An Explainable Artificial Intelligence Model to Predict Malignant Cerebral Edema after Acute Anterior Circulating Large Hemisphere Infarction.

INTRODUCTION: Malignant cerebral edema (MCE) is a serious complication and the main cause of poor prognosis in patients with large-hemisphere infarction (LHI). Therefore, the rapid and accurate identification of potential patients with MCE is essential for timely therapy. This study utilized an artificial intelligence-based machine learning approach to establish an interpretable model for predicting MCE in patients with LHI. METHODS: This study included 314 patients with LHI not undergoing recanalization therapy. The patients were divided into MCE and non-MCE groups, the extreme Gradient boosting (XGBoost) model was developed. A confusion matrix was used to measure the prediction performance of the XGBoost model. We also utilized the SHapley Additive extension (SHAP) method to explain the XGBoost model. Decision curve analysis and receiver operating characteristic (ROC) curve were performed to evaluate the net benefits of the model. RESULTS: MCE was observed in 121(38.5%) of the 314 patients with LHI. The model showed excellent predictive performance, with an area under the curve of 0.916. The SHAP method revealed the top 10 predictive variables of the MCE such as ASPECTS score, NIHSS score, CS score, APACHE II score, HbA1c, AF, NLR, PLT, GCS and Age based on their importance ranking. CONCLUSION: An interpretable predictive model can increase transparency and help doctors accurately predict the occurrence of MCE in LHI patients, not undergoing recanalization therapy within 48h from onset, providing patients with better treatment strategies and enabling optimal resource allocation.

External validation and comparison of MBE, EDEMA, and modified EDEMA scores for predicting malignant cerebral EDEMA in Chinese patients with large hemispheric infarction patients without revascularization.

BACKGROUND: Malignant cerebral edema (MCE) is a severe condition characterized by rapid neurological deterioration and a potentially poor prognosis. Scoring systems including the malignant brain edema (MBE) score, Enhanced Detection of Edema in Malignant Anterior Circulation Stroke score (EDEMA), and modified EDEMA score, have been developed to predict MCE in patients with large hemispheric infarction (LHI). We aimed to externally validate and comparethe predictive efficacy of these scores in LHI patients within 48 h of onset and not undergoing reperfusion therapy. METHODS: Demographic, clinical and radiological data were retrospectively collected from LHI patients within 48 h of onset and not receiving reperfusion therapy. Patients were divided into MCE and non-MCE group. The calibration, discrimination, and clinical practicability of the three scores were verified using Hosmer-Lemeshow goodness-of-fit test, receiver operating characteristic (ROC) curve analysis and decision curve analysis (DCA), respectively. Finally, continuous net reclassification improvement (NRI) and integrated discrimination improvement (IDI) were applied to determine the discrimination performance of the three scores. RESULTS: A total of 314 patients were included in the study, with 122 cases being MCE patients. The Hosmer-Lemeshow goodness-of-fit test showed excellent fitting ability across the MBE (p = 0.36), EDEMA (p = 0.61), and modified EDEMA scores (p = 0.62) in our patients. The MBE, EDEMA, and modified EDEMA scores had the AUCs of 0.855 (95 % CI 0.818-0.898), 0.782 (95 % CI 0.727-0.837) and 0.878 (95 % CI 0.844-0.919) respectively. The MBE (NRI, 0.33; 95 % CI, 0.11-0.56, p = 0.003 and IDI, 0.11; 95 % CI, 0.03-0.18; p = 0.004) and modified EDEMA scores (NRI, 1.10; 95 % CI, 0.94-1.26; p < 0.001 and IDI, 0.17; 95 % CI, 0.13-0.20, p < 0.001) showed better performance than the EDEMA score. DCA demonstrated that the modified EDEMA score outperformed the other two scores, possessing heightened clinical usefulness. CONCLUSIONS: The MBE, EDEMA, and modified EDEMA scores for predicting MCE are also applicable in non-revascularization LHI patients within 48 h of onset. Both the MBE and modified EDEMA scores demonstrated higher predictive validity as predictive tools for MCE in LHI patients than the EDEMA score. Furthermore, the modified EDEMA score could be a suitable prediction tool in Chinese patients for its excellent clinical utility.

Acute respiratory distress syndrome heterogeneity and the septic ARDS subgroup.

Acute respiratory distress syndrome (ARDS) is an acute diffuse inflammatory lung injury characterized by the damage of alveolar epithelial cells and pulmonary capillary endothelial cells. It is mainly manifested by non-cardiogenic pulmonary edema, resulting from intrapulmonary and extrapulmonary risk factors. ARDS is often accompanied by immune system disturbance, both locally in the lungs and systemically. As a common heterogeneous disease in critical care medicine, researchers are often faced with the failure of clinical trials. Latent class analysis had been used to compensate for poor outcomes and found that targeted treatment after subgrouping contribute to ARDS therapy. The subphenotype of ARDS caused by sepsis has garnered attention due to its refractory nature and detrimental consequences. Sepsis stands as the most predominant extrapulmonary cause of ARDS, accounting for approximately 32% of ARDS cases. Studies indicate that sepsis-induced ARDS tends to be more severe than ARDS caused by other factors, leading to poorer prognosis and higher mortality rate. This comprehensive review delves into the immunological mechanisms of sepsis-ARDS, the heterogeneity of ARDS and existing research on targeted treatments, aiming to providing mechanism understanding and exploring ideas for accurate treatment of ARDS or sepsis-ARDS.

Development and validation of a nomogram for the risk prediction of malignant cerebral edema after acute large hemispheric infarction involving the anterior circulation.

Background: Malignant cerebral edema (MCE) is a life-threatening complication of large hemisphere infarction (LHI). Therefore, a fast, accurate, and convenient tool for predicting MCE can guide triage services and facilitate shared decision-making. In this study, we aimed to develop and validate a nomogram for the early prediction of MCE risk in acute LHI involving the anterior circulation and to understand the potential mechanism of MCE. Methods: This retrospective study included 312 consecutive patients with LHI from 1 January 2019 to 28 February 2023. The patients were divided into MCE and non-MCE groups. MCE was defined as an obvious mass effect with ≥5 mm midline shift or basal cistern effacement. Least absolute shrinkage and selection operator (LASSO) and logistic regression were performed to explore the MCE-associated factors, including medical records, laboratory data, computed tomography (CT) scans, and independent clinic risk factors. The independent factors were further incorporated to construct a nomogram for MCE prediction. Results: Among the 312 patients with LHI, 120 developed MCE. The following eight factors were independently associated with MCE: Glasgow Coma Scale score (p = 0.007), baseline National Institutes of Health Stroke Scale score (p = 0.006), Alberta Stroke Program Early CT Score (p < 0.001), admission monocyte count (p = 0.004), white blood cell count (p = 0.002), HbA1c level (p < 0.001), history of hypertension (p = 0.027), and history of atrial fibrillation (p = 0.114). These characteristics were further used to establish a nomogram for predicting prognosis. The nomogram achieved an AUC-ROC of 0.89 (95% CI, 0.82-0.96). Conclusion: Our nomogram based on LASSO-logistic regression is accurate and useful for the early prediction of MCE after LHI. This model can serve as a precise and practical tool for clinical decision-making in patients with LHI who may require aggressive therapeutic approaches.

Developing and validating a nomogram for cognitive impairment in the older people based on the NHANES.

Objective: To use the United States National Health and Nutrition Examination Study (NHANES) to develop and validate a risk-prediction nomogram for cognitive impairment in people aged over 60 years. Methods: A total of 2,802 participants (aged ≥ 60 years) from NHANES were analyzed. The least absolute shrinkage and selection operator (LASSO) regression model and multivariable logistic regression analysis were used for variable selection and model development. ROC-AUC, calibration curve, and decision curve analysis (DCA) were used to evaluate the nomogram's performance. Results: The nomogram included five predictors, namely sex, moderate activity, taste problem, age, and education. It demonstrated satisfying discrimination with a AUC of 0.744 (95% confidence interval, 0.696-0.791). The nomogram was well-calibrated according to the calibration curve. The DCA demonstrated that the nomogram was clinically useful. Conclusion: The risk-prediction nomogram for cognitive impairment in people aged over 60 years was effective. All predictors included in this nomogram can be easily accessed from its' user.

δ-opioid Receptor, Microglia and Neuroinflammation.

Neuroinflammation underlies the pathophysiology of multiple age-related neurological disorders. Microglia, the resident immune cells of the central nervous system, are critically involved in neuroinflammatory regulation and neural survival. Modulating microglial activation is thus a promising approach to alleviate neuronal injury. Our serial studies have revealed a neuroprotective role of the δ-opioid receptor (DOR) in several acute and chronic cerebral injuries by regulating neuroinflammation and cellular oxidative stress. More recently, we found an endogenous mechanism for the inhibition of neuroinflammation is closely related to DOR's modulation of microglia. Our recent studies showed that DOR activation could strongly protect neurons from hypoxia- and lipopolysaccharide (LPS)-induced injury by inhibiting microglial pro-inflammatory transformation, while knocking-down DOR or restraining DOR activity promoted microglia activation and the relevant inflammatory events with an aggravation of cell injury. This novel finding highlights a therapeutic potential of DOR in numerous age-related neurological disorders through the modulation of neuroinflammation by targeting microglia. This review summarized the current data regarding the role of microglia in neuroinflammation, oxidative stress, and age-related neurological diseases focusing on the pharmacological effects and signaling transduction of DOR in microglia.

Angiotensin-converting enzyme 2 inhibits inflammation and apoptosis in high glucose-stimulated microvascular endothelial cell damage by regulating the JAK2/STAT3 signaling pathway.

Mounting evidence supports that angiotensin-converting enzyme 2 (ACE2) may exert a vital function in multiple complications induced by diabetes. The aim of this research was to verify the function of ACE2 in diabetic angiopathy (DA). In our study, it was revealed that high glucose (HG) treatment impeded cell proliferation and induced cell apoptosis. Moreover, ACE2 level was reduced in HG-stimulated HMEC-1 cells. Functional assays demonstrated that ACE2 addition promoted cell viability, suppressed apoptosis, oxidative stress, ROS generation, and inflammation in HG-stimulated HMEC-1 cells. Furthermore, the activation of the JAK2/STAT3 pathway induced by HG was impeded by overexpression of ACE2. Besides, JAK2/STAT3 pathway inhibitor AG490 reversed the changes of cell viability, apoptosis, oxidative stress, and inflammation caused by ACE2 deletion in HG-treated HMEC-1 cells. In sum, our findings highlighted that ACE2 promoted the viability and restrained the oxidative stress, inflammation, and apoptosis in HG-induced microvascular endothelial cells (VECs) injury via regulating the JAK2/STAT3 pathway, suggesting ACE2 might be a potential therapeutic target for DA treatment.

The Efficacy of Group Acceptance and Commitment Therapy for Preventing Post-Stroke Depression: A Randomized Controlled Trial.

BACKGROUND AND PURPOSE: Post-stroke depression (PSD) is a common psychiatric complication of stroke and is associated with the subsequent prognosis, yet still lacking of enough attention. PSD is preventable, and psychotherapy is an alternative prophylactic treatment which needs more solid evidences to confirm its efficacy. In this study, group Acceptance and Commitment Therapy (G-ACT) was performed in acute stroke patients to see if it can effectively relieve depressive symptoms and improve neurological function. The efficacy was also evaluated in stroke patients of different severity. METHODS: One hundred and four hospitalized patients with acute ischemic stroke were enrolled according to the inclusion criteria and exclusion criteria. After baseline evaluation, they were randomly allocated to the intervention (G-ACT) group and the control (usual care) group. Patients in the control group received routine stroke treatment, while those in the intervention group were given additional G-ACT treatment (5 sessions, 45-55 min/session). Both of the two groups were assessed with 24-item Hamilton Depression Scale (HAMD-24), National Institutes of Health Stroke Scale (NIHSS), and Barthel Index (BI) at baseline, 2 weeks, 1 month, and 3 months follow-up. Patients were further divided into the mild stroke group (NIHSS 0-3) and the moderate stroke group (NIHSS 4-9), HAMD scores at different time points were also assessed. RESULTS: The HAMD score of G-ACT group was significantly lower than that of control group at 1 month (p = 0.018) and 3 months follow-up (p = 0.001). As to the NIHSS score, there was no significant difference between the two groups within the follow-up period (p > 0.05). The BI score of the two groups was statistically different at 2 weeks (p = 0.033) and 1 month (p = 0.019), while no difference was shown at 3 months (p = 0.191). In acute phase, the HAMD score of moderate stroke patients was significantly higher than that of mild ones (p < 0.001). After G-ACT treatment, both mild and moderate stroke patients showed lower HAMD score at 3 months follow-up (p = 0.004; p = 0.033). CONCLUSIONS: G-ACT seems to be a viable and effective treatment for preventing PSD in the acute phase of stroke, while the efficacy of which on improving neurological deficits needs to be further evaluated.

Cerebral arterial fenestration associated with stroke and other cerebrovascular diseases.

BACKGROUND: Cerebral arterial fenestration is a rare vascular malformation that has not been fully understood. Whether it is related to cerebrovascular diseases remains to be determined. In this study, we aimed to investigate the imaging characteristics of cerebral fenestrations, the clinical characteristics of fenestrations complicated with cerebrovascular diseases, and the correlation between fenestrations and cerebrovascular diseases. METHODS: We reviewed the magnetic resonance imaging and computed tomography (CT) imaging findings of patients with cerebrovascular fenestrations in the Third Affiliated Hospital of Soochow University from January 2016 to December 2020, mainly focused on the shape and location of fenestrations. According to the location of fenestrated arteries, patients were divided into the internal carotid arterial system (ICAS) group and the vertebrobasilar arterial system (VAS) group. For patients complicated with cerebrovascular diseases, detailed data about the demographics and clinical characteristics were recorded. Stroke patients with injured lesions located in the territories of fenestrated arteries were further screened out and analyzed. Moreover, the proportions of cerebrovascular diseases including stroke between the ICAS group and the VAS group were compared. RESULTS: A total of 280 cerebrovascular fenestrations were found in 274 patients (six patients had two fenestrations). The most frequently involved vessels were the anterior cerebral artery (123/280), the basilar artery (76/280) and the vertebral artery (35/280). As to the shape of fenestrations, slit-like fenestrations accounted for 63.2% (177/280), followed by convex-lens-like type 26.1% (73/280) and duplicated type 10.7% (30/280). A total of 70 patients were complicated with cerebrovascular diseases, including ischemic stroke 64.3% (45/70), hemorrhagic stroke 22.9% (16/70), aneurysm 10% (7/70), arteriovenous malformation 1.4% (1/70) and cavernous hemangioma 1.4% (1/70). There were no significant differences between the ICAS group and the VAS group in terms of the demographics and clinical characteristics. Furthermore, among the 61 patients complicated with stroke, 16 patients' stroke lesions were located in the territories of fenestrated arteries, including 12.5% (2/16) in the ICAS and 87.5% (14/16) in the VAS. In addition, compared with the ICAS group, the proportions of cerebrovascular diseases including stroke in patients with fenestrations were higher in the VAS group (P < 0.05). CONCLUSIONS: Cerebral arterial fenestrations are most commonly found in the anterior cerebral artery, the basilar artery and the vertebral artery. Vertebrobasilar fenestrations are more related to cerebrovascular diseases, especially stroke.

Educational attainment protects against epilepsy independent of cognitive function: A Mendelian randomization study.

OBJECTIVE: Observational studies have suggested that increased levels of education and cognition are associated with a reduced risk of epilepsy. However, such associations are easily influenced by confounding or reverse causality. Hence, we conducted a two-sample univariable and multivariable Mendelian randomization (MR) to estimate the total and independent causal effects of educational attainment and cognition on epilepsy risk. METHODS: We performed MR estimates on International League Against Epilepsy (ILAE) Consortium genome-wide association study (GWAS) data (15 212 epilepsy cases and 29 677 controls). We then validated the results in FinnGen (3424 epilepsy cases and 110 963 controls) and applied meta-analysis to all the results. RESULTS: In the meta-analysis of the ILAE and FinnGen results, genetically determined increased educational attainment was associated with a reduced risk of epilepsy (odds ratio [OR] 0.84, 95% confidence interval [CI] 0.80-0.88; P < .001). Similarly, genetically determined increased cognitive function was associated with a reduced risk of epilepsy (OR 0.94, 95% CI 0.88-1.00, P = .043). When educational attainment and cognitive function were included in the same multivariable MR, only educational attainment was still associated with a reduced risk of epilepsy (OR 0.88, 95% CI 0.81-0.95, P = .002). SIGNIFICANCE: This MR study provides evidence to support that increased educational attainment can reduce the risk of developing epilepsy independent of cognitive function.

Pituitary tumor apoplexy associated with extrapontine myelinolysis during pregnancy: A case report.

RATIONALE: Pituitary tumor apoplexy (PTA) is a rare clinical syndrome which requires urgent diagnosis and treatment due to its life-threatening consequences. Management of undiagnosed pituitary tumor before pregnancy is a problem during pregnancy. PATIENT CONCERNS: We reported a case with PTA which was not diagnosed before pregnancy presenting with vomiting associated with hyponatremia during the third trimester. After supplying the sodium the patient presented with dysarthria and hemiplegia. DIAGNOSES: MRI examination showed PTA accompanied with extrapontine myelinolysis (EPM). INTERVENTIONS: The patient was given hydrocortisone according to the symptoms gradually to taper off dose, at the same times oral levothyroxine therapy (25µg/day) was given. OUTCOMES: The patient delivered a healthy baby via cesarean section at hospital at 38 + 1 week of gestation. We performed MRI examination regularly and the tumor regressed significantly 8 months postpartum. LESSONS: We reported a case as PTA associated with EPM. Headache during pregnancy is often nonspecific, so careful medical history inquiry is very important.

Serum Creatinine Protects Against Amyotrophic Lateral Sclerosis: a Mendelian Randomization Study.

Association between serum creatinine (sCr) and amyotrophic lateral sclerosis (ALS) has been reported in previous observational studies, but results are at risk of confounding bias and reverse causation. Therefore, whether such association is casual remains unclear. Herein, we performed a two-sample Mendelian randomization study to evaluate the causal relationship between sCr and ALS in both European and East Asian populations. Our analysis was conducted using summary statistics from genome-wide association studies with 358,072 individuals for sCr and 80,610 individuals for ALS in European population, and 142,097 individuals for sCr and 4,084 individuals for ALS in East Asian population. The inverse-variance weighted method was used to estimate the casual-effect of sCr on ALS in both populations, and other MR methods were also performed as sensitivity analyses. We found evidence that genetically predicted sCr was inversely associated with risk of ALS (OR, 0.92; 95% CI, 0.85-0.99; P = 0.028) in European population. However, there was no strong evidence for a causal relationship between sCr and ALS in East Asian population (OR, 0.92; 95% CI, 0.84-1.01; P = 0.084). This study provides evidence that sCr protects against ALS in European population but not in East Asian population.

OIP5-AS1 Attenuates Microangiopathy in Diabetic Mouse by Regulating miR-200b/ACE2.

OBJECTIVE: This study aimed to investigate OIP5-AS1 effects on microangiopathy in diabetic mouse. METHODS: The expression levels of OIP5-AS1, miR-200b, and ACE2 expression were measured by RT-qPCR. Western blot was conducted to detect The ACE2 and Ang-(1-7) expression. Luciferase reporter assays were used to identify the interaction between miR-200b and OIP5-AS1 or ACE2. Morris water maze test was performed for detecting cognitive function. RESULTS: Our results indicated that diabetic mice exhibited much lower OIP5-AS1 expression in the hippocampus than normal mice. Diabetic mice of OIP5-AS1 KO group showed remarkably lower OIP5-AS1 expression in the hippocampus, longer escape latency and lower percentage of CD31+ cells in the hippocampusthan those of WT group. OIP5-AS1 knockdown directly up-regulated miR-200b expression and ACE2 was directly inhibited by miR-200b. Relative to normal mice, diabetic mice had markedly higher miR-200b expression and lower ACE2 expression in the hippocampus. Diabetic mice of OIP5-AS1 KO group were with obviously higher miR-200b expression and lower ACE2 expression in the hippocampus than those of WT group. Compared with diabetic mice of OIP5-AS1 KO group, those of WT group, OIP5-AS1 KO + miR-200b inhibitor group and OIP5-AS1 KO + ACE2 group had obviously shorter escape latency and higher percentage of CD31+ cells and more caspase-3 protein expression in the hippocampus. CONCLUSIONS: OIP5-AS1 attenuated microangiopathy in diabetic mouse by regulating miR-200b/ACE2.

δ-Opioid Receptor Activation Attenuates the Oligomer Formation Induced by Hypoxia and/or α-Synuclein Overexpression/Mutation Through Dual Signaling Pathways.

We have recently demonstrated that δ-opioid receptor (DOR) activation attenuates α-synuclein expression/aggregation induced by MPP(+) and/or severe hypoxia. Since α-synuclein plays a critical role in the pathogenesis of Parkinson's disease, DOR activation may trigger an antiparkinson pathway(s) against α-synuclein-induced injury. However, the underlying mechanism is unknown yet. In HEK293T and PC12 cells, we investigated the effects of DOR activation on the oligomer formation induced by α-synuclein overexpression and mutation in normoxic and hypoxic conditions and explored the potential signaling pathways for DOR protection. We found that (1) increased expression of both wild-type and A53T-mutant α-synuclein led to the formation of α-synuclein oligomers and cytotoxic injury; (2) DOR activation largely attenuated the formation of toxic α-synuclein oligomers induced by α-synuclein overexpression/mutation and/or hypoxia; (3) DOR activation attenuated α-synuclein-induced cytotoxicity through TORC1/SIK1/CREB, but not the phospho-CREB pathway, while DOR activation reduced hypoxic cell injury through the phospho-CREB mechanism; and (4) the interaction of α-synuclein and the DJ-1 was involved in the mechanisms for DOR-mediated protection against α-synuclein oligomer formation. Our findings suggest that DOR attenuates the formation of toxic α-synuclein oligomers through the phos-CREB pathway under hypoxic conditions, and through TORC1/SIK1/CREB pathways in the conditions of α-synuclein overexpression and mutation. The DJ-1 gene was involved in the DOR protection against parkinsonian injury.

δ-Opioid Receptor-Nrf-2-Mediated Inhibition of Inflammatory Cytokines in Neonatal Hypoxic-Ischemic Encephalopathy.

Neonatal hypoxic-ischemic encephalopathy (HIE) causes serious neurological disability; there are, however, currently few promising therapies for it. We have recently shown that δ-opioid receptor (DOR) is neuroprotective by downregulating TNF-α. Since hypoxia-ischemia (HI) triggers a robust inflammatory response, which exacerbates HI brain damage, we investigated, in this study, whether DOR activation could regulate inflammatory cytokine expression, thereby playing a protective effect on the neonatal brain under HI. Twenty-five neonatal rats were randomly divided into five groups: (1) control (control); (2) HI; (3) HI with saline (HI + NS); (4) DOR activation with UFP-512 (a potent and specific DOR agonist) under HI conditions (HI + U); and (5) DOR inhibition using NT treatment under HI conditions (HI + NT). The rats were sacrificed by decapitation at 24 h after HI, and their brains were rapidly removed for measurements. The protein expression of TNF-α, IL-6, ICAM-1, IL-10, IL-18, NQO-1, Nrf-2, and HO-1 was measured using Western blot. In the hemispheres exposed to HI, DOR activation significantly decreased the expressions of TNF-α, IL-6, and ICAM-1 in the cortex, while it significantly increased IL-10 and had no effect on IL-18 in the same region. In contrast, DOR had no appreciable effect on inflammatory cytokine expression in non-cortical tissues including hippocampal, subcortical, and cerebellar tissues. Moreover, HI stress triggered an upregulation of Nrf-2 nuclear protein as well as some of its downstream anti-inflammatory genes such as HO-1 and NQO-1 in the cortex, while DOR activation further augmented such a protective reaction against HI injury. DOR plays an important role in protecting against HI by regulating the expression of inflammatory and anti-inflammatory cytokines in the cortex, which is likely mediated by the Nrf-2/HO-1/NQO-1 signaling.

The delta-opioid receptor and Parkinson's disease.

Parkinson's disease (PD) is a common degenerative neurological disease leading to a series of familial, medical, and social problems. Although it is known that the major characteristics of PD pathophysiology are the dysfunction of basal ganglia due to injury/loss of dopaminergic neurons in the substantia nigra pars compacta dopaminergic and exhaustion of corpus striatum dopamine, therapeutic modalities for PD are limited in clinical settings up to date. It is of utmost importance to better understand PD pathophysiology and explore new solutions for this serious neurodegenerative disorder. Our recent work and those of others suggest that the delta-opioid receptor (DOR) is neuroprotective and serves an antiparkinsonism role in the brain. This review summarizes recent progress in this field and explores potential mechanisms for DOR-mediated antiparkinsonism.

Neuroprotection Against Hypoxic/Ischemic Injury: δ-Opioid Receptors and BDNF-TrkB Pathway.

The delta-opioid receptor (DOR) is one of three classic opioid receptors in the opioid system. It was traditionally thought to be primarily involved in modulating the transmission of messages along pain signaling pathway. Although there were scattered studies on its other neural functions, inconsistent results and contradicting conclusions were found in past literatures, especially in terms of DOR's role in a hypoxic/ischemic brain. Taking inspiration from the finding that the turtle brain exhibits a higher DOR density and greater tolerance to hypoxic/ischemic insult than the mammalian brain, we clarified DOR's specific role in the brain against hypoxic/ischemic injury and reconciled previous controversies in this aspect. Our serial studies have strongly demonstrated that DOR is a unique neuroprotector against hypoxic/ischemic injury in the brain, which has been well confirmed in current research. Moreover, mechanistic studies have shown that during acute phases of hypoxic/ischemic stress, DOR protects the neurons mainly by the stabilization of ionic homeostasis, inhibition of excitatory transmitter release, and attenuation of disrupted neuronal transmission. During prolonged hypoxia/ischemia, however, DOR neuroprotection involves a variety of signaling pathways. More recently, our data suggest that DOR may display its neuroprotective role via the BDNF-TrkB pathway. This review concisely summarizes the progress in this field.

Catalpol preserves neural function and attenuates the pathology of Alzheimer's disease in mice.

Alzheimer's disease (AD) is the most common form of dementia and there currently are no effective treatment strategies available. Catalpol is an iridoid glucoside, and large quantities can be isolated from the genus Rehmannia (Orobanchaceae). The present study assessed whether catalpol had any protective effects against Alzheimer's disease using a murine model. Reactive oxygen species (ROS)-associated enzymes as well as soluble Aß40 and Aß42 were detected using kits. Thioflavin­S staining was performed to detect senile plaques and reverse-transcription quantitative polymerase chain reaction was used to assess iroquois homeobox protein 3 (IRX3) and obesity­associated genes, while western blot analysis was used for ß­secretase 1 (BACE1), insulin­degrading enzyme (IDE) and neprilysin (NEP) detection. The Morris water maze was used to detect the learning ability and spatial memory. The results revealed that catalpol was able to reduce the oxidative stress in the cerebral cortex by regulating the activities and concentration of ROS­associated enzymes superoxide dismutase, glutathione peroxidase and catalase, however not malondialdehyde. Catalpol was also identified to be able to reduce the levels of soluble Aß40 and Aß42 in the cerebral cortex and thus inhibit the formation of senile plaques. These effects were observed to be regulated by IDE, however not by BACE1 or NEP. It is suggested that catalpol is not capable of directly regulating the expression of IRX3 and obesity­associated genes. Subsequent to the treatment with catalpol, impairments in learning and memory were also observed to be relieved using the Morris water maze test. The results of the present study indicate that catalpol may be a potential drug for the treatment of neurodegenerative diseases such as AD.