The neuroprotective activities in vivo were determined in two in vivo models of global and focal cerebral ischemia. Among the title compounds, 9t, 9u, 9y, and 9z exhibited good neuroprotection in vivo and in vitro, which were selected and further studied to determine their mechanism of action. 9t, 9u, 9y and 9z protected PC12 cells against glutamate-induced apoptosis in a dose-dependent manner via caspase-3 pathway. Moreover, the four compounds significantly reduced brain infarct area and exhibited excellent neuroprotective activities in the in vivo MCAO model. Compounds 9t, 9u, 9y, and 9z, as potent neuroprotective agents with anti- neurotoxicity activity in vitro and anticerebral infarction efficacy in vivo, might serve as a useful molecular tool for further physiology and pathophysiology function studies, leading to potential clinical therapeutic agents for ischemic injury.

Mesenchymal stem cell-derived exosomes overexpressing SRC-3 protect mice from cerebral ischemia by inhibiting ferroptosis

BackgroundThe treatment for cerebral ischemia remains limited, and new therapeutic strategies are urgently needed. Exosome has shown great promise for the treatment of cerebral ischemia. Steroid receptor coactivator-3 (SRC-3) was reported to be involved in neurological performances. In this study, we aimed to investigate the protective effects of mesenchymal stem cell (MSC)-derived exosomes overexpressing SRC-3 on cerebral ischemia in mice. MethodsThe mice were treated with an intracerebroventricular injection of GFP-overexpressed exosomes (GFP-exo) and SRC-3-overexpressed exosomes (SRC3-exo) in a middle cerebral artery occlusion (MCAO) model of cerebral ischemia. ResultsThe results showed that SRC3-exo treatment significantly inhibited lipid peroxidation and ferroptosis of the neurons subjected to oxygen-glucose deprivation. It further suppressed the activation of microglia and astrocytes, and decreased the production of pro-inflammatory cytokines in the brains of MCAO mice. Furthermore, SRC3-exo treatment reduced the water content of brain tissue and infarct size, which alleviated the neurological damage and improved neurological performances in the MCAO mice. ConclusionsOur results suggest that MSC-derived exosomes expressing SRC3 can be a therapeutic strategy for cerebral ischemia by inhibiting ferroptosis.

Astragaloside IV combined with ligustrazine ameliorates abnormal mitochondrial dynamics via Drp1 SUMO/deSUMOylation in cerebral ischemia-reperfusion injury.

Astragaloside IV (AST IV) and ligustrazine (Lig), the main ingredients of Astragali Radix and Chuanxiong Rhizoma respectively, have demonstrated significant benefits in treatment of cerebral ischemia -reperfusion injury (CIRI); however, the mechanisms underlying its benificial effects remain unclear. SUMO-1ylation and deSUMO-2/3ylation of dynamin-related protein 1 (Drp1) results in mitochondrial homeostasis imbalance following CIRI, which subsequently aggravates cell damage. This study investigates the mechanisms by which AST IV combined with Lig protects against CIRI, focusing on the involvement of SUMOylation in mitochondrial dynamics. Rats were administrated AST IV and Lig for 7 days, and middle cerebral artery occlusion was established to mimic CIRI. Neural function, cerebral infarction volume, cerebral blood flow, cognitive function, cortical pathological lesions, and mitochondrial morphology were measured. SH-SY5Y cells were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) injury. Mitochondrial membrane potential and lactic dehydrogenase (LDH), reactive oxygen species (ROS), and adenosine triphosphate (ATP) levels were assessed with commercial kits. Moreover, co-immunoprecipitation (Co-IP) was used to detect the binding of SUMO1 and SUMO2/3 to Drp1. The protein expressions of Drp1, Fis1, MFF, OPA1, Mfn1, Mfn2, SUMO1, SUMO2/3, SENP1, SENP2, SENP3, SENP5, and SENP6 were measured using western blot. In rats with CIRI, AST IV and Lig improved neurological and cognitive functions, restored CBF, reduced brain infarct volume, and alleviated cortical neuron and mitochondrial damage. Moreover, in SH-SY5Y cells, the combination of AST IV and Lig enhanced cellular viability, decreased release of LDH and ROS, increased ATP content, and improved mitochondrial membrane potential. Furthermore, AST IV combined with Lig reduced the binding of Drp1 with SUMO1, increased the binding of Drp1 with SUMO2/3, suppressed the expressions of Drp1, Fis1, MFF, and SENP3, and increased the expressions of OPA1, Mfn1, Mfn2, SENP1, SENP2, and SENP5. SUMO1 overexpression promoted mitochondrial fission and inhibited mitochondrial fusion, whereas SUMO2/3 overexpression suppressed mitochondrial fission. AST IV combined with Lig could reverse the effects of SUMO1 overexpression while enhancing those of SUMO2/3 overexpression. This study posits that the combination of AST IV and Lig has the potential to reduce the SUMO-1ylation of Drp1, augment the SUMO-2/3ylation of Drp1, and thereby exert a protective effect against CIRI.

Electroacupuncture Promotes Angiogenesis in Mice with Cerebral Ischemia by Inhibiting miR-7.

To observe the angiogenesis effect of electroacupuncture (EA) at Shuigou acupoint (GV 26) in the treatment of cerebral ischemia, and explore the value of miRNA-7 (miR-7) in it. First, 48 mice were randomly divided into sham operation, middle cerebral artery occlusion (MCAO) model, and EA treatment groups. Then 9 mice were divided into carrier control group, miR-7 knockout group and miR-7 overexpression group (n=3 each group). Finally, 20 mice were divided into model and carrier control group, model and miR-7 knockout group, EA treatment and carrier control group and EA treatment and miR-7 overexpression group, with 3-6 mice in each group. The MCAO model was established in the MCAO and EA groups. Neurological deficit score and 2,3,5-triphenyltetrazolium chloride (TTC) staining were used to evaluate the severity of cerebral ischemia. Hematoxylin-eosin staining was used to describe basic pathological changes. Immunohistochemistry was used to quantify cerebral microvessel density. Real-time PCR and Western blot were used to detect the expression of miR-7 and its downstream target genes Krüppel-like factor 4/vascular endothelial growth factor (KLF4/VEGF) and angiopoietin-2 (ANG-2) in the ischemic cerebral cortex. After EA, neurological deficit scores and infarction volumes decreased, and the density of cerebral microvessels increased. In the MCAO group, miR-7 expression was higher than that in the sham group (P<0.01). After EA at GV 26, miR-7 expression decreased (P<0.01) and the expression of downstream target genes KLF4/VEGF and ANG-2 increased as compared with the MCAO group (P<0.01). After EA combined with overexpression of miR-7, the expression of downstream target genes KLF4/VEGF and ANG-2 decreased compared to the control EA group (P<0.01). After miR-7 knockdown, the expression of KLF4/VEGF and ANG-2 increased (P<0.05 or P<0.01). EA could promote angiogenesis in MCAO mice likely by inhibiting the expression of miR-7 and relieving inhibition of downstream target genes KLF4/VEGF and ANG-2.

Advancements in research on the immune-inflammatory mechanisms mediated by NLRP3 inflammasome in ischemic stroke and the regulatory role of natural plant products.

Ischemic stroke (IS) is a major cause of mortality and disability among adults. Recanalization of blood vessels to facilitate timely reperfusion is the primary clinical approach; however, reperfusion itself may trigger cerebral ischemia-reperfusion injury. Emerging evidence strongly implicates the NLRP3 inflammasome as a potential therapeutic target, playing a key role in cerebral ischemia and reperfusion injury. The aberrant expression and function of NLRP3 inflammasome-mediated inflammation in cerebral ischemia have garnered considerable attention as a recent research focus. Accordingly, this review provides a comprehensive summary of the signaling pathways, pathological mechanisms, and intricate interactions involving NLRP3 inflammasomes in cerebral ischemia-reperfusion injury. Moreover, notable progress has been made in investigating the impact of natural plant products (e.g., Proanthocyanidins, methylliensinine, salidroside, α-asarone, acacia, curcumin, morin, ginsenoside Rd, paeoniflorin, breviscapine, sulforaphane, etc.) on regulating cerebral ischemia and reperfusion by modulating the NLRP3 inflammasome and mitigating the release of inflammatory cytokines. These findings aim to present novel insights that could contribute to the prevention and treatment of cerebral ischemia and reperfusion injury.

Optimal Angiographic Goal and Number of Passes for Octogenarians Undergoing Endovascular Stroke Thrombectomy

BackgroundThe optimal recanalization goal and number of endovascular thrombectomy (EVT) passes for elderly patients with large vessel occlusion (LVO) strokes is unclear. MethodsConsecutive patients 80 years or older undergoing EVT were identified from 2016 to 2022 at a single center. Clinical information, procedural details, and modified treatment in cerebral ischemia (mTICI) scores were collected. Primary outcome was modified Rankin scale (mRS) at 90 days. Bivariate and multivariable analyses were conducted to assess associations between mTICI scores, EVT passes, and 90-day outcomes. Results126 patients were identified. At 90 days, mTICI 2b recanalization resulted in high rates of poor outcomes (8.7% functional independence and 60.9% mortality) not significantly different from mTICI 0, 1 or 2a (median mRS 6 vs. 6, p=0.61). Complete recanalization (mTICI 2c or 3) led to significantly better mRS outcomes at 90 days compared to mTICI 2b (median mRS 4 vs. 6, adjusted p=0.038), with 26.8% functional independence and 37.8% mortality. In multivariable analysis, complete recanalization was significantly associated with better 90-day outcomes than mTICI 2b or lower recanalization (OR 4.24 [95%CI 1.46-12.3]; p=0.002), while the number of passes was not independently associated with worse outcomes (p=0.98). ConclusionsFor octogenarians, mTICI 2b recanalization yields limited clinical benefit and results in poor 90-day outcomes. In contrast, complete recanalization is independently associated with significantly better outcomes. Thus, once the decision is made to pursue EVT in the elderly, mTICI 2c or better recanalization should be the angiographic goal. Providers should not withhold thrombectomy passes based on age alone.

First pass effect in patients undergoing endovascular treatment for posterior circulation acute ischemic stroke

ObjectiveThis study aims to investigate the impact of first pass effect (FPE) on outcomes in the posterior circulation acute ischemic stroke (PC-AIS) and the independent predictors of FPE. MethodsThis was a multicenter, retrospective study. PC-AIS patients who underwent endovascular treatment were reviewed. The cohort achieving complete or nearly complete reperfusion (defined as expanded treatment in cerebralischemia [eTICI] ≥ 2c) was categorized into the FPE and multiple pass effect (MPE) groups. FPE was defined as achieving eTICI ≥ 2c with a single pass and without the use of rescue therapy. Modified FPE (mFPE) was defined as meeting the criteria for FPE but with eTICI ≥ 2b. The association of FPE with 90-day clinical outcomes and predictors for FPE were both investigated. ResultsThe study included a total of 328 patients, with 69 patients (21 %) in the FPE group. For primary outcome, FPE had a significant higher favorable outcome (mRS ≤ 3) rate than MPE (65.2 % vs. 44.8 %, p = 0.003). Similar outcomes were observed in the mFPE. Furthermore, FPE was significantly associated with favorable outcome (adjusted OR 2.23, 95 % CI 1.06-4.73, p = 0.036). Positive predictors for FPE included occlusion in the distal basilar artery, the first-line aspiration or combination, and cardioembolic etiology. Negative predictors for FPE included hypertension and general anesthesia. ConclusionFor PC-AIS patients due to large or medium vessel occlusion, FPE is associated with favorable clinical outcomes. The first-line techniques of aspiration or combination, as well as avoiding general anesthesia, contribute to a better realization of FPE.

Nanoparticle Delivery in Microvascular after Cerebral Ischemia: A Simulation Study

Nanodrug delivery systems have been used in the diagnosis and treatment of ischemic stroke. However, the delivery mechanisms of nanoparticles within microvascular after cerebral ischemia have not been systematically revealed. This study aims to investigate the binding of different nanoparticles to the walls of ischemic brain microvascular through numerical simulations. In this study, 3D models of cerebral microvascular based on ischemic pathological changes are constructed. After building the mesh of microvascular, computational fluid dynamics is used to simulate blood flow and nanoparticle delivery. The simulation results show that the total amount of binding nanoparticles with small size is higher than that with large size. The large-sized nanoparticles are more easily delivered to the stenosis. The density of the nanoparticles has no significant effect on delivery. Furthermore, the study finds that the presence of red blood cells can significantly enhance the delivery efficiency of nanoparticles. In addition to evaluating the forces exerted on the nanoparticles, the impact of the binding affinity of the modified ligand on nanoparticles to the target receptor on delivery is investigated. In summary, selecting suitable nanoparticles according to different targets will improve the delivery efficiency of nanodrugs. The microvascular delivery model of nanoparticles proposed in this study may be helpful in the design of nanoparticles for diagnosis and treatment of cerebral ischemia.

Abstract TMP90: Extension of Subarachnoid Hemorrhage Following Mechanical Thrombectomy is Associated With Clinical Outcomes: A Subgroup Analysis of CLEAR Trial

Introduction: Subarachnoid hemorrhage (SAH) following mechanical thrombectomy (MT) is not uncommon. The prognostic implication for these patients remains unclear and may be affected by the extension of SAH. Methods: We included patients with SAH detected on CT after MT from CLEAR Study (The Vesalio NeVa Stent Retriever Study for Treatment of Large Vessel Occlusion Strokes). SAH was further classified according to extension degree into diffuse (&gt; 1 extraparenchymal compartment) and non-diffuse. Unadjusted and adjusted logistic regressions were used to measure the association of both groups with modified Rankin Scale (mRS) (mRS) score at 90 days. Results: Among 139 patients, 20 SAH patients qualified for final analysis (10 with diffuse SAH: 10 with non-diffuse SAH). There were no statistically significant differences for sex, thrombolytics administration, pre mRS score, baseline NIHSS score, and procedure access (p &gt;0.1) while there were statistically significant imbalances for age and site of occlusion (p=0.02). At the end of the procedure, there was no statistically significant difference in successful recanalization rates defined as a Modified Treatment in Cerebral Ischemia (mTICI) score of 2b or greater (100% in non-diffuse vs. 90% diffuse, P&gt;0.99). However, non-diffuse SAH group were significantly associated with reduced disability at 90 days in both unadjusted (Common odds ratio [cOR] 11.09, 95% confidence interval [CI] (1.72-71.37), p = 0.01) and adjusted models (cOR 12.32, 95% CI 1.49-102.05, p = 0.02). Additionally, non-diffuse SAH group were significantly associated with significantly improved 90-day good functional outcomes defined as mRS 0-2 in unadjusted analysis (80% vs. 30%, OR 9.33, 95% CI 1.99-72.99, p = 0.03) but not in adjusted analysis (OR 7.84, 95% CI 0.55-109.94, p = 0.13). Median NIHSS at 24 hours was significantly lower in non-diffuse group compared to diffuse group (3 [2-6] vs. 17.5 [12-19], p&lt; 0.001) while mortality was reduced to half but did not reach a statistical significance level (10% vs. 20%, p&gt;0.99). Conclusions: Non-diffuse SAH was associated with better clinical outcomes compared to diffuse SAH. These findings may inform adjustable management approaches according to extension degree of SAH.

Competitive leptomeningeal flow impact on thrombectomy reperfusion grade rating

BackgroundCompetitive leptomeningeal flow (CLF) can be observed immediately after mechanical thrombectomy (MT) reperfusion with retrograde contrast clearing of the distal leptomeningeal branches from non-contrast opacified flow through different vascular territories....

Nose-to Brain Delivery of Resveratrol, a Non-Invasive Method for the Treatment of Cerebral Ischemia

Cerebral ischemia represents a particular condition among neurological diseases due to its high frequency, high associated mortality, and the permanent disability in patients that survive it. Numerous studies in animal models have demonstrated the protective properties of resveratrol against cerebral ischemia. Resveratrol is a soluble molecule in polar solvents with high membrane permeability; however, it is rapidly metabolized at the liver and is also a substrate of the ATP binding cassette transporters located at the blood–brain barrier. These circumstances reduced bioavailability of resveratrol to the brain. In this review, we examined nasal resveratrol’s formulations including nanocarriers such as nanostructured lipid carriers, nanoemulsions, nanoparticles, bilosomes, cubosomal, and transferosomes that are directly transported to the brain. An intranasal administration route evades resveratrol transformation due to liver metabolism. Components of nanoformulations increased resveratrol absorption to the brain by enhancing permeation through specific approaches and also maintaining stability during storage. Both characteristics improved the delivery of resveratrol with conserved antioxidant capacity and protective properties for neurological models. Although demonstration that the nanoformulations prevents resveratrol’s blood–brain barrier retention is missing, properties of resveratrol’s nanoformulation encourage testing in clinical trials; however, regulatory approval for a novel nanocarrier in nasal drug delivery is complicated and needs approval.

The Use of Neuromarker NSE, S100-B, GFAP Proteins in the Diagnosis and Treatment of Cerebral Ischemia in Patients with Aneurysmal Subarachnoid Hemorrhage

   The incidence of non-traumatic subarachnoid hemorrhage due to rupture of cerebral aneurysms and subsequent disability motivates the search for predictors of severe course and unfavorable outcome of the disease for early intensive treatment. NSE, S100-B, GFAP markers have proven themselves well for assessing the dynamics of treatment for diseases of the nervous system and detecting neurological nosologies. The use of the above proteins in aneurysmal hemorrhage opens up new perspectives in assessing the clinical status of the patient in the early stages, developing further treatment strategies, as well as helps draw conclusions about the outcome of the disease and possible disability of the patient. The studies collected in the review motivate continued research of the neuromarkers in aneurysmal hemorrhage.

Aspiration thrombectomy versus stent retriever thrombectomy as a first-line approach for cardiogenic cerebral embolism and cryptogenic stroke in large vessels of the anterior circulation.

This study aims to compare the clinical efficacy of aspiration thrombectomy and stent retriever thrombectomy as first-line approaches for anterior circulation large vessel cardiogenic cerebral embolism and cryptogenic stroke. This retrospective observational study included patients with anterior circulation large vessel cardiogenic cerebral embolism and cryptogenic stroke treated with endovascular therapy. Patients were grouped according to the first-line approach they received: aspiration thrombectomy or stent retriever thrombectomy. The primary outcome measure was the change in the National Institute of Health Stroke Scale (NIHSS) score from preoperative to immediate postoperative and from preoperative to discharge. Secondary indicators included the rate of favorable prognosis at discharge [Modified Rankin Scale (mRS) score ≤ 2], successful vessel recanalization rate [modified Treatment in Cerebral Ischemia (mTICI) score ≥ 2b], time from successful femoral artery puncture to successful vessel recanalization, and perioperative complications. The study included 127 cases, with 1 case withdrawal after enrollment due to a stroke of another determined cause, with 83 in the aspiration thrombectomy group and 43 cases in the stent retriever thrombectomy group. The change in NIHSS score from preoperative to immediate postoperative was 5 (1, 8) in the aspiration thrombectomy group and 1 (0, 4.5) in the stent retriever thrombectomy group. The change from preoperative to discharge was 8 (5, 12) in the aspiration thrombectomy group and 4 (0, 9) in the stent retriever thrombectomy group. The aspiration thrombectomy group exhibited significantly better prognosis rates and shorter time from successful femoral artery puncture to successful vessel recanalization. There were no significant differences between the two groups in terms of successful vessel recanalization rates and perioperative complications. As a first-line approach for anterior circulation large vessel cardiogenic cerebral embolism and cryptogenic stroke, aspiration thrombectomy leads to better improvement in neurological functional deficits and prognosis rates compared to stent retriever thrombectomy.

The History of Endovascular Stroke Treatment: From Local Intraarterial Fibrinolysis to Stent Retriever Thrombectomy

Background Acute thromboembolic occlusions of large intracranial arteries are associated with high rates of permanent disability and mortality. Intravenous thrombolysis (IVT) in these patients resulted in an inadequate rate of recanalization and has had limited clinical success. Various endovascular procedures have been attempted to remove intracranial thrombi and reopen occluded vessels. These technical innovations led to the publication of initial case reports, but the methods ultimately did not endure. Endovascular treatment of acute cerebral ischemia was performed only rarely and in selected centers as part of individualized curative attempts. The Solitaire stent was originally developed to treat intracranial aneurysms through stent-assisted coil occlusion. The suggestion that this stent could also be used for intracranial thrombectomy was made as early as 2003 and was clinically confirmed in 2008. Releasing a Solitaire stent into an embolically occluded large cerebral artery, with an incubation time of approximately 3 minutes and slow retraction of the stent, has led to unprecedented success rates of thrombus removal and (sub)total recanalization in more than 90 % of patients. Methods This review article aimed to describe the steps in the development of endovascular stroke therapy, beginning with intra-arterial thrombolysis and early technical innovations leading to the eventual success of stent retriever thrombectomy. Conclusion The potential for mechanical recanalization of acutely occluded large cerebral arteries could not be fully exploited until the advent of stent retriever thrombectomy. The entire concept of stroke treatment fundamentally changed after complete and rapid recanalization first became possible. Randomized controlled trials have shown superiority of stent retriever thrombectomy over IVT. An unparalleled boom in endovascular stroke therapy followed. Key Points: 

Primary results from the CLEAR study of a novel stent retriever with drop zone technology

BackgroundChallenges to revascularization of large vessel occlusions (LVOs) persist. Current stent retrievers have limited effectiveness for removing organized thrombi. The NeVa device is a novel stent retriever designed to capture...

The Role of Necroptosis in Cerebral Ischemic Stroke.

Cerebral ischemia, also known as ischemic stroke, accounts for nearly 85% of all strokes and is the leading cause of disability worldwide. Due to disrupted blood supply to the brain, cerebral ischemic injury is trigged by a series of complex pathophysiological events including excitotoxicity, oxidative stress, inflammation, and cell death. Currently, there are few treatments for cerebral ischemia owing to an incomplete understanding of the molecular and cellular mechanisms. Accumulated evidence indicates that various types of programmed cell death contribute to cerebral ischemic injury, including apoptosis, ferroptosis, pyroptosis and necroptosis. Among these, necroptosis is morphologically similar to necrosis and is mediated by receptor-interacting serine/threonine protein kinase-1 and -3 and mixed lineage kinase domain-like protein. Necroptosis inhibitors have been shown to exert inhibitory effects on cerebral ischemic injury and neuroinflammation. In this review, we will discuss the current research progress regarding necroptosis in cerebral ischemia as well as the application of necroptosis inhibitors for potential therapeutic intervention in ischemic stroke.

Effects of combined electroacupuncture and medication therapy on the RhoA/ROCK-2 signaling pathway in the striatal region of rats afflicted by cerebral ischemia

ObjectiveTo investigate the effects of electroacupuncture(EA), gastrodin(Gas), and their combination on the signaling pathways involving Ras homologous gene family member A (RhoA) and Rho-associated frizzled helix protein kinase (ROCK-2) within the striatal region of rats subjected to cerebral ischemia. Additionally, we aim to elucidate the therapeutic effects and potential underlying mechanisms associated with the concurrent application of electroacupuncture and medication in the treatment of cerebral ischemia. MethodsRats were randomly assigned to one of five groups, namely, the sham operation (Sham) group, model group, EA group, Gas group, and the EA combined with Gas group (referred to as the "EA+Gas group"). Each group consisted of ten rats. Following the induction of cerebral ischemia, the EA group and EA+Gas group received EA stimulation at the Baihui(GV20) and Zusanli(ST36) acupoints for 30 min per session, administered once daily for 14 consecutive days. The Gas group and EA+Gas group were intraperitoneally injected with Gas at a dosage of 10 mg/kg, also administered once daily for 14 consecutive days. Nissl staining was employed to observe morphological alterations in the striatal nerve cells of rats in each group. Immunohistochemistry and western blot techniques were employed to evaluate the expression levels of striatal RhoA and ROCK-2 proteins. ResultsIn comparison to the Sham group, the model group exhibited a substantial reduction in the number of striatal nerve cells on the ischemic side, accompanied by notable changes in cell morphology, characterized by reduced cytoplasm, defective and atrophied cytosol, solidified nuclei, loosely arranged cells, and enlarged intercellular spaces. Additionally, there was a notable increase in the positive expression of RhoA and ROCK-2. In contrast, when compared to the model group, the EA, Gas, and EA+Gas groups demonstrated an elevated number of normal nerve cells within the ischemic striatal region, with a significant improvement in cell count and morphology. Furthermore, positive expression levels of RhoA and ROCK-2 were notably reduced in these groups. Compared with the EA group or the GAS group, the number of normal nerve cells in the striatum on the ischemic side of the EA+GAS group was further increased, and the positive expression level of RhoA and ROCK-2 were both further reduced. ConclusionThe protective mechanism underlying the therapeutic efficacy of EA combined with Gas against cerebral ischemic striatal injury in rats may be associated with the inhibition of the activation of the RhoA/ROCK-2 signaling pathway. Importantly, the therapeutic effects observed with the combination of electroacupuncture and medication were superior to those achieved with EA alone or the sole administration of Gas.

β-asarone improves cognitive impairment and alleviates autophagy in mice with vascular dementia via the cAMP/PKA/CREB pathway

BackgroundVascular dementia (VD) is the second most common type of dementia after Alzheimer's disease. β-asarone, a major component of Acorus tatarinowii Schott, is important in neurodegenerative and neurovascular diseases. Studies have confirmed that β-asarone can mitigate autophagy and reduce damage in hypoxic cells. We also reported that β-asarone improves learning and memory. This study further clarifies whether β-asarone attenuates cerebral ischaemic injury by acting through the cAMP/PKA/CREB pathway in VD model mice. MethodsHere, genes and potential pathways that may be targeted by β-asarone for the treatment of transient cerebral ischaemia (TCI) and cognitive impairment (CI) were obtained using network pharmacology. The two-vessel occlusion method was used to establish the VD model. The Morris water maze test was used to evaluate the effects on memory. Then, the protein levels of mitofusin-2 (Mfn2), brain-derived neurotrophic factor (BDNF), optic atrophy 1 (OPA1), cyclic adenosine monophosphate (cAMP), myelin basic protein (MBP), matrix metalloproteinase-9 (MMP9) and neuron specific enolase (NSE) were determined by ELISA. The levels of superoxide dismutase (SOD) and malonaldehyde (MDA) were measured using commercial kits. Then, qRT-PCR was employed to investigate the expression of the candidate genes screened from the protein-protein interaction (PPI) network. Furthermore, the expression of the autophagy-related proteins Beclin-1, (microtubule-associated protein light chain 3) LC3, p62, postsynaptic density protein 95 (PSD95), protein kinase A (PKA), pPKA, cyclic-AMP response binding protein (CREB), and pCREB was determined by western blotting. The expression of autophagy-related proteins, PSD95 and translocase of outer mitochondrial membrane 20 (TOM20) was determined by immunofluorescence analyses. ResultsThe network pharmacological analysis showed 234 targets related to β-asarone, 1,118 genes related to TCI and 2,039 genes associated with CI. Our results confirm that β-asarone treatment not only alleviated brain damage in the VD model by improving mitochondrial and synaptic function, reducing neuronal injury and upregulating the expression of antioxidants but also effectively improved the cognitive behaviour of VD model mice. Moreover, β-asarone downregulated VD-induced RELA and CCND1 mRNA expression. In addition, we validated that β-asarone increased the phosphorylation of PKA and CREB and upregulated cAMP protein expression. The results showed that the cAMP/PKA/CREB signalling pathway was upregulated. Moreover, β-asarone administration decreased the protein expression levels of Beclin-1 and LC3 and increased the expression levels of p62 in VD model mice. Conclusionsβ-asarone inhibits Beclin-1-dependent autophagy and upregulates the cAMP/PKA/CREB signalling pathway to attenuate mitochondrial and synaptic damage from cerebral ischaemia and improve learning and cognitive abilities in VD model mice.

Ginsenoside Rg1 treats ischemic stroke by regulating CKLF1/CCR5 axis-induced neuronal cell pyroptosis

BackgroundIschemic stroke, a severe and life-threatening neurodegenerative condition, currently relies on thrombolytic therapy with limited therapeutic window and potential risks of hemorrhagic transformation. Thus, there is a crucial need to explore novel therapeutic agents for ischemic stroke. Ginsenoside Rg1 (Rg1), a potential neuroprotective agent, exhibits anti-ischemic effects attributed to its anti-inflammatory, anti-oxidant, and anti-apoptotic properties. Nevertheless, the precise underlying mechanism of action remains to be fully elucidated. PurposeThis study aimed to explore whether Rg1 exerts anti-ischemic stroke effects by inhibiting pyroptotic neuronal cell death through modulation of the chemokine like factor 1 (CKLF1)/ C-C chemokine receptor type 5 (CCR5) axis. MethodsIn this study, the MCAO model was used as an ischemic stroke model, and experimental tests were performed after 6 hours of ischemia. The anti-ischemic effect of Rg1 was examined by TTC staining, nissl-staining and neurobehavioral tests. In the in vitro experiments, PC12 cells were subjected to stimulation with CKLF1′s mimetic peptide C27 to assess the potential of CKLF1 to induce focal neuronal cell death. Additionally, the impact of CKLF1 mimetic peptide C27, antagonistic peptide C19, and CCR5 inhibitor MVC on PC12 cells subjected to oxygen-glucose deprivation (OGD) and subsequently treated with Rg1 was investigated. In vivo, Rg1 treatment was examined by quantitative real-time PCR (qPCR), ELISA, immunohistochemistry (IHC), immunofluorescence (IF), western blot (WB), and co-immunoprecipitate (Co-IP) assays to perspective whether Rg1 treatment reduces CKLF1/CCR5 axis-induced pyroptotic neuronal cell death. In addition, to further explore the biological significance of CKLF1 in ischemic stroke, CKLF1−/− rats were used as the observation subjects in this study. ResultsThe in vitro results suggested that CKLF1 was able to induce neuronal cells to undergo pyroptosis. In vivo pharmacodynamic results showed that Rg1 treatment was able to significantly improve symptoms in ischemic stroke rats. In addition, Rg1 treatment was able to inhibit the interaction between CKLF1 and CCR5 after ischemic stroke and inhibited CKLF1/CCR5 axis-induced pyroptosis. The results of related experiments in CKLF1−/− rats showed that Rg1 lost its therapeutic effect after CKLF1 knockdown. ConclusionOur findings indicate that the activation of the NLRP3 inflammasome is initiated by the CKLF1/CCR5 axis, facilitated through the activation of the NF-κB pathway, ultimately resulting in the pyroptosis of neuronal cells. Conversely, Rg1 demonstrates the capability to mitigate neuronal cell damage following CKLF1-induced effects by suppressing the expression of CKLF1. Thus, CKLF1 represents a crucial target for Rg1 in the context of cerebral ischemia treatment, and it also holds promise as a potential target for drug screening in the management of ischemic stroke.

From Text to Insight: A Natural Language Processing-Based Analysis of Topics and Trends in Neurosurgery.

Neurosurgical research is a rapidly evolving field, with new research topics emerging continually. To provide a clearer understanding of the evolving research landscape, our study aimed to identify and analyze the prevalent research topics and trends in Neurosurgery. We used BERTopic, an advanced natural language processing-based topic modeling approach, to analyze papers published in the journal Neurosurgery . Using this method, topics were identified based on unique sets of keywords that encapsulated the core themes of each article. Linear regression models were then trained on the topic probabilities to identify trends over time, allowing us to identify "hot" (growing in prominence) and "cold" (decreasing in prominence) topics. We also performed a focused analysis of the trends in the current decade. Our analysis led to the categorization of 12 438 documents into 49 distinct topics. The topics covered a wide range of themes, with the most commonly identified topics being "Spinal Neurosurgery" and "Treatment of Cerebral Ischemia." The hottest topics of the current decade were "Peripheral Nerve Surgery," "Unruptured Aneurysms," and "Endovascular Treatments" while the cold topics were "Chiari Malformations," "Thromboembolism Prophylaxis," and "Infections." Our study underscores the dynamic nature of neurosurgical research and the evolving focus of the field. The insights derived from the analysis can guide future research directions, inform policy decisions, and identify emerging areas of interest. The use of natural language processing in synthesizing and analyzing large volumes of academic literature demonstrates the potential of advanced analytical techniques in understanding the research landscape, paving the way for similar analyses across other medical disciplines.