Dl-3-n-Butylphthalide Alleviates Secondary Brain Damage and Improves Working Memory After Stroke in Cynomolgus Monkeys.

BACKGROUND: Remote secondary neurodegeneration is associated with poststroke cognitive impairment (PSCI). Dl-3-n-butylphthalide (NBP) improves PSCI clinically. However, whether it ameliorates PSCI by alleviating secondary neurodegeneration remains uncertain. Nonhuman primates provide more relevant models than rodents for human stroke and PSCI. This study investigated the effects of NBP on PSCI and secondary neurodegeneration in cynomolgus monkeys after permanent left middle cerebral artery occlusion (MCAO). METHODS: Thirteen adult male cynomolgus monkeys were randomly assigned to sham (n=4), MCAO+placebo (n=5), and MCAO+NBP groups (n=4). The MCAO+placebo and MCAO+NBP groups received saline and NBP injections intravenously, respectively, starting at 6-hour postsurgery for 2 weeks, followed by soybean oil and NBP orally, respectively, for 10 weeks after MCAO. Infarct size was assessed at week 4 by magnetic resonance imaging. Working memory and executive function were evaluated dynamically using the delayed response task and object retrieval detour task, respectively. Neuron loss, glia proliferation, and neuroinflammation in the ipsilateral dorsal lateral prefrontal cortex, thalamus, and hippocampus were analyzed by immunostaining 12 weeks after MCAO. RESULTS: Infarcts were located in the left middle cerebral artery region, apart from the ipsilateral dorsal lateral prefrontal cortex, thalamus, or hippocampus, with no significant difference between the MCAO+placebo and MCAO+NBP group. Higher success in delayed response task was achieved at weeks 4, 8, and 12 after NBP compared with placebo treatments (P<0.05), but not in the object retrieval detour task (all P>0.05). More neurons and less microglia, astrocytes, CD68-positive microglia, tumor necrosis factor-α, and inducible NO synthase were observed in the ipsilateral dorsal lateral prefrontal cortex and thalamus after 12 weeks of NBP treatment (P<0.05), but not in the hippocampus (P>0.05). CONCLUSIONS: Our findings indicate that NBP improves working memory by alleviating remote secondary neurodegeneration and neuroinflammation in the ipsilateral dorsal lateral prefrontal cortex and thalamus after MCAO in cynomolgus monkeys.

Network Pharmacology Prediction and Experimental Verification for Anti-Ferroptosis of Edaravone After Experimental Intracerebral Hemorrhage.

Neuronal ferroptosis plays an important role in secondary brain injuries after intracerebral hemorrhage (ICH). Edaravone (Eda) is a promising free radical scavenger that inhibits ferroptosis in neurological diseases. However, its protective effects and underlying mechanisms in ameliorating post-ICH ferroptosis remain unclear. We employed a network pharmacology approach to determine the core targets of Eda against ICH. Forty-two rats were subjected to successful striatal autologous whole blood injection (n=28) or sham operation (n=14). The 28 blood-injected rats were randomly assigned to either the Eda or vehicle group (n=14) for immediate administration and then for 3 consecutive days. Hemin-induced HT22 cells were used for in vitro studies. The effects of Eda in ICH on ferroptosis and the MEK/ERK pathway were investigated in vivo and in vitro. Network pharmacology-based analysis revealed that candidate targets of Eda-treated ICH might be related to ferroptosis; among which prostaglandin G/H synthase 2 (PTGS2) was a ferroptosis marker. In vivo experiments showed that Eda alleviated sensorimotor deficits and decreased PTGS2 expression (all p<0.05) after ICH. Eda rescued neuron pathological changes after ICH (increased NeuN+ cells and decreased FJC+ cells, all p<0.01). In vitro experiments showed that Eda reduced intracellular reactive oxygen species and reversed mitochondria damage. Eda repressed ferroptosis by decreasing malondialdehyde and iron deposition and by influencing ferroptosis-related protein expression (all p<0.05) in ICH rats and hemin-induced HT22 cells. Mechanically, Eda significantly suppressed phosphorylated-MEK and phosphorylated-ERK1/2 expression. These results indicate that Eda has protective effects on ICH injury through ferroptosis and MEK/ERK pathway suppression.

Polystyrene microplastics reduce Cr(VI) and decrease its aquatic toxicity under simulated sunlight.

Microplastics (MPs) serve as vectors for chromium (Cr), influencing its fate and toxicity in aquatic environments, and have attracted much attention recently. However, it is still unknown whether MPs mediate Cr species transformation under sunlight irradiation. This study confirmed that polystyrene (PS) MPs could reduce Cr(VI) to Cr(III) under sunlight irradiation, with a photoreduction rate constant of 0.0023 h-1. PS MPs-mediated Cr(VI) reduction was predominantly dependent on O2•- and simultaneously suppressed by 1O2, •OH and 3PS* . Aged PS MPs were exposed to simulated sunlight irradiation for 0, 200, 500, and 800 h, and Cr(VI) reduction was hindered by increased 1O2 and •OH formation and light-screening effects (decreased photon absorption). The size, functional groups and concentration of PS MPs and environmental factors (e.g., humic acid, pH, Mg2+, Fe3+ and O2) strongly affected Cr(VI) reduction. Furthermore, Cr(VI) reduction induced by PS MPs could occur in reservoir water, and the reduction rate was faster than that in double distilled (DD) water. Correspondingly, PS MPs (1 mg/L) decreased the oxidative stress induced by Cr(VI) to Lemna minor in reservoir water after 96 h of sunlight irradiation. This study provided deep insight into how PS MPs affect Cr species transformations and hazardous effects in realistic aquatic environments under sunlight conditions.

Altered excitability of motor neuron pathways after stroke: more than upper motor neuron impairments.

BACKGROUND: Previous studies have suggested that impairment occurs in the lower motor neuron (LMN) pathway after stroke, but more research remains to be supported. OBJECTIVE: In this study, we tested the hypotheses: (1) both motor cortex and peripheral nerve pathways have decreased excitability and structural damage after stroke; (2) parameters of transcranial magnetic stimulation motor evoked potentials (TMS-MEP) can be used as predictors of motor function and stroke prognosis. METHODS: We studied five male cynomolgus monkeys with ischaemic stroke. TMS-MEP, cranial MRI, behavioural assessment, neurological scales and pathology were applied. RESULTS: Elevated resting motor threshold (RMT) (p<0.05), decreased TMS-MEP amplitudes (p<0.05) and negative RMT lateralisation were detected in both the affected motor cortex (AMC) and the paretic side median nerve (PMN) at 2 weeks poststroke. Disturbed structure and loose arrangement of myelin sheaths were observed in the PMN through H&E staining and LFB staining at 12 weeks poststroke. The primate Rankin Scale (used for assess the stroke prognosis) scores at 2-12 weeks after middle cerebral artery occlusion were [1, (1; 3)], [1, (1;2)], [1, (1; 1.5)] and [1, (1; 1.5)], respectively. The RMT and RMT lateralisation (AMC) were predictors of stroke prognosis, and the RMT lateralisation of PMN and latency of AMC were predictors of motor impairment. CONCLUSIONS: Both upper motor neuron (UMN) and LMN pathway excitability is reduced after stroke, and structural damage in median nerve 12 weeks after stroke occur. In addition, RMT and RMT lateralisation are predictors of stroke prognosis and motor impairment.

Is Cerebral Amyloid-ß Deposition Related to Post-stroke Cognitive Impairment?

Approximately two-thirds of ischemic stroke patients suffer from different levels of post-stroke cognitive impairment (PSCI), but the underlying mechanisms of PSCI remain unclear. Cerebral amyloid-ß (Aß) deposition, a pathological hallmark of Alzheimer's disease, has been discovered in the brains of stroke patients in some autopsy studies. However, less is known about the role of Aß pathology in the development of PSCI. It is hypothesized that cerebral ischemic injury may lead to neurotoxic Aß accumulation in the brain, which further induces secondary neurodegeneration and progressive cognitive decline after stroke onset. In this review, we summarized available evidence from pre-clinical and clinical studies relevant to the aforementioned hypothesis. We found inconsistency in the results obtained from studies in rodents, nonhuman primates, and stroke patients. Moreover, the causal relationship between post-stroke cerebral Aß deposition and PSCI has been uncertain and controversial. Taken together, evidence supporting the hypothesis that brain ischemia induces cerebral Aß deposition has been insufficient so far. And, there is still no consensus regarding the contribution of cerebral amyloid pathology to PSCI. Other non-amyloid neurodegenerative mechanisms might be involved and remain to be fully elucidated.

Aspirin Therapy in Cardiovascular Disease with Glucose-6-Phosphate Dehydrogenase Deficiency, Safe or Not?

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common human enzyme defect, which may present as acute hemolysis, neonatal jaundice, or chronic hemolysis. Ingestion of fava beans, as well as infection and certain drugs, are the most typical causes of acute hemolysis in people with G6PD deficiency. Aspirin, the cornerstone in current therapies for the prevention of cardiovascular disease (CVD), is occasionally reported to induce acute hemolysis in G6PD-deficient individuals. G6PD deficiency is typically asymptomatic and many CVD patients with this enzyme defect start to take long-term aspirin therapy without G6PD activity examination; however, no consensus on the safety of aspirin in this population has been reached. A few studies have reported on this issue and produced contradictory results. In this review, we discuss the possible mechanisms of aspirin-induced hemolysis, and summarize clinical evidence regarding the safety of aspirin in subjects with G6PD deficiency.