The protective role of endothelial GLUT1 in ischemic stroke.

OBJECTIVE: To provide thorough insight on the protective role of endothelial glucose transporter 1 (GLUT1) in ischemic stroke. METHODS: We comprehensively review the role of endothelial GLUT1 in ischemic stroke by narrating the findings concerning biological characteristics of GLUT1 in brain in depth, summarizing the changes of endothelial GLUT1 expression and activity during ischemic stroke, discussing how GLUT1 achieves its neuroprotective effect via maintaining endothelial function, and identifying some outstanding blind spots in current studies. RESULTS: Endothelial GLUT1 maintains persistent high glucose and energy requirements of the brain by transporting glucose through the blood-brain barrier, which preserves endothelial function and is beneficial to stroke prognosis. CONCLUSION: This review underscores the potential involvement of GLUT1 trafficking, activity modulation, and degradation, and we look forward to more clinical and animal studies to illuminate these mechanisms.

Iron Deposition in Parkinson's Disease: A Mini-Review.

Iron deposition is crucial pathological changes observed in patients with Parkinson's disease (PD). Recently, scientists have actively explored therapeutic approaches targeting iron deposition in PD. However, several clinical studies have failed to yield consistent results. In this review, we provide an overview of iron deposition in PD, from both basic research and clinical perspectives. PD patients exhibit abnormalities in various iron metabolism-related proteins, leading to disruptions in iron distribution, transport, storage, and circulation, ultimately resulting in iron deposition. Excess iron can induce oxidative stress and iron-related cell death, and exacerbate mitochondrial dysfunction, contributing to the progression of PD pathology. Magnetic resonance imaging studies have indicated that the characteristics of iron deposition in the brains of PD patients vary. Iron deposition correlates with the clinical symptoms of PD, and patients with different disease courses and clinical presentations display distinct patterns of iron deposition. These iron deposition patterns may contribute to PD diagnosis. Iron deposition is a promising target for PD treatment. However, further research is required to elucidate the underlying mechanisms and their impacts on PD.

Supra-Blan2 t score as a multisystem-based risk score to predict poor 3-month outcome in acute ischemic stroke patients with intravenous thrombolysis.

AIM: To develop and validate a novel weighted score integrating multisystem laboratory and clinical variables to predict poor 3-month outcome (mRS score of 3-6) in acute ischemic stroke (AIS) patients with intravenous thrombolysis (IVT) therapy. METHODS: We retrospectively analyzed data from Trial of Revascularization Treatment for Acute Ischemic Stroke study. The Supra-Blan2 t score was derived using the data on age, the National Institutes of Health Stroke Scale score, history of atrial fibrillation, blood sugar level, neutrophil count, direct bilirubin level, platelet-lymphocyte ratio, and TnI level in the derivation cohort of 433 patients, and validated in a cohort of 525 patients. Furthermore, we compared the performance of the Supra-Blan2 t score with DRAGON, TURN, and SPAN-100 scores. RESULTS: The discrimination capacity in the derivation and validation cohorts was good for poor 3-month outcome (the area under the curve was 0.821 and 0.843, respectively). The cumulative incidence of poor 3-month outcome significantly increased across risk categories in the derivation (low-risk, 9.2%; medium-risk, 17.4%; and high-risk, 58.8%) and validation cohorts (12.7%, 36.5%, and 73.6%, respectively). The performance of the Supra-Blan2 t score was similar to or superior to DRAGON, TURN, and SPAN-100 scores. CONCLUSION: The Supra-Blan2 t score, based on easily available multisystem laboratory and clinical variables, reliably predicted poor 3-month functional outcome in AIS patients treated with IVT therapy featuring good calibration and discrimination.

The experimental approach for the interleaved joint modulation of PHIP and NMR.

Nuclear spin hyperpolarization derived from parahydrogen is a technique for enhancing nuclear magnetic resonance (NMR) sensitivity. The key to hyperpolarization experiments is to achieve rapid transfer and detection to minimize relaxation losses, while also avoiding bubbles or turbulence to guarantee high spectral resolution. In this article, we describe an experimental approach for the interleaved joint modulation of parahydrogen-induced polarization and NMR. We provide schematic diagrams of parahydrogen-based polarizer with in situ high-pressure detection capability and low-field polarization transfer. This approach can help to control the experimental process and acquire experimental information, one example of which is the attainment of the highest hyperpolarization signal intensity at 3.6 s after closing the valve. The polarizer demonstrates in situ detection capability, allowing sample to be restabilized within 0.3 ± 0.1 s and high-resolution NMR sampling under a pressure of 3 bars. Moreover, it can transfer polarized samples from the polarization transfer field to the detection region of NMR within 1 ± 0.3 s for completing signal amplification by reversible exchange experiments.

Elevated Serum Lactate Dehydrogenase Predicts Unfavorable Outcomes After rt-PA Thrombolysis in Ischemic Stroke Patients.

Background and Purpose: Currently, acute ischemic stroke (AIS) is one of the most common and serious diseases in the world and is associated with very high mortality and morbidity even after thrombolysis therapy. This study aims to research the relationship between lactic dehydrogenase (LDH) and prognosis in AIS patients treated with intravenous rtPA. Method: This study (a Multicenter Clinical Trial of Revascularization Treatment for Acute Ischemic Stroke, TRAIS) included 527 AIS patients in 5 cooperative medical institutions in China from January 2018 to February 2021. The primary outcome was major disability and death within 3 months (mRS score of 3-6), and the secondary outcomes were early neurological improvement (ENI), early neurological deterioration (END), moderate-severe cerebral edema (CE), and symptomatic intracranial hemorrhage (sICH). Results: The mean age of the 527 patients was 65.6 ± 11.7 years, and the median baseline NIHSS score was 4 (interquartile range, 2-7). The median serum LDH level was 184 U/L (interquartile range, 163-212 U/L). In total, 287 (54.5%) patients acquired ENI, 68 (13.0%) patients suffered END, 53 (12.1%) patients were observed with moderate-severe CE, and 28 (6.2%) patients showed sICH. Within 3 months, 127 (25.15%) patients experienced the primary outcome and 42 (8.3%) patients died. Serum LDH levels before thrombolysis showed an independent association with the risk of primary outcome [adjusted odds ratio, 3.787; (95% CI, 1.525-9.404); P = 0.014]. When log-transformed LDH increased each standard deviation, the risk of primary outcome was raised by 80.1% (95% CI, 28.9-251.7%). A positive linear dependence between the risk of primary outcome and serum LDH levels (P of linearity = 0.0248, P of non-linearity = 0.8284) was shown in multivariable-adjusted spline regression models. Pre-thrombolysis LDH quartile also provided a conventional risk model and significant improvement of the prediction for clinical outcomes, with a net reclassification improvement index (NRI) = 41.86% (P < 0.001) and integrated discrimination improvement (IDI) = 4.68% (P < 0.001). Conclusions: Elevated serum LDH levels predicted unfavorable clinical outcomes after intravenous thrombolysis in AIS patients.

Predictive value of different bilirubin subtypes for clinical outcomes in patients with acute ischemic stroke receiving thrombolysis therapy.

AIMS: To explore the association of total bilirubin (TBIL), direct bilirubin (DBIL), and indirect bilirubin (IBIL) levels with, as well as the incremental predictive value of different bilirubin subtypes for, poor outcomes in acute ischemic stroke patients after thrombolysis. METHODS: We analyzed 588 individuals out of 718 AIS participants, and all patients were followed up at 3 months after thrombolysis. The primary outcome was 3-month death and major disability (modified Rankin Scale (mRS) score of 3-6). The secondary outcomes were 3-month mortality (mRS score of 6), moderate-severe cerebral edema, and symptomatic intracranial hemorrhage (sICH), respectively. RESULTS: Elevated DBIL pre-thrombolysis was associated with an increased risk of primary outcome (OR 3.228; 95% CI 1.595-6.535; p for trend = 0.014) after fully adjustment. Elevated TBIL pre-thrombolysis showed the similar results (OR 2.185; 95% CI 1.111-4.298; p for trend = 0.047), while IBIL pre-thrombolysis was not significantly associated with primary outcome (OR 1.895; 95% CI 0.974-3.687; p for trend = 0.090). Multivariable-adjusted spline regression model showed a positive linear dose-response relationship between DBIL pre-thrombolysis and risk of primary outcome (p for linearity = 0.004). Adding DBIL pre-thrombolysis into conventional model had greater incremental predictive value for primary outcome, with net reclassification improvement (NRI) 95% CI = 0.275 (0.084-0.466) and integrated discrimination improvement (IDI) 95% CI = 0.011 (0.001-0.024). Increased DBIL post-thrombolysis had an association with primary outcome (OR 2.416; 95%CI 1.184-4.930; p for trend = 0.039), and it also elevated the incremental predictive value for primary outcome, with NRI (95% CI) = 0.259 (0.066-0.453) and IDI (95% CI) = 0.025 (0.008-0.043). CONCLUSION: Increased DBIL pre-thrombolysis had a stronger association with, as well as greater incremental predictive value for, poor outcomes than TBIL and IBIL did in AIS patients after thrombolysis, which should be understood in the context of retrospective design. The effect of DBIL on targeted populations should be investigated in further researches.

Determining the enantioselectivity of asymmetric hydrogenation through parahydrogen-induced hyperpolarization.

Asymmetric hydrogenation plays an essential role for both academic research and industry to produce enantiomeric pure chiral molecules. Although nuclear magnetic resonance (NMR) is powerful in determining the yields of hydrogenation, it is still challenging to use NMR for chirality-related analysis. Herein, we applied parahydrogen-induced hyperpolarization (PHIP) NMR to determine the enantioselectivity of asymmetric hydrogenation and the absolute chirality of products. We hyperpolarized two types of unsaturated amino acid precursors, i.e., methyl-α-acetoamido cinnamate and (E)-ethyl 3-acetamidobut-2-enoate. Hydrogenation of prochiral substrates with parahydrogen gave temporary hyperpolarized diastereoisomers, which exhibit different PHIP patterns distinguishable in 1H NMR. After assigning the NMR peaks by density functional theory calculations, we simulated the PHIP patterns of all the possible temporary hyperpolarized diastereoisomers and unambiguously assigned the chirality of the products and the enantioselectivity of asymmetric hydrogenation. Our work demonstrates the application and potential of PHIP in revealing the mechanism of asymmetric hydrogenation.

Morinda officinalis oligosaccharides alleviate depressive-like behaviors in post-stroke rats via suppressing NLRP3 inflammasome to inhibit hippocampal inflammation.

AIMS: Morinda officinalis oligosaccharides (MOOs), a traditional Chinese medicine, have been used to treat mild and moderate depressive episodes. In this study, we investigated whether MOOs can ameliorate depressive-like behaviors in post-stroke depression (PSD) rats and further explored its mechanism by suppressing microglial NLRP3 inflammasome activation to inhibit hippocampal inflammation. METHODS: Behavioral tests were performed to evaluate the effect of MOOs on depressive-like behaviors in PSD rats. The effects of MOOs on the expression of IL-18, IL-1ß, and nucleotide-binding domain leucine-rich repeat (NLR) family pyrin domain containing 3 (NLRP3) inflammasome were measured in both PSD rats and lipopolysaccharide (LPS) and adenosine triphosphate (ATP) stimulated primary rat microglia by reverse transcription polymerase chain reaction (RT-PCR), immunofluorescence and Western blot analysis. Adeno-associated virus (AAV) was injected into the hippocampus to regulate NLRP3 inflammasome expression. The detailed molecular mechanism underlying the effects of MOOs was analyzed by Western blot and immunofluorescence. RESULTS: MOOs can alleviate depressive-like behaviors in PSD rats. PSD rats showed increased expression of IL-18, IL-1ß, and NLRP3 inflammasome in the ischemic hippocampus, while MOOs reversed the elevation. NLRP3 downregulation ameliorated depressive-like behaviors and hippocampal inflammation response in PSD rats, while NLRP3 upregulation inhibited the effect of MOOs on depressive-like behaviors and hippocampal inflammation response in PSD rats. Moreover, we found that NLRP3 was mainly expressed on microglia. In vitro, MOOs effectively inhibited the expression of IL-18, IL-1ß, and NLRP3 inflammasome in LPS + ATP treated primary rat microglia. We also showed that modulation of NLRP3 inflammasome by MOOs was associated with the IκB/NF-κB p65 signaling pathway. CONCLUSION: Overall, our study reveals the antidepressive effect of MOOs on PSD rats through modulation of microglial NLRP3 inflammasome. We also provide a novel insight into hippocampal inflammation response in PSD pathology and put forward NLRP3 inflammasome as a potential therapeutic target for PSD.

The role of leukocytes in acute ischemic stroke-related thrombosis: a notable but neglected topic.

Ischemic stroke is one of the most serious diseases today, and only a minority of patients are provided with effective clinical treatment. Importantly, leukocytes have gradually been discovered to play vital roles in stroke thrombosis, including promoting the activation of thrombin and the adhesion and aggregation of platelets. However, they have not received enough attention in the field of acute ischemic stroke. It is possible that we could not only prevent stroke-related thrombosis by inhibiting leukocyte activation, but also target leukocyte components to dissolve thrombi in the cerebral artery. In this review, we expound the mechanisms by which leukocytes are activated and participate in the formation of stroke thrombus, then describe the histopathology of leukocytes in thrombi of stroke patients and the influence of leukocyte composition on vascular recanalization effects and patient prognosis. Finally, we discuss the relevant antithrombotic strategies targeting leukocytes.

Aroused and Impulsive Effects of Colour Stimuli on Lateral and Logical Abilities.

The purpose of this study was to explore the influence of environmental colour on people's lateral and logical abilities. This was done by evaluating study participants' response time and error rate when completing six types of psychometric tests that were performed in various hue backgrounds on a computer. To maximise the colour stimulation provided by the monitor, the experiment was carried out in a dark laboratory. Analysis of participants' response time and error rate showed that different colours could significantly influence arousal and impulsiveness, which suggests that colour has indirect impacts on cognitive abilities. Further analysis revealed that different colours had various effects depending on the type of psychometric test given. These findings suggest that future research on environmental design should consider how to effectively use colour to impact people's performance and behaviour.

Morinda officinalis oligosaccharides ameliorate depressive-like behaviors in poststroke rats through upregulating GLUT3 to improve synaptic activity.

Poststroke depression (PSD) is one of the most common psychiatric diseases afflicting stroke survivors, yet the underlying mechanism is poorly understood. The pathophysiology of PSD is presumably multifactorial, involving ischemia-induced disturbance in the context of psychosocial distress. The homeostasis of glucose metabolism is crucial to neural activity. In this study, we showed that glucose consumption was decreased in the medial prefrontal cortex (mPFC) of PSD rats. The suppressed glucose metabolism was due to decreased glucose transporter-3 (GLUT3) expression, the most abundant and specific glucose transporter of neurons. We also found Morinda officinalis oligosaccharides (MOOs), approved as an antidepressive Chinese medicine, through upregulating GLUT3 expression in the mPFC, improved glucose metabolism, and enhanced synaptic activity, which ultimately ameliorated depressive-like behavior in PSD rats. We further confirmed the mechanism that MOOs induce GLUT3 expression via the PKA/pCREB pathway in PSD rats. Our work showed that MOOs treatment is capable of restoring GLUT3 level to improve depressive-like behaviors in PSD rats. We also propose GLUT3 as a potential therapeutic target for PSD and emphasize the importance of metabolism disturbance in PSD pathology.

Structural brain changes in Ser129-phosphorylated alpha-synuclein rats based on voxel-based morphometry.

Parkinson's disease has become one of the most common neurodegenerative diseases. Pathological changes typically manifest following dopaminergic neuron loss in the substantia nigra and abnormal alpha-synuclein (α-syn) aggregation in the neurons. α-Syn is the major component of Lewy bodies. However, research pertaining to the spread of abnormal α-syn aggregations, which results in specific damage to the brain structure and function, is lacking. In the present study, full-length human α-syn fibrils were injected into the medial forebrain bundle of rats, with an experimental endpoint of 6 months. Histological analysis was conducted to observe the pathological progress of abnormal endogenous α-syn aggregation and nerve fiber quality. Changes in gray and white matter integrity were quantitatively analyzed using voxel-based morphometry (VBM). Behavioral changes were observed over the 6-month period. Histological analysis showed reduced dopamine transporter levels in the striatum of the experimental rats; widespread abnormal endogenous α-syn accumulation; and damaged, sparse, and disordered nerve fibers in the experimental group. VBM showed that at 6 months after surgery, bilateral anterior limbic, bilateral inferior limbic, right hippocampal, and right cortical volumes had reduced, whereas thalamic volume had increased in the experimental group compared with that in the control group. Damage to the limbic and thalamic fiber structure may occur in the earlier stages of Parkinson's disease.

The Rodent Models of Dyskinesia and Their Behavioral Assessment.

Dyskinesia, a major motor complication resulting from dopamine replacement treatment, manifests as involuntary hyperkinetic or dystonic movements. This condition poses a challenge to the treatment of Parkinson's disease. So far, several behavioral models based on rodent with dyskinesia have been established. These models have provided an important platform for evaluating the curative effect of drugs at the preclinical research level over the past two decades. However, there are differences in the modeling and behavioral testing procedures among various laboratories that adversely affect the rat and mouse models as credible experimental tools in this field. This article systematically reviews the history, the pros and cons, and the controversies surrounding rodent models of dyskinesia as well as their behavioral assessment protocols. A summary of factors that influence the behavioral assessment in the rodent dyskinesia models is also presented, including the degree of dopamine denervation, stereotaxic lesion sites, drug regimen, monitoring styles, priming effect, and individual and strain differences. Besides, recent breakthroughs like the genetic mouse models and the bilateral intoxication models for dyskinesia are also discussed.

TRH Analog, Taltirelin Improves Motor Function of Hemi-PD Rats Without Inducing Dyskinesia via Sustained Dopamine Stimulating Effect.

Thyrotropin-releasing hormone (TRH) and its analogs are able to stimulate the release of the endogenic dopamine (DA) in the central nervous system. However, this effect has not been tested in the Parkinson's disease (PD), which is characterized by the DA deficiency due to the dopaminergic neurons loss in the substantia nigra. Here, we investigated the therapeutic effect of Taltirelin, a long-acting TRH analog on 6-hydroxydopamine-lesioned hemi-Parkinsonian rat model. 1-10 mg/kg Taltirelin i.p. administration significantly improved the locomotor function and halted the electrophysiological abnormities of PD animals without inducing dyskinesia even with high-dose for 7 days treatment. Microdialysis showed that Taltirelin gently and persistently promoted DA release in the cortex and striatum, while L-DOPA induced a sharp rise of DA especially in the cortex. The DA-releasing effect of Taltirelin was alleviated by reserpine, vanoxerine (GBR12909) or AMPT, indicating a mechanism involving vesicular monoamine transporter-2 (VMAT-2), dopamine transporter (DAT) and tyrosine hydroxylase (TH). The in vivo and in vitro experiments further supported that Taltirelin affected the regulation of TH expression in striatal neurons, which was mediated by p-ERK1/2. Together, this study demonstrated that Taltirelin improved motor function of hemi-PD rats without inducing dyskinesia, thus supporting a further exploration of Taltirelin for PD treatment.

TRH Analog, Taltirelin Protects Dopaminergic Neurons From Neurotoxicity of MPTP and Rotenone.

Dopaminergic neurons loss is one of the main pathological characters of Parkinson's disease (PD), while no suitable neuroprotective agents have been in clinical use. Thyrotropin-releasing hormone (TRH) and its analogs protect neurons from ischemia and various cytotoxins, but whether the effect also applies in PD models remain unclear. Here, we showed that Taltirelin, a long-acting TRH analog, exhibited the neuroprotective effect in both cellular and animal models of PD. The in vitro study demonstrated that Taltirelin (5 µM) reduced the generation of reactive oxygen species (ROS) induced by MPP+ or rotenone, alleviated apoptosis and rescued the viability of SH-SY5Y cells and rat primary midbrain neurons. Interestingly, SH-SY5Y cells treated with Taltirelin also displayed lower level of p-tau (S396) and asparagine endopeptidase (AEP) cleavage products, tau N368 and α-synuclein N103 fragments, accompanied by a lower intracellular monoamine oxidase-B (MAO-B) activity. In the subacute MPTP-induced and chronic rotenone-induced PD mice models, we found Taltirelin (1 mg/kg) significantly improved the locomotor function and preserved dopaminergic neurons in the substantia nigra (SN). In accordance with the in vitro study, Taltirelin down-regulated the levels of p-tau (S396), p-α-synuclein (S129) tau N368 and α-synuclein N103 fragments in SN and striatum. Together, this study demonstrates that Taltirelin may exert neuroprotective effect via inhibiting MAO-B and reducing the oxidative stress and apoptosis, preventing AEP activation and its subsequent pathological cleavage of tau and α-synuclein, thus provides evidence for Taltirelin in protective treatment of PD.