Dietary salt promotes cognitive impairment through repression of SIRT3/PINK1-mediated mitophagy and fission.

Dietary salt is increasingly recognized as an independent risk factor for cognitive impairment. However, the exact mechanisms are not yet fully understood. Mitochondria, which play a crucial role in energy metabolism, are implicated in cognitive function through processes such as mitochondrial dynamics and mitophagy. While mitochondrial dysfunction is acknowledged as a significant determinant of cognitive function, the specific relationship between salt-induced cognitive impairment and mitochondrial health has yet to be fully elucidated. Here, we explored the underlying mechanism of cognitive impairment of mice and N2a cells treated with high-salt focusing on the mitochondrial homeostasis with western blotting, immunofluorescence, electron microscopy, RNA sequencing, and more. We further explored the potential role of SIRT3 in salt-induced mitochondrial dysfunction and synaptic alteration through plasmid transfection and siRNA. High salt diet significantly inhibited mitochondrial fission and blocked mitophagy, leading to dysfunctional mitochondria and impaired synaptic plasticity. Our findings demonstrated that SIRT3 not only promote mitochondrial fission by modulating phosphorylated DRP1, but also rescue mitophagy through promoting PINK1/Parkin-dependent pathway. Overall, our data for the first time indicate that mitochondrial homeostasis imbalance is a driver of impaired synaptic plasticity in a cognitive impairment phenotype that is exacerbated by a long-term high-salt diet, and highlight the protective role of SIRT3 in this process.

High salt diet induces cognitive impairment and is linked to the activation of IGF1R/mTOR/p70S6K signaling.

A high-salt diet (HSD) has been associated with various health issues, including hypertension and cardiovascular diseases. However, recent studies have revealed a potential link between high salt intake and cognitive impairment. This study aims to investigate the effects of high salt intake on autophagy, tau protein hyperphosphorylation, and synaptic function and their potential associations with cognitive impairment. To explore these mechanisms, 8-month-old male C57BL/6 mice were fed either a normal diet (0.4% NaCl) or an HSD (8% NaCl) for 3 months, and Neuro-2a cells were incubated with normal medium or NaCl medium (80 mM). Behavioral tests revealed learning and memory deficits in mice fed the HSD. We further discovered that the HSD decreased autophagy, as indicated by diminished levels of the autophagy-associated proteins Beclin-1 and LC3, along with an elevated p62 protein level. HSD feeding significantly decreased insulin-like growth factor-1 receptor (IGF1R) expression in the brain of C57BL/6 mice and activated mechanistic target of rapamycin (mTOR) signaling. In addition, the HSD reduced synaptophysin and postsynaptic density protein 95 (PSD95) expression in the hippocampus and caused synaptic loss in mice. We also found amyloid ß accumulation and hyperphosphorylation of tau protein at different loci both in vivo and in vitro. Overall, this study highlights the clinical significance of understanding the impact of an HSD on cognitive function. By targeting the IGF1R/mTOR/p70S6K pathway or promoting autophagy, it may be possible to mitigate the negative effects of high salt intake on cognitive function.

Berberine Rescues D-Ribose-Induced Alzheimer's Pathology via Promoting Mitophagy.

Mitochondrial dysfunction is considered an early event of Alzheimer disease (AD). D-ribose is a natural monosaccharide that exists in cells, especially in mitochondria, and can lead to cognitive dysfunction. However, the reason for this is unclear. Berberine (BBR) is an isoquinoline alkaloid that can target mitochondria and has great prospect in the treatment of AD. The methylation of PINK1 reinforces the burden of Alzheimer's pathology. This study explores the role of BBR and D-ribose in the mitophagy and cognitive function of AD related to DNA methylation. APP/PS1 mice and N2a cells were treated with D-ribose, BBR, and mitophagy inhibitor Mdivi-1 to observe their effects on mitochondrial morphology, mitophagy, neuron histology, AD pathology, animal behavior, and PINK1 methylation. The results showed that D-ribose induced mitochondrial dysfunction, mitophagy damage, and cognitive impairment. However, BBR inhibition of PINK1 promoter methylation can reverse the above effects caused by D-ribose, improve mitochondrial function, and restore mitophagy through the PINK1-Parkin pathway, thus reducing cognitive deficits and the burden of AD pathology. This experiment puts a new light on the mechanism of action of D-ribose in cognitive impairment and reveals new insights in the use of BBR for AD treatment.

The efficacy of ginger for the treatment of migraine: A meta-analysis of randomized controlled studies.

INTRODUCTION: The efficacy of ginger for migraine remains controversial. We conduct a systematic review and meta-analysis to explore the influence of ginger versus placebo on treatment in migraine patients. METHODS: We have searched PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases through September 2020 for randomized controlled trials (RCTs) assessing the effect of ginger versus placebo on treatment efficacy in migraine patients. This meta-analysis is performed using the random-effect model. RESULTS: Three RCTs are included in the meta-analysis. Overall, compared with control group in migraine patients, ginger treatment is associated with substantially improved pain free at 2 h (RR = 1.79; 95% CI = 1.04-3.09; P = 0.04) and reduced pain scores at 2 h (MD = -1.27; 95% CI = -1.46 to -1.07; P < 0.00001), but reveals no obvious impact on treatment response (RR = 2.04; 95% CI = 0.35-11.94; P = 0.43) or total adverse events (RR = 0.80; 95% CI = 0.46-1.41; P = 0.44). The incidence of nausea and vomiting is obviously lower in ginger group than that in control group. CONCLUSIONS: Ginger is safe and effective in treating migraine patients with pain outcomes assessed at 2 h.

Anti-Cognitive Decline by Yinxing-Mihuan-Oral-Liquid via Activating CREB/BDNF Signaling and Inhibiting Neuroinflammatory Process.

BACKGROUND: Cognitive decline in the normal aging process is one of the most common and prominent problems. Delaying and alleviating cognitive impairment is an important strategy of anti-aging. This study is to aim at investigating the effects of Yinxing-Mihuan-Oral-Liquid(GMOL) on the CREB/BDNF signaling in the normal aging process.METHODS: SD rats were randomly divided into GMOL group and control group. The Morris water maze (MWM) was introduced for behavioral test. Immunohistochemistry and immunofluorescence were used for cAMP response element binding protein 1(CREB1), p-CREB(Ser133), brain-derived neurotrophic factor(BDNF), synaptophysin(SYP) and glial fibrillary acidic protein(GFAP). Western blot was conducted for investigating the levels of CREB1 and p-CREB(Ser133), BDNF, SYP, GFAP and interleukin 6(IL-6). RESULTS:  Our data showed that compared with the control group, GMOL group had higher expression of memory-related proteins, decreased inflammatory factors, and enhanced spatial learning and memory ability.CONCLUSION: The study results show that GMOL ameliorates cognitive impairment of the normal aged SD rats via enhancing the expression of memory biomarkers and inhibiting inflammatory process. The potential neuroprotective role of GMOL in the process of aging may be related to mitigating cognitive decline via activating CREB/BDNF signaling and inhibiting inflammatory process.

Activation of microglial GLP-1R in the trigeminal nucleus caudalis suppresses central sensitization of chronic migraine after recurrent nitroglycerin stimulation.

BACKGROUND: Central sensitization is considered a critical pathogenic mechanism of chronic migraine (CM). Activation of microglia in the trigeminal nucleus caudalis (TNC) contributes to this progression. Microglial glucagon-like peptide-1 receptor (GLP-1R) activation can alleviate pain; however, whether it is involved in the mechanism of CM has not been determined. Thus, this study aims to investigate the precise role of GLP-1R in the central sensitization of CM. METHODS: Repeated nitroglycerin injection-treated mice were used as a CM animal model in the experiment. To identify the distribution and cell localization of GLP-1R in the TNC, we performed immunofluorescence staining. Changes in the expression of GLP-1R, Iba-1, PI3K and p-Akt in the TNC were examined by western blotting. To confirm the effect of GLP-1R and PI3K/Akt in CM, a GLP-1R selective agonist (liraglutide) and antagonist (exendin(9-39)) and a PI3K selective antagonist (LY294002) were administered. Mechanical hypersensitivity was measured through von Frey filaments. To investigate the role of GLP-1R in central sensitization, calcitonin gene-related peptide (CGRP) and c-fos were determined using western blotting and immunofluorescence. To determine the changes in microglial activation, IL-1ß and TNF-α were examined by western blotting, and the number and morphology of microglia were measured by immunofluorescence. We also confirmed the effect of GLP-1R on microglial activation in lipopolysaccharide-treated BV-2 microglia. RESULTS: The protein expression of GLP-1R was increased in the TNC after nitroglycerin injection. GLP-1R was colocalized with microglia and astrocytes in the TNC and was fully expressed in BV-2 microglia. The GLP-1R agonist liraglutide alleviated basal allodynia and suppressed the upregulation of CGRP, c-fos and PI3K/p-Akt in the TNC. Similarly, the PI3K inhibitor LY294002 prevented nitroglycerin-induced hyperalgesia. In addition, activating GLP-1R reduced Iba-1, IL-1ß and TNF-α release and inhibited TNC microglial number and morphological changes (process retraction) following nitroglycerin administration. In vitro, the protein levels of IL-1ß and TNF-α in lipopolysaccharide-stimulated BV-2 microglia were also decreased by liraglutide. CONCLUSIONS: These findings suggest that microglial GLP-1R activation in the TNC may suppress the central sensitization of CM by regulating TNC microglial activation via the PI3K/Akt pathway.

Outer membrane vesicles enhance tau phosphorylation and contribute to cognitive impairment.

Outer membrane vesicles (OMVs) are nanosized vesicles produced by the gut microbiota (GM). The GM is well-known to be involved in the pathological process of Alzheimer's disease (AD). However, the mechanism of OMVs is not clear. In the present study, we demonstrated the involvement of OMVs in the development of cognitive (learning and memory) dysfunction induced by blood-brain barrier (BBB) disruption. More important, further study showed that OMVs induced tau phosphorylation by activating glycogen synthase kinase 3ß (GSK-3ß) in the hippocampus. OMVs activated astrocytes and microglia, increased secretion of inflammatory cytokines (nuclear factor κB, interleukin-1ß, and tumour necrosis factor-α) in the hippocampus. Therefore, OMVs increase the permeability of the BBB and promote the activation of astrocytes and microglia, inducing an inflammatory response and tau hyperphosphorylation by activating the GSK-3ß pathway and finally leading to cognitive impairment.

The role of high high-sensitivity C-reactive protein levels at admission on poor prognosis after acute ischemic stroke.

OBJECTIVE: Plasma high hypersensitive C-reactive protein (hs-CRP) levels are associated with risk and prognosis of vascular diseases. The clinical implications of markedly elevated hs-CRP levels are more discovered in the onset and development of stroke. The aim of this study is to determine the association of plasma hs-CRP levels on the prognosis in patients with acute ischemic stroke. METHODS: Retrospective analysis of a single-center database of consecutive cases for acute cerebral infarction (ACI) from January 1 2012 to December 30 2016 was performed. Significant predictors of the dependent variable variance were identified by standard linear, univariate and multivariate, or binary logistic regression modeling. Multivariate regression analysis was introduced to investigate the relationship between plasma hs-CRP levels at admission and change in National Institutes of Health Stroke Scale (NIHSS) score at discharge. RESULTS: The percentages of hypertension, diabetes mellitus, hyperlipidemia, atrial fibrillation, body mass index (BMI) and chronic kidney disease were raised with the increase of hs-CRP plasma concentration at admission among all patients (p < 0.05). ACI patients with large-artery atherosclerosis had an increasing percentage with the increase of hs-CRP mean value (p < 0.05). The initial NIHSS scores, the acute infection rate and age advance also increased with the increase of hs-CRP plasma concentration at admission (p < 0.05). The ratio of neurological improvement increased with the decrease of plasma hs-CRP concentration (p < 0.05). The neurological deterioration and poor prognosis increased with the increase of plasma hs-CRP concentration (p < 0.05). CONCLUSION: High plasma hs-CRP levels are associated with worse outcomes in the ACI patients. Monitoring plasma hs-CRP levels and cutting down the elevated plasma hs-CRP levels will be beneficial in screening and treatment decisions for the prognosis of acute ischemic stroke.

Role of S-100ß in stroke.

The S-100ß levels are associated with a variety of acute disorders and other chronic diseases, such as head injury, stroke, metastatic melanoma, cardiac surgery, bone fractures, burns and contusions. The serum S-100ß levels seem to increase with the volume of tissue damage. Higher serum S-100ß levels have been observed after brain damage or stroke. A number of studies have evidenced the clinical value of S-100ß in the diagnosis and prognosis of stroke while the S-100ß marker is elevated in the peripheral blood during the acute phase of stroke. However, the clinical usefulness of S-100ß biomarker in the diagnosis and prognosis of stroke has a limitation due to its low discriminating ability in stroke diagnosis and prognosis.

The alliance with expanding blood volume and correcting anemia is an effective therapeutic measure for the adult anemia patients of acute cerebral infarction.

Purpose/aim of the study: Various factors are believed to be involved in the etiology of cerebral infarction. Anemia has been shown to deteriorate in association with ischemic stroke. However, the exact clinical association between anemia and ischemic stroke still remains unclear. We evaluated the clinical features of adult anemia patients with acute cerebral infarction and seek a better treatment different from the other causes of cerebral infarction, and to provide a reference for the diagnosis and treatment of these anemia patients with acute cerebral infarction. METHODS: Thirty-two adult patients of acute cerebral infarction with anemia were included in this study. A primary discharge diagnosis of acute cerebral infarction with anemia was done, and all subjects were evaluated as retrospective data. The clinical features were analyzed. A chi-square test was used to analyze the associations between different variables. Therapeutic interventions and outcomes were analyzed under t-test, compared between the two groups. RESULTS: The NIHSS score in the patients with the administration of EBV/CA (Expanding blood volume and correcting anemia) more lowed than Non-EBV/CA in 7 days and 14 days after initial hospitalization. The mRS score in the patients with the administration of EBV/CA also more lowed than Non-EBV/CA in 14 days. Moreover, the correlation between Hb-serum-level and NIHSS scores in the time of initial hospitalization is negative significantly. CONCLUSIONS: Anemia is associated with increased neuronal damage and deterioration of acute cerebral infarction in the adults. Expanding blood volume and correcting anemia are effective therapeutic measures in the adult patients of acute cerebral infarctions with anemia.

Chronic Cerebral Hypoperfusion Promotes Amyloid-Beta Pathogenesis via Activating ß/γ-Secretases.

Chronic cerebral hypoperfusion (CCH) contributes to the Alzheimer's-like pathogenesis, but the relationship between CCH and the occurrence of Alzheimer's disease (AD) remains obscure. The aim is to elucidate the potential pathophysiological mechanism in the field of amyloid-beta (Aß) pathology induced by CCH. A rat model of CCH has been developed with permanent bilateral occlusion of common carotid arteries (BCCAO). The cognitive function of rats was tested by the Morris water maze. The levels of Aß (Aß40 and Aß42) and soluble amyloid precursor protein (sAPP: sAPPα and sAPPß) were determined by enzyme linked immunosorbent assay. The expression of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), presenilin1 (PS1), nicastrin (NCT), anterior pharynx-defective 1alpha (Aph-1α) and presenilin enhancer 2 (Pen-2), sAPPα and sAPPß were detected by Western blotting. Morris water maze test showed that CCH induced decline in learning and memory related to Aß levels in the hippocampus. The levels of sAPPα, ADAM10 and ADAM17 in the hippocampus of CCH rats were higher than the control ones (P < 0.05); the levels of sAPPß, BACE and BACE1 increased more than the control ones (P < 0.05). CCH intervention (1-week or 4-week) markedly increased the expression of PS1, Aph-1α and Pen-2 in the hippocampus of rats, but had no effect on NCT. CCH contributed to cognitive impairment and altered the amyloidogenic and non-amyloidogenic pathway of APP processing by boosting the activity of ß-secretase/γ-secretase and α-secretase respectively. The non-amyloidogenic pathway can't overcome the damage role of the amyloidogenic pathway in the process of chronic cerebral hypoperfusion which promotes amyloid-beta pathogenesis.

Insulin resistance in ischemic stroke.

Insulin resistance often refers to a pathological condition in which cells fail to respond to the normal actions of insulin. Increasing literature has noted a critical role of insulin resistance in the pathogenesis of ischemic stroke. Insulin resistance plays an important role in the pathogenesis of ischemic stroke via enhancing advanced changes of atherosclerosis. A variety of literature indicates that insulin resistance enhances platelet adhesion, activation and aggregation which are conducive to the occurrence of ischemic stroke. Insulin resistance also induces hemodynamic disturbances and contributes to the onset of ischemic stroke. In addition, insulin resistance may augment the role of the modifiable risk factors in ischemic stroke and induce the occurrence of ischemic stroke. Preclinical and clinical studies have supported that improving insulin resistance may be an effective measure to prevent or delay ischemic stroke.

Role of RAGE in Alzheimer's Disease.

Receptor for advanced glycation end products (RAGE) is a receptor of the immunoglobulin super family that plays various important roles under physiological and pathological conditions. Compelling evidence suggests that RAGE acts as both an inflammatory intermediary and a critical inducer of oxidative stress, underlying RAGE-induced Alzheimer-like pathophysiological changes that drive the process of Alzheimer's disease (AD). A critical role of RAGE in AD includes beta-amyloid (Aß) production and accumulation, the formation of neurofibrillary tangles, failure of synaptic transmission, and neuronal degeneration. The steady-state level of Aß depends on the balance between production and clearance. RAGE plays an important role in the Aß clearance. RAGE acts as an important transporter via regulating influx of circulating Aß into brain, whereas the efflux of brain-derived Aß into the circulation via BBB is implemented by LRP1. RAGE could be an important contributor to Aß generation via enhancing the activity of ß- and/or γ-secretases and activating inflammatory response and oxidative stress. However, sRAGE-Aß interactions could inhibit Aß neurotoxicity and promote Aß clearance from brain. Meanwhile, RAGE could be a promoting factor for the synaptic dysfunction and neuronal circuit dysfunction which are both the material structure of cognition, and the physiological and pathological basis of cognition. In addition, RAGE could be a trigger for the pathogenesis of Aß and tau hyper-phosphorylation which both participate in the process of cognitive impairment. Preclinical and clinical studies have supported that RAGE inhibitors could be useful in the treatment of AD. Thus, an effective measure to inhibit RAGE may be a novel drug target in AD.

Oligodendrocytes and Alzheimer's disease.

Extensive evidence has indicated that the breakdown of myelin is associated with Alzheimer's disease (AD) since the vulnerability of oligodendrocytes under Alzheimer's pathology easily induces the myelin breakdown and the loss of the myelin sheath which might be the initiating step in the changes of the earliest stage of AD prior to appearance of amyloid and tau pathology. Considerable research implicated that beta-amyloid (Aß)-mediated oligodendrocyte dysfunction and myelin breakdown may be via neuroinflammation, oxidative stress and/or apoptosis. It also seems that the oligodendrocyte dysfunction is triggered by the formation of neurofibrillary tangles (NFTs) through inflammation and oxidative stress as the common pathophysiological base. Impaired repair of oligodendrocyte precursor cells (OPCs) might possibly enhance the disease progress under decreased self-healing ability from aging process and pathological factors including Aß pathology and/or NFTs. Thus, these results have suggested that targeting oligodendrocytes may be a novel therapeutic intervention for the prevention and treatment of AD.

Role of insulin resistance in Alzheimer's disease.

A critical role of insulin resistance (IR) in Alzheimer's disease (AD) includes beta-amyloid (Aß) production and accumulation, the formation of neurofibrillary tangles (NFTs), failure of synaptic transmission and neuronal degeneration. Aß is sequentially cleavaged from APP by two proteolytic enzymes: ß-secretase and γ-secretase. IR could regulate Aß production via enhancing ß- and γ-secretase activity. Meanwhile, IR induces oxidative stress and inflammation in the brain which contributes to Aß and tau pathology. Aß accumulation can enhance IR through Aß-mediated inflammation and oxidative stress. IR is a possible linking between amyloid plaques and NFTs pathology via oxidative stress and neuroinflammation. Additionally, IR could disrupt acetylcholine activity, and accelerate axon degeneration and failures in axonal transport, and lead to cognitive impairment in AD. Preclinical and clinical studies have supported that insulin could be useful in the treatment of AD. Thus, an effective measure to inhibit IR may be a novel drug target in AD.

Microglia, neuroinflammation, and beta-amyloid protein in Alzheimer's disease.

Compelling evidence from basic molecular biology has demonstrated the dual roles of microglia in the pathogenesis of Alzheimer's disease (AD). On one hand, microglia are involved in AD pathogenesis by releasing inflammatory mediators such as inflammatory cytokines, complement components, chemokines, and free radicals that are all known to contribute to beta-amyloid (Aß) production and accumulation. On the other hand, microglia are also known to play a beneficial role in generating anti-Aß antibodies and stimulating clearance of amyloid plaques. Aß itself, an inducer of microglia activation and neuroinflammation, has been considered as an underlying and unifying factor in the development of AD. A vicious cycle of inflammation has been formed between Aß accumulation, activated microglia, and microglial inflammatory mediators, which enhance Aß deposition and neuroinflammation. Thus, inhibiting the vicious cycle seems to be a promising treatment to restrain further development of AD. With increasing research efforts on microglia in AD, intervention of microglia activation and neuroinflammation in AD may provide a potential target for AD therapy in spite of the provisional failure of nonsteroidal antiinflammatory drugs in clinical trials.

Anti-IgLON5 disease: A case with intestinal obstruction and peripheral neuropathy.

IgLON5 autoimmunity is a novel antibody-mediated disorder characterized by serum and/or cerebrospinal fluid (CSF) positivity for IgLON5 antibody. Anti-IgLON5 disease mainly manifests as sleep disturbances, movement disorders and brainstem syndromes. In this study, we report the case of a patient with anti-IgLON5 disease who presented with abdominal distension, abdominal pain, intermittent dysuria and constipation, and intermittent lightning pain in the extremities, which are atypical of anti-IgLON5 disease and could easily lead to misdiagnosis. After performing autoantibody screening, we considered anti-IgLON5 disease. The patient was started on a course of immunotherapy with intravenous dexamethasone, intravenous immunoglobulin (IVIG) and oral azathioprine (Imuran). Following treatment, the manifestations nearly resolved. The clinical manifestations of anti-IgLON5 disease are diverse and may present in different combinations, which can easily lead to misdiagnosis. Early recognition and treatment of this autoimmune disease with immunosuppressive agents may lead to better outcomes.

Isolated unilateral brachial plexus injury following carbon monoxide intoxication: a case report and literature review.

Carbon monoxide (CO) is a gas that has no odor or color, making it difficult to detect until exposure leads to coma or death. CO poisoning is one of the most common and deadly poisonings around the world. CO poisoning is a common and often fatal form of poisoning worldwide. A toxic effect of CO is tissue hypoxia, which leads to systemic complications. Additionally, there may be severe neurological symptoms and delayed complications following CO poisoning. However, peripheral neuropathy is relatively rare after CO poisoning. Previously, only one case of unilateral plexopathy after CO poisoning, accompanied by rhabdomyolysis and cognitive dysfunction, has been reported. In this report, an isolated unilateral brachial plexopathy following CO intoxication is described. A key mechanism in this case may be CO-induced spinal cord ischemia. Immediate administration of hyperbaric oxygen therapy (HBOT) is crucial to prevent peripheral neuropathy after acute CO intoxication. Hyperbaric oxygen therapy (HBOT) should be administered immediately after acute CO intoxication to prevent peripheral neuropathy. Additionally, peripheral neuropathy following acute CO intoxication may benefit from consistent rehabilitation training.

Efficacy and safety of batroxobin in patients with acute ischemic stroke: A multicenter retrospective analysis.

AIMS: The objective of this study was to evaluate the effectiveness of batroxobin in improving functional outcomes and reducing stroke recurrence among patients with acute ischemic stroke beyond the therapeutic time window for thrombolytic therapy. METHODS: This multicenter, retrospective study enrolled 492 patients with acute moderate-to-severe ischemic stroke within 24 h. 238 patients were given standard (basic) therapy. On the basis of standard treatment, 254 patients received an initial intravenous infusion of batroxobin 10 U on day 1, followed by subsequent infusions of batroxobin 5 U on the 3rd and 5th days, respectively. RESULTS: In the batroxobin group, 8.3% of patients experienced recurrence stroke, compared to 17.2% in the control group (HR, 0.433; 95% CI, 0.248 to 0.757; p = 0.003). Furthermore, intravenous batroxobin significantly improved the distribution of 90-120 day disability. Moderate-to-severe bleeding events were reported in three patients (1.2%) in the batroxobin group and one patient (0.4%) in the control group (p = 0.369). CONCLUSIONS: Among patients with acute moderate-to-severe ischemic stroke beyond the time window for thrombolytic therapy, treatment with intravenous batroxobin had a lower risk of stroke recurrence and a better recovery of function outcome without increasing bleeding events. Prospective studies are needed to further confirm.