Rhynchophylline promotes stem cell autonomous metabolic homeostasis.

Rhynchophylline (Rhy) effectively obstructs the expansive signaling pathways of degenerative diseases, including Alzheimer disease, Parkinson disease, epilepsy and amyotrophic lateral sclerosis, and stimulates neurogenesis. Maintenance of stemness and cell proliferation requires sophisticated intracellular environments to achieve pluripotency via specific expression of genes and proteins. We examined whether Rhy promotes this regulation in bone marrow human mesenchymal stromal cells (BM-hMSCs). Results revealed (i) Rhy modulated biological activity by regulating the mitochondria, N-methyl-D-aspartate receptor subunit, and levels of FGFß (basic fibroblast growth factor), BDNF (brain-derived neurotrophic factor), OXTR (oxytocin receptor) and ATP (Adenosine triphosphate); (ii) Rhy altered expression level of BM-MSC proliferation/differentiation-related transcription genes; and (iii) interestingly, Rhy amplified the glycolytic flow ratio and lactate dehydrogenase activity while reducing pyruvate dehydrogenase activity, indicating a BM-hMSC metabolic shift of mitochondrial oxidative phosphorylation into aerobic glycolysis. Altogether, we demonstrated a novel mechanism of action for Rhy-induced BM-hMSC modification, which can enhance the cell transplantation approach by amplifying the metabolic activity of stem cells.

Human stem cells transplanted into the rat stroke brain migrate to the spleen via lymphatic and inflammation pathways.

Despite mounting evidence of a massive peripheral inflammatory response accompanying stroke, the ability of intracerebrally transplanted cells to migrate to the periphery and sequester systemic inflammation remains unexamined. Here, we tested the hypothesis that human bone marrow mesenchymal stromal cells intracerebrally transplanted in the brain of adult rats subjected to experimental stroke can migrate to the spleen, a vital organ that confers peripheral inflammation after stroke. Sham or experimental stroke was induced in adult Sprague-Dawley rats by a 1 hour middle cerebral artery occlusion model. One hour after surgery, rats were intracerebrally injected with human bone marrow mesenchymal stromal cells (3×105/9 µL), then euthanized on day 1, 3, or 7 for immunohistochemical assays. Cell migration assays were performed for human bone marrow mesenchymal stromal cells using Boyden chambers with the bottom plate consisting of microglia, lymphatic endothelial cells, or both, and treated with different doses of tumor necrosis factor-α. Plates were processed in a fluorescence reader at different time points. Immunofluorescence microscopy on different days after the stroke revealed that stem cells engrafted in the stroke brain but, interestingly, homed to the spleen via lymphatic vessels, and were propelled by inflammatory signals. Experiments using human bone marrow mesenchymal stromal cells co-cultured with lymphatic endothelial cells or microglia, and treated with tumor necrosis factor-α, further indicated the key roles of the lymphatic system and inflammation in directing stem cell migration. This study is the first to demonstrate brain-to-periphery migration of stem cells, advancing the novel concept of harnessing the lymphatic system in mobilizing stem cells to sequester peripheral inflammation as a brain repair strategy.

Pituitary Adenylate Cyclase Activating Polypeptide Elicits Neuroprotection Against Acute Ischemic Neuronal Cell Death Associated with NMDA Receptors.

BACKGROUND/AIMS: The endogenous neurotrophic peptides pituitary adenylate cyclase-activating polypeptides (PACAP-27/38) protect against stroke, but the molecular mechanism remains unknown. METHODS: Primary rat neural cells were exposed to PACAP-27 or PACAP-38 before induction of experimental acute ischemic stroke via oxygen-glucose deprivation-reperfusion (OGD/R) injury. To reveal PACAP's role in neuroprotection, we employed fluorescent live/dead cell viability and caspase 3 assays, optical densitometry of mitochondrial dehydrogenase and cell growth, glutathione disulfide luciferase activity, ELISA for high mobility group box1 extracellular concentration, ATP bioluminescence, Western blot analysis of PACAP, NMDA subunits, apoptosis regulator Bcl-2, social interaction hormone oxytocin, and trophic factor BDNF, and immunocytochemical analysis of PACAP. RESULTS: Both PACAP-27 and PACAP-38 (PACAP-27/38) increased cell viability, decreased oxidative stress-induced cell damage, maintained mitochondrial activity, prevented the release of high mobility group box1, and reduced cytochrome c/caspase 3-induced apoptosis. PACAP-27/38 increased the protein expression levels of BDNF, Bcl-2, oxytocin, and precursor PACAP. N-methyl-D-aspartate receptor (NMDAR)-induced excitotoxicity contributes to the cell death associated with stroke. PACAP-27/38 modulated the protein expression levels of NMDAR subunits. PACAP-27/38 increased the protein expression levels of the GluN1 subunit, and decreased that of the GluN2B and GluN2D subunits. PACAP-27, but not PACAP-38, increased the expression level of the GluN2C subunit. CONCLUSION: This study provides evidence that PACAP regulated NMDAR subunits, affording neuroprotection after OGD/R injury.

The relationship between the effect of matured hop extract and physical activity on reducing body fat: re-analysis of data from a randomized, double-blind, placebo-controlled parallel group study.

BACKGROUND: We recently reported that successive ingestion of matured hop extract (MHE), produced by oxidation of hops, results in a reduction of body fat in healthy overweight participants. A combined effect of MHE and physical activity on body fat has not been investigated. Thus, we re-analyzed data from the previous study to explore the relationship between the effect of MHE and walking as an index of physical activity. METHODS: This analysis uses existing data from a randomized, double-blind, placebo-controlled parallel group study in which MHE (active) or placebo was given for 12 w to 200 healthy overweight Japanese, from May to December 2014. Correlation between the change in abdominal fat areas at 12 w and the number of steps taken per day was tested by Spearman's correlation coefficient test. The subjects were stratified using the average number of steps per day of Japanese into walking less and walking more subgroups (WL and WM, respectively) as follows: placebo (WL, n = 43; WM, n = 44) and active (WL, n = 49; WM, n = 42). Reductions in total, visceral, and subcutaneous fat area (TFA, VFA and SFA, respectively) were evaluated. The interaction effect between ingestion (active/placebo) and walking (WL/WM) was analyzed using two-way analysis of variance (ANOVA). RESULTS: There was a significant negative correlation between the change in VFA and daily steps taken in the active group (r = - 0.208, P = 0.048). No significant correlation in TFA or SFA. Although the interaction effect in TFA was not significant, the main effect of ingestion was significant (P = 0.045). In contrast, the interaction effect in VFA was suggested to be synergistic (P = 0.055). CONCLUSION: The results suggested that MHE ingestion combined with light intensity exercise would induce a greater reduction in VFA which would be beneficial for obese or overweight individuals in reducing obesity and obesity-related diseases. TRIAL REGISTRATION: UMIN-CTR UMIN000014185 registered 6 June 2014.

Increased Amyloid Precursor Protein and Tau Expression Manifests as Key Secondary Cell Death in Chronic Traumatic Brain Injury.

In testing the hypothesis of Alzheimer's disease (AD)-like pathology in late stage traumatic brain injury (TBI), we evaluated AD pathological markers in late stage TBI model. Sprague-Dawley male rats were subjected to moderate controlled cortical impact (CCI) injury, and 6 months later euthanized and brain tissues harvested. Results from H&E staining revealed significant 33% and 10% reduction in the ipsilateral and contralateral hippocampal CA3 interneurons, increased MHCII-activated inflammatory cells in many gray matter (8-20-fold increase) and white matter (6-30-fold increased) regions of both the ipsilateral and contralateral hemispheres, decreased cell cycle regulating protein marker by 1.6- and 1-fold in the SVZ and a 2.3- and 1.5-fold reductions in the ipsilateral and contralateral dentate gyrus, diminution of immature neuronal marker by two- and onefold in both the ipsilateral and contralateral SVZ and dentate gyrus, and amplified amyloid precursor protein (APP) distribution volumes in white matter including corpus callosum, fornix, and internal capsule (4-38-fold increase), as well as in the cortical gray matter, such as the striatum hilus, SVZ, and dentate gyrus (6-40-fold increase) in TBI animals compared to controls (P's < 0.001). Surrogate AD-like phenotypic markers revealed a significant accumulation of phosphorylated tau (AT8) and oligomeric tau (T22) within the neuronal cell bodies in ipsilateral and contralateral cortex, and dentate gyrus relative to sham control, further supporting the rampant neurodegenerative pathology in TBI secondary cell death. These findings indicate that AD-like pathological features may prove to be valuable markers and therapeutic targets for late stage TBI. J. Cell. Physiol. 232: 665-677, 2017. © 2016 Wiley Periodicals, Inc.

NSI-189, a small molecule with neurogenic properties, exerts behavioral, and neurostructural benefits in stroke rats.

Enhancing neurogenesis may be a powerful stroke therapy. Here, we tested in a rat model of ischemic stroke the beneficial effects of NSI-189, an orally active, new molecular entity (mol. wt. 366) with enhanced neurogenic activity, and indicated as an anti-depressant drug in a clinical trial (Fava et al., , Molecular Psychiatry, DOI: 10.1038/mp.2015.178) and being tested in a Phase 2 efficacy trial (ClinicalTrials.gov, , ClinicalTrials.gov Identifier: NCT02695472) for treatment of major depression. Oral administration of NSI-189 in adult Sprague-Dawley rats starting at 6 hr after middle cerebral artery occlusion, and daily thereafter over the next 12 weeks resulted in significant amelioration of stroke-induced motor and neurological deficits, which was maintained up to 24 weeks post-stroke. Histopathological assessment of stroke brains from NSI-189-treated animals revealed significant increments in neurite outgrowth as evidenced by MAP2 immunoreactivity that was prominently detected in the hippocampus and partially in the cortex. These results suggest NSI-189 actively stimulated remodeling of the stroke brain. Parallel in vitro studies further probed this remodeling process and demonstrated that oxygen glucose deprivation and reperfusion (OGD/R) initiated typical cell death processes, which were reversed by NSI-189 treatment characterized by significant attenuation of OGD/R-mediated hippocampal cell death and increased Ki67 and MAP2 expression, coupled with upregulation of neurogenic factors such as BDNF and SCF. These findings support the use of oral NSI-189 as a therapeutic agent well beyond the initial 6-hr time window to accelerate and enhance the overall functional improvement in the initial 6 months post stroke.

Extracellular HMGB1 Modulates Glutamate Metabolism Associated with Kainic Acid-Induced Epilepsy-Like Hyperactivity in Primary Rat Neural Cells.

BACKGROUND/AIMS: Neuroinflammatory processes have been implicated in the pathophysiology of seizure/epilepsy. High mobility group box 1 (HMGB1), a non-histone DNA binding protein, behaves like an inflammatory cytokine in response to epileptogenic insults. Kainic acid (KA) is an excitotoxic reagent commonly used to induce epilepsy in rodents. However, the molecular mechanism by which KA-induced HMGB1 affords the initiation of epilepsy, especially the role of extracellular HMGB1 in neurotransmitter expression, remains to be elucidated. METHODS: Experimental early stage of epilepsy-related hyperexcitability was induced in primary rat neural cells (PRNCs) by KA administration. We measured the localization of HMGB1, cell viability, mitochondrial activity, and expression level of glutamate metabolism-associated enzymes. RESULTS: KA induced the translocation of HMGB1 from nucleus to cytosol, and its release from the neural cells. The translocation is associated with post-translational modifications. An increase in extracellular HMGB1 decreased PRNC cell viability and mitochondrial activity, downregulated expression of glutamate decarboxylase67 (GAD67) and glutamate dehydrogenase (GLUD1/2), and increased intracellular glutamate concentration and major histocompatibility complex II (MHC II) level. CONCLUSIONS: That a surge in extracellular HMGB1 approximated seizure initiation suggests a key pathophysiological contribution of HMGB1 to the onset of epilepsy-related hyperexcitability.

Matured hop extract reduces body fat in healthy overweight humans: a randomized, double-blind, placebo-controlled parallel group study.

BACKGROUND: Hops are the main components of beer that provide flavor and bitterness. Iso-α-acids, the bitter components of beer, have been reported to reduce body fat in humans, but the bitterness induced by effective doses of iso-α-acids precludes their acceptance as a nutrient. The matured hop bitter acids (MHBA) of oxidized hops appear to have a more pleasant bitterness compared to the sharper bitterness of iso-α-acids. While there has been little information concerning the identity of the MHBA compounds and their physiological effects, MHBA was recently found to be primarily composed of oxides derived from α-acids, and structurally similar to iso-α-acids. Here, we investigated the effects of matured hop extract (MHE) containing MHBA on reducing abdominal body fat in healthy subjects with a body mass index (BMI) of 25 to below 30 kg/m(2), classified as "obese level 1" in Japan or as "overweight" by the WHO. TRIAL DESIGN: A randomized, double-blind, placebo-controlled parallel group study. METHODS: Two hundred subjects (male and female aged 20 to below 65 years with a BMI of 25 or more and less than 30 kg/m(2)) were randomly assigned to two groups. During a 12-week ingestion period, the subjects in each group ingested daily 350 mL of test-beverage, either containing MHE (with 35 mg MHBA), i.e. the namely active beverage, or a placebo beverage without MHE. The primary endpoint was reduction of the abdominal fat area as determined by CT scanning after continual ingestion of MHE for 12 weeks. RESULTS: Compared to the placebo group, a significant reduction was observed in the visceral fat area after 8 and 12 w, and in the total fat area after 12 w in the active group. There was also a concomitant decrease in body fat ratio in the active group compared to the placebo group. No adverse events related to the test beverages or clinically relevant abnormal changes in the circulatory, blood and urine parameters were observed in either group. CONCLUSIONS: The present study suggests that continual ingestion of MHE safely reduces body fat, particularly the abdominal visceral fat of healthy overweight subjects. TRIAL REGISTRATION: UMIN-CTR UMIN000014185.

Intravenous transplants of human adipose-derived stem cell protect the brain from traumatic brain injury-induced neurodegeneration and motor and cognitive impairments: cell graft biodistribution and soluble factors in young and aged rats.

Traumatic brain injury (TBI) survivors exhibit motor and cognitive symptoms from the primary injury that can become aggravated over time because of secondary cell death. In the present in vivo study, we examined the beneficial effects of human adipose-derived stem cells (hADSCs) in a controlled cortical impact model of mild TBI using young (6 months) and aged (20 months) F344 rats. Animals were transplanted intravenously with 4 × 10(6) hADSCs (Tx), conditioned media (CM), or vehicle (unconditioned media) at 3 h after TBI. Significant amelioration of motor and cognitive functions was revealed in young, but not aged, Tx and CM groups. Fluorescent imaging in vivo and ex vivo revealed 1,1' dioactadecyl-3-3-3',3'-tetramethylindotricarbocyanine iodide-labeled hADSCs in peripheral organs and brain after TBI. Spatiotemporal deposition of hADSCs differed between young and aged rats, most notably reduced migration to the aged spleen. Significant reduction in cortical damage and hippocampal cell loss was observed in both Tx and CM groups in young rats, whereas less neuroprotection was detected in the aged rats and mainly in the Tx group but not the CM group. CM harvested from hADSCs with silencing of either NEAT1 (nuclear enriched abundant transcript 1) or MALAT1 (metastasis associated lung adenocarcinoma transcript 1), long noncoding RNAs (lncRNAs) known to play a role in gene expression, lost the efficacy in our model. Altogether, hADSCs are promising therapeutic cells for TBI, and lncRNAs in the secretome is an important mechanism of cell therapy. Furthermore, hADSCs showed reduced efficacy in aged rats, which may in part result from decreased homing of the cells to the spleen.

Alpha-synuclein as a pathological link between chronic traumatic brain injury and Parkinson's disease.

The long-term consequences of traumatic brain injury (TBI) are closely associated with the development of histopathological deficits. Notably, TBI may predispose long-term survivors to age-related neurodegenerative diseases, such as Parkinson's disease (PD), which is characterized by a gradual degeneration of the nigrostriatal dopaminergic neurons. However, preclinical studies on the pathophysiological changes in substantia nigra (SN) after chronic TBI are lacking. In the present in vivo study, we examined the pathological link between PD-associated dopaminergic neuronal loss and chronic TBI. Sixty days post-TBI, rats were euthanized and brain tissues harvested. Immunostaining was performed using tyrosine hydroxylase (TH), an enzyme required for the synthesis of dopamine in neurons, α-synuclein, a presynaptic protein that plays a role in synaptic vesicle recycling, and major histocompatibility complex II (MHCII), a protein found in antigen presenting cells such as inflammatory microglia cells, all key players in PD pathology. Unbiased stereology analyses revealed significant decrease of TH-positive expression in the surviving dopaminergic neurons of the SN pars compacta (SNpc) relative to sham control. In parallel, increased α-synuclein accumulation was detected in the ipsilateral SN compared to the contralateral SN in TBI animals or sham control. In addition, exacerbation of MHCII+ cells was recognized in the SN and cerebral peduncle ipsilateral to injury relative to contralateral side and sham control. These results suggest α-synuclein as a pathological link between chronic effects of TBI and PD symptoms as evidenced by significant overexpression and abnormal accumulation of α-synuclein in inflammation-infiltrated SN of rats exposed to chronic TBI.

Intravenous Bone Marrow Stem Cell Grafts Preferentially Migrate to Spleen and Abrogate Chronic Inflammation in Stroke.

BACKGROUND AND PURPOSE: Adult stem cell therapy is an experimental stroke treatment. Here, we assessed homing and anti-inflammatory effects of bone marrow stromal cells (hBMSCs) in chronic stroke. METHODS: At 60 days post stroke, adult Sprague-Dawley rats received intravenous hBMSCs (4×10(6) labeled or nonlabeled cells) or vehicle (saline). A sham surgery group served as additional control. In vivo imaging was conducted between 1 hour and 11 days post transplantation, followed by histological examination. RESULTS: Labeled hBMSCs migrated to spleen which emitted significantly higher fluorescent signal across all time points, especially during the first hour, and were modestly detected in the head region at the 12 hours and 11 days, compared with nonlabeled hBMSCs and vehicle-infused stroke animals, or sham (P<0.05). At 11 days post transplantation, ex vivo imaging confirmed preferential hBMSC migration to the spleen over the brain. Hematoxylin and eosin staining revealed significant 15% and 30% reductions in striatal infarct and peri-infarct area, and a trend of rescue against neuronal loss in the hippocampus. Unbiased stereology showed significant 75% and 60% decrements in major histocompatibility complex II-activated inflammatory cells in gray and white matter, and a 43% diminution in tumor necrosis factor-α cell density in the spleen of transplanted stroke animals compared with vehicle-infused stroke animals (P<0.05). Human antigen immunostaining revealed 0.03% hBMSCs survived in spleen and only 0.0007% in brain. MSC migration to spleen, but not brain, inversely correlated with reduced infarct, peri-infarct, and inflammation. CONCLUSIONS: hBMSC transplantation is therapeutic in chronic stroke possibly by abrogating the inflammation-plagued secondary cell death.

[A Case of an Elderly Diabetic Patient Developing Wernicke Encephalopathy without Alcohol Abuse or an Unbalanced Diet].

A 70-year-old man with a 28-year history of type 2 diabetes mellitus was admitted due to persistent vomiting and neurological abnormalities in Nov 2012. He had developed gait disturbance and diplopia for six months during antiplatelet therapy, which was initiated following the diagnosis of a cerebellar infarction in June 2012. He had nystagmus, truncal ataxia and an ocular motility disorder, and the MRI study showed increased FLAIR and DWI signals in the peri-third ventricle and periaqueductal region, in addition to the cerebellar vermis. Wernicke encephalopathy was suspected according to his symptoms, and thiamine administration dramatically improved his condition. He did not have a history of alcohol abuse or poor eating habits; however, various coexisting factors, including diabetes mellitus, pyloric stenosis and the use of antiulcer drugs and insulin, were considered to be responsible for Wernicke encephalopathy. This case demonstrates the importance of distinguishing Wernicke encephalopathy from cerebrovascular disease in elderly patients.

DJ-1 ameliorates ischemic cell death in vitro possibly via mitochondrial pathway.

DJ-1 is an important redox-reactive neuroprotective protein implicated in regulation of oxidative stress after ischemia. However the molecular mechanism, especially the mitochondrial function, by which DJ-1 protects neuronal cells in stroke remains to be elucidated. The aim of this study was to reveal whether DJ-1 translocates into the mitochondria in exerting neuroprotection against an in vitro model of stroke. Human neural progenitor cells (hNPCs) were initially exposed to oxygen-glucose deprivation and reperfusion injury, and thereafter, DJ-1 translocation was measured by immunocytochemistry and its secretion by hNPCs was detected by enzyme-linked immunosorbant assay (ELISA). Exposure of hNPCs to experimental stroke injury resulted in DJ-1 translocation into the mitochondria. Moreover, significant levels of DJ-1 protein were secreted by the injured hNPCs. Our findings revealed that DJ-1 principally participates in the early phase of stroke involving the mitochondrial pathway. DJ-1 was detected immediately after stroke and efficiently translocated into the mitochondria offering a new venue for developing treatment strategies against ischemic stroke.

Adult stem cell transplantation: is gender a factor in stemness?

Cell therapy now constitutes an important area of regenerative medicine. The aging of the population has mandated the discovery and development of new and innovative therapeutic modalities to combat devastating disorders such as stroke. Menstrual blood and Sertoli cells represent two sources of viable transplantable cells that are gender-specific, both of which appear to have potential as donor cells for transplantation in stroke. During the subacute phase of stroke, the use of autologous cells offers effective and practical clinical application and is suggestive of the many benefits of using the aforementioned gender-specific cells. For example, in addition to being exceptionally immunosuppressive, testis-derived Sertoli cells secrete many growth and trophic factors and have been shown to aid in the functional recovery of animals transplanted with fetal dopaminergic cells. Correspondingly, menstrual blood cells are easily obtainable and exhibit angiogenic characteristics, proliferative capability, and pluripotency. Of further interest is the ability of menstrual blood cells, following transplantation in stroke models, to migrate to the infarct site, secrete neurotrophic factors, regulate the inflammatory response, and be steered towards neural differentiation. From cell isolation to transplantation, we emphasize in this review paper the practicality and relevance of the experimental and clinical use of gender-specific stem cells, such as Sertoli cells and menstrual blood cells, in the treatment of stroke.

Cross-Sectional Study of Flood Damage Assumptions in Medical Facilities Using Geographic Information Systems.

Introduction Floods not only directly damage medical facilities but also hinder access to medical facilities, potentially disrupting local medical services. The scale of damage that medical facilities suffer from floods in Japan is unknown. In this study, we assessed the potential impact of floods on Japanese healthcare facilities by facility characteristics. Methods We conducted a cross-sectional study involving medical facilities registered in the Japan Medical Association Regional Medical Information System. Geographic data for the inundation area was obtained from open data of the Japanese government. Facilities that overlap with flooded areas were designated as affected facilities. The primary outcomes were the percentage of damaged facilities and beds. We calculated odds ratios (OR) and 95% confidence intervals (95%CI) using the Wald method to assess the impact of disaster base hospital designation on damage extent. Results We included 140,826 general clinics and 8,126 hospitals, which had 137,731 and 1,483,347 beds, respectively. The planned scale of flooding is estimated to affect 8.0% of general clinics and 10.8% of their beds. For hospitals, these figures were 8.8% and 7.8%, respectively. The maximum potential scale of flooding is estimated to affect 23.6% of general clinics and 23.9% of their beds. For hospitals, these figures were 22.5% and 20.6%, respectively. At the planned scale of flooding, there was no difference found in the rate of damaged facilities between disaster base hospitals and non-disaster base hospitals, and the rate of damaged beds was lower at non-disaster base hospitals (OR = 0.92, 95%CI = 0.71-1.18 for damaged facilities and OR = 0.79, 95%CI = 0.78-0.80 for damaged beds). At the maximum potential scale of flooding, there was no difference found in the expected damage between disaster base hospitals and non-disaster base hospitals (OR = 1.14, 95%CI = 0.95-1.38 for damaged facilities and OR = 0.99, 95%CI = 0.98-1.00 for damaged beds). Conclusion In Japan, floods can hinder nationwide medical functions, particularly in certain regions. Healthcare professionals should assess potential flood damage in advance and ensure that their workplace's business continuity plan includes appropriate countermeasures.

Progressive Supranuclear Palsy Diagnosed After a Severe Fall Trauma in a Patient Who Experienced Episodes of Easy Falling.

Progressive supranuclear palsy (PSP) is characterized by parkinsonism, downward gaze disorder, and a tendency to fall due to degeneration of the basal ganglia, the brain stem, and the cerebellum. We report a case of PSP that was diagnosed following a traumatic hemopneumothorax caused by a fall while descending stairs. A 79-year-old man experienced lightheadedness and frequent falls for two years. He fell on stairs at home and was transferred to our hospital due to mobility issues. He was hospitalized and treated for traumatic hemopneumothorax. Neurological examination revealed vertical ocular motility disorder, positive Myerson's sign, increased muscle stiffness, and increased limb tendon reflexes. Brain MRI showed a hummingbird sign. In this case, a midbrain area of 58.1 mm2 was consistent with PSP. He had no medication history that could have caused falls. He was diagnosed with PSP based on clinical and imaging findings, and treatment with levodopa was initiated. Two months later, walking showed limited improvement, and living at home became difficult. He was discharged to a care facility. PSP is a risk factor for frequent falls in the elderly. PSP usually requires three to four years for diagnosis, although falls appear earlier than in other forms of degenerative parkinsonism. Additionally, PSP often results in repeated dynamic falls due to a decreased perception of danger associated with reduced frontal lobe function. As a result, the severity of trauma from falls in PSP tends to be higher than in other neurodegenerative diseases. Therefore, early diagnosis of PSP may help improve patients' quality of life and prevent trauma. Despite frequent falls over two years, the cause was not thoroughly investigated until the patient experienced severe trauma. The lesson from this case is the importance of a thorough neurological examination and sagittal MRI for elderly patients experiencing repeated falls, to consider the possibility of PSP. Furthermore, quantitative evaluation of MRI enhances the diagnostic accuracy of PSP.

Ischemic stroke brain sends indirect cell death signals to the heart.

BACKGROUND AND PURPOSE: Ischemic stroke is a leading cause of mortality and morbidity in the world and may be associated with cardiac myocyte vulnerability. However, it remains uncertain how an ischemic brain contributes to cardiac alternations. Here, we used experimental stroke models to reveal the pathological effects of the ischemic brain on the heart. METHODS: For the in vitro study, primary rat neuronal cells were subjected to 90-minute oxygen-glucose deprivation (OGD). Two hours after OGD, the supernatant was collected and cryopreserved until further biological assays. Primary rat cardiac myocytes were exposed to ischemic-reperfusion injury and subsequently to the supernatant derived from either the OGD or non-OGD-exposed primary rat neuronal cells for 2, 6, 24, or 48 hours. Thereafter, we measured cell viability and mitochondrial activity in rat cardiac myocytes. For the in vivo study, we subjected adult rats to transient middle cerebral artery occlusion, and their brains and hearts were harvested for immunohistochemical analyses at 3 months later. RESULTS: The supernatant from the OGD, but not the non-OGD-exposed primary rat neuronal cells, caused significant reduction in cell viability and mitochondrial activity in rat cardiac myocytes. Ischemic stroke animals displayed phenotypic expression of necrosis, apoptosis, and autophagy in their hearts, which paralleled the detection of these same cell death markers in their brains. CONCLUSIONS: Ischemic stroke was accompanied by cardiac myocyte death, indicating a close pathological link between brain and heart. These results suggest a vigilant assessment of the heart condition in stroke patients, likely requiring the need to treat systemic cardiac symptoms after an ischemic brain episode.

Vasculogenesis in experimental stroke after human cerebral endothelial cell transplantation.

BACKGROUND AND PURPOSE: Despite the reported functional recovery in transplanted stroke models and patients, the mechanism of action underlying stem cell therapy remains not well understood. Here, we examined the role of stem cell-mediated vascular repair in stroke. METHODS: Adult rats were exposed to transient occlusion of the middle cerebral artery and 3 hours later randomly stereotaxically transplantated with 100K, 200K, or 400K human cerebral endothelial cell 6 viable cells or vehicle. Animals underwent neurological examination and motor test up to day 7 after transplantation then euthanized for immunostaining against neuronal, vascular, and specific human antigens. A parallel in vitro study cocultured rat primary neuronal cells with human cerebral endothelial cell 6 under oxygen-glucose deprivation and treated with vascular endothelial growth factor (VEGF) and anti-VEGF. RESULTS: Stroke animals that received vehicle infusion displayed typical occlusion of the middle cerebral artery-induced behavioral impairments that were dose-dependently reduced in transplanted stroke animals at days 3 and 7 after transplantation and accompanied by increased expression of host neuronal and vascular markers adjacent to the transplanted cells. Some transplanted cells showed a microvascular phenotype and juxtaposed to the host vasculature. Infarct volume in transplanted stroke animals was significantly smaller than vehicle-infused stroke animals. Moreover, rat neurons cocultured with human cerebral endothelial cell 6 or treated with VEGF exhibited significantly less oxygen-glucose deprivation-induced cell death that was blocked by anti-VEGF treatment. CONCLUSIONS: We found attenuation of behavioral and histological deficits coupled with robust vasculogenesis and neurogenesis in endothelial cell-transplanted stroke animals, suggesting that targeting vascular repair sets in motion a regenerative process in experimental stroke possibly via the VEGF pathway.

Delta opioid receptor and its peptide: a receptor-ligand neuroprotection.

In pursuit of neurological therapies, the opioid system, specifically delta opioid receptors and delta opioid peptides, demonstrates promising therapeutic potential for stroke, Parkinson's disease, and other degenerative neurological conditions. Recent studies offer strong evidence in support of the therapeutic use of delta opioid receptors, and provide insights into the underlying mechanisms of action. Delta opioid receptors have been shown to confer protective effects by mediating ionic homeostasis and activating endogenous neuroprotective pathways. Additionally, delta opioid agonists such as (D-Ala 2, D-Leu 5) enkephalin (DADLE) have been shown to decrease apoptosis and promote neuronal survival. In its entirety, the delta opioid system represents a promising target for neural therapies.