Perivascular macrophages in cerebrovascular diseases.

Cerebrovascular diseases are a major cause of stroke and dementia, both requiring long-term care. These diseases involve multiple pathophysiologies, with mitochondrial dysfunction being a crucial contributor to the initiation of inflammation, apoptosis, and oxidative stress, resulting in injuries to neurovascular units that include neuronal cell death, endothelial cell death, glial activation, and blood-brain barrier disruption. To maintain brain homeostasis against these pathogenic conditions, brain immune cells, including border-associated macrophages and microglia, play significant roles as brain innate immunity cells in the pathophysiology of cerebrovascular injury. Although microglia have long been recognized as significant contributors to neuroinflammation, attention has recently shifted to border-associated macrophages, such as perivascular macrophages (PVMs), which have been studied based on their crucial roles in the brain. These cells are strategically positioned around the walls of brain vessels, where they mainly perform critical functions, such as perivascular drainage, cerebrovascular flexibility, phagocytic activity, antigen presentation, activation of inflammatory responses, and preservation of blood-brain barrier integrity. Although PVMs act as scavenger and surveillant cells under normal conditions, these cells exert harmful effects under pathological conditions. PVMs detect mitochondrial dysfunction in injured cells and implement pathological changes to regulate brain homeostasis. Therefore, PVMs are promising as they play a significant role in mitochondrial dysfunction and, in turn, disrupt the homeostatic condition. Herein, we summarize the significant roles of PVMs in cerebrovascular diseases, especially ischemic and hemorrhagic stroke and dementia, mainly in correlation with inflammation. A better understanding of the biology and pathobiology of PVMs may lead to new insights on and therapeutic strategies for cerebrovascular diseases.

Persistent brain exposure to high sodium induces stroke onset by upregulation of cerebral microbleeds and oxidative stress in hypertensive rats.

High salt intake induces hypertension and enhances stroke onset. However, whether an increase in brain sodium exposure itself is harmful and has poor prognosis remains unknown. Therefore, we employed hypertensive rats that underwent intracerebroventricular (ICV) infusion of sodium for 28 days and evaluated stroke onset and related cytotoxic brain injuries. Forty-seven spontaneously hypertensive stroke-prone (SHRSP) and 39 normotensive rats (Wistar Kyoto rats [WKY]) underwent persistent ICV infusion of the following four solutions: artificial cerebrospinal fluid, 0.9%, 2.7%, and 9% saline for 28 days. We evaluated stroke onset and all-cause mortality between SHRSP and WKY at each ICV sodium concentration as the primary endpoints. Our secondary objective was to explore histological brain injuries associated with SHRSP induced by high sodium ICV. The results indicated that ICV infusion of 2.7% and 9% sodium showed a significant increase in stroke onset, decrease in body weight, and increase rate of brain water content in SHRSP compared to WKY. Increased blood pressure was not observed for ICV infusion of high sodium, while serum sodium concentration was significantly increased in SHRSP compared to WKY. Histological evaluations revealed that higher sodium infusion significantly increased the number of activated microglia, superoxide, neuronal cell loss, and microbleeds compared to WKY and SHRSP with 0.9% sodium. We conclude that persistent exposure to high sodium in the brain is one of the risk factors for stroke onset upregulating cerebral microbleeds and oxidative stress in hypertensive rats.

Pretreatment with Clodronate Improved Neurological Function by Preventing Reduction of Posthemorrhagic Cerebral Blood Flow in Experimental Subarachnoid Hemorrhage.

BACKGROUND: Brain perivascular macrophages (PVMs) are potential treatment targets for subarachnoid hemorrhage (SAH), and previous studies revealed that their depletion by clodronate (CLD) improved outcomes after experimental SAH. However, the underlying mechanisms are not well understood. Therefore, we investigated whether reducing PVMs by CLD pretreatment improves SAH prognosis by inhibiting posthemorrhagic impairment of cerebral blood flow (CBF). METHODS: In total, 80 male Sprague-Dawley rats received an intracerebroventricular injection of the vehicle (liposomes) or CLD. Subsequently, the rats were categorized into the prechiasmatic saline injection (sham) and blood injection (SAH) groups after 72 h. We assessed its effects on weak and severe SAH, which were induced by 200- and 300-µL arterial blood injections, respectively. In addition, neurological function at 72 h and CBF changes from before the intervention to 5 min after were assessed in rats after sham/SAH induction as the primary and secondary end points, respectively. RESULTS: CLD significantly reduced PVMs before SAH induction. Although pretreatment with CLD in the weak SAH group provided no additive effects on the primary end point, rats in the severe SAH group showed significant improvement in the rotarod test. In the severe SAH group, CLD inhibited acute reduction of CBF and tended to decrease hypoxia-inducible factor 1α expression. Furthermore, CLD reduced the number of PVMs in rats subjected to sham and SAH surgery, although no effects were observed in oxidative stress and inflammation. CONCLUSIONS: Our study proposes that pretreatment with CLD-targeting PVMs can improve the prognosis of severe SAH through a candidate mechanism of inhibition of posthemorrhagic CBF reduction.

Calorie restriction and pravastatin administration during pregnancy in obese rhesus macaques modulates maternal and infant metabolism and infant brain and behavioral development.

Background: Maternal obesity has been associated with a higher risk of pregnancy-related complications in mothers and offspring; however, effective interventions have not yet been developed. We tested two interventions, calorie restriction and pravastatin administration, during pregnancy in a rhesus macaque model with the hypothesis that these interventions would normalize metabolic dysregulation in pregnant mothers leading to an improvement in infant metabolic and cognitive/social development. Methods: A total of 19 obese mothers were assigned to either one of the two intervention groups (n = 5 for calorie restriction; n = 7 for pravastatin) or an obese control group (n = 7) with no intervention, and maternal gestational samples and postnatal infant samples were compared with lean control mothers (n = 6) using metabolomics methods. Results: Gestational calorie restriction normalized one-carbon metabolism dysregulation in obese mothers, but altered energy metabolism in her offspring. Although administration of pravastatin during pregnancy tended to normalize blood cholesterol in the mothers, it potentially impacted the gut microbiome and kidney function of their offspring. In the offspring, both calorie restriction and pravastatin administration during pregnancy tended to normalize the activity of AMPK in the brain at 6 months, and while results of the Visual Paired-Comparison test, which measures infant recognition memory, was not significantly impacted by either of the interventions, gestational pravastatin administration, but not calorie restriction, tended to normalize anxiety assessed by the Human Intruder test. Conclusions: Although the two interventions tested in a non-human primate model led to some improvements in metabolism and/or infant brain development, negative impacts were also found in both mothers and infants. Our study emphasizes the importance of assessing gestational interventions for maternal obesity on both maternal and offspring long-term outcomes.

Effects of Microvascular Decompression on Pain Relief and Quality of Life in Late Elderly Patients with Trigeminal Neuralgia.

Pharmacotherapy is frequently selected over surgical interventions for late elderly patients with trigeminal neuralgia (TN). However, medication may affect these patients' activities of daily living (ADL). Hence, we investigated the effect of the surgical treatment of TN on ADL in older patients. This study included 11 late elderly patients >75 years old and 26 nonlate elderly patients who underwent microvascular decompression (MVD) for TN at our hospital from June 2017 to August 2021. We evaluated pre- and postsurgical ADL using the Barthel Index (BI) score, side effects of antineuralgic drugs, the BNI pain intensity score, and perioperative medication. The BI score of late elderly patients significantly improved postoperatively, particularly in transfer (pre: 10.5; post: 13.2), mobility (pre: 10; post: 12.7), and feeding (pre: 5.9 points; post: 10 points). Additionally, antineuralgic drugs caused preoperative disturbances of transfer and mobility. Trends of a longer disease duration and frequent occurrence of side effects were observed in all patients in the elderly group, compared to only 9 out of 26 patients in the younger group (100% vs. 35%, p = 0.0002). In addition, drowsiness was observed more frequently in the late elderly group (73% vs. 23%, p = 0.0084). However, the change in scores indicating improvement after surgery was significantly greater in the late elderly group, although both pre- and postoperative scores were higher in the nonlate elderly group (11.4 ± 1.9 vs. 6.9 ± 0.7, p = 0.027). Surgical treatment can improve older patients' ADL because it relieves pain and facilitates discontinuation of antineuralgic drugs. Consequently, MVD can be positively recommended for older patients with TN if general anesthesia is acceptable.

Yogurt Supplementation Attenuates Insulin Resistance in Obese Mice by Reducing Metabolic Endotoxemia and Inflammation.

BACKGROUND: Inflammation is an underlying mechanism for the development of obesity-related health complications. Yogurt consumption inhibits obesity-associated inflammation, but the tissue-specific mechanisms have not been adequately described. OBJECTIVES: We aimed to determine the tissue-specific responses by which yogurt supplementation inhibits inflammation. METHODS: C57BL/6 male mice (5 wk old) were fed a Teklad Global 14% Protein Rodent Maintenance diet as a control or a high-fat diet (60% calories from fat) to induce obesity for 11 wk, followed by feeding a Western diet (WD; 43% carbohydrate and 42% fat) or WD supplemented with 5.6% lyophilized yogurt powder for 3 wk to test for the impact of yogurt supplementation. Markers of metabolic endotoxemia and inflammation were assessed in plasma and tissues. Cecal and fecal microbiota were profiled by 16S rRNA sequencing. RESULTS: In obese mice, relative to the WD control group, yogurt supplementation attenuated HOMA-IR by 57% (P = 0.020), plasma TNF-α by 31% (P < 0.05) and colonic IFN-γ by 46% (P = 0.0034), which were accompanied by a 40% reduction in plasma LPS binding protein (LBP) (P = 0.0019) and 45% less colonic Lbp expression (P = 0.037), as well as alteration in the beta diversity of cecal microbiota (P = 0.0090) and relative abundance of certain cecal microbes (e.g., Lachnospiraceae Dorea longicatena with P = 0.049). There were no differences in the LBP, Lbp, and Cd14 levels in the liver and small intestine between obese mice with and without yogurt supplementation (P > 0.05). CONCLUSIONS: Yogurt consumption inhibits obesity-induced inflammation in mice by modulating colonic endotoxin detoxification, changing the gut microbiota, and improving glucose metabolism. This work helps to establish the underlying mechanisms by which yogurt consumption affects markers of metabolic and immune health.

Bold-S Signs on Computed Tomography Angiography Are Sensitive Markers for Diagnosing Subcortical Hemorrhage Due to Dural Arteriovenous Fistulae on Emergent Admission.

An optimal treatment strategy for subcortical hematomas caused by dural arteriovenous fistulae (dAVF) is important because of the high rebleeding rate. However, it is very difficult to diagnose that on admission. Therefore, an early sensitive predictive marker for subcortical hemorrhage caused by dAVF is necessary, especially during the first contact on admission. S-shaped dilated vessels around the hematoma (bold-S sign) on computed tomography angiography (CTA) performed during admission could be one such marker. Herein, we evaluated the characteristics of these vessels. Among 273 patients with intracerebral hemorrhage between April 2012 and March 2020, 67 patients with subcortical hematomas who underwent CTA on admission without arteriovenous malformations were included. The patients in the dAVF group (n = 7) showed fewer disturbances in consciousness, milder neurological deficits, and more frequent seizures than patients without dAVF (without dAVF group, n = 60). All patients in the dAVF group had dilated S-shaped vessels (2.59 ± 0.27 mm) around the hematomas, and only 20% of the patients in the without dAVF group had these vessels (1.69 ± 0.22 mm). The ratio of the ipsilateral S-shaped/contralateral largest vessels was 1.80 ± 0.29 in the dAVF group and 1.07 ± 0.16 in the group without dAVF. We called the dilated S-shaped vessels the "bold-S sign," with a cutoff ratio of 1.5. Bold-S sign findings are novel and help in diagnosing subcortical hematomas caused by dAVF on admission.

Microscopic observation of morphological changes in cerebral arteries and veins in hyperacute phase after experimental subarachnoid hemorrhage: an in-vivo analysis.

This observational study examined morphological changes in superficial cerebral arteries and veins, which were correlated with increased intracranial pressure (ICP)-dependent and -independent hypoperfusion in hyperacute phase after subarachnoid hemorrhage (SAH). The prechiasmatic injection model was used, and 32 male Sprague-Dawley rats were divided into the sham-operated, saline-injected (V group, ICP increase), and arterial blood-injected (SAH group, subarachnoid blood and plus increase) groups. Morphological changes in cortical arteries and veins were observed through the cranial window with a microscope before and up to 10 min after the injection. At 24 h, the stenotic and obstructive cortical arteries and veins were counted. After 6 min, 60% of rats in the V group showed vasodilatation, whereas all rats in the SAH group demonstrated vasodilation and vasoconstriction (arterial instability) within 10 min. Similar acute venous congestive changes were observed within 10 min in the V and SAH groups. At 24 h, stenotic and obstructive arteries and veins were observed in the SAH group. Neurological deteriorations were observed at 1 h in the V and SAH groups, and at 23 h in the SAH group. The sham-operated group showed no evident vascular changes and neurological deterioration. The same phenomena, including arterial changes after 6 min and immediate venous changes in the V and SAH groups, may have resulted from ICP increase, whereas subarachnoid blood-related factors produced arterial instability within 5 min after blood injection. Subarachnoid blood plays a significant role in hyperacute SAH pathophysiology in addition to ICP increase.

Multi-omic brain and behavioral correlates of cell-free fetal DNA methylation in macaque maternal obesity models.

Maternal obesity during pregnancy is associated with neurodevelopmental disorder (NDD) risk. We utilized integrative multi-omics to examine maternal obesity effects on offspring neurodevelopment in rhesus macaques by comparison to lean controls and two interventions. Differentially methylated regions (DMRs) from longitudinal maternal blood-derived cell-free fetal DNA (cffDNA) significantly overlapped with DMRs from infant brain. The DMRs were enriched for neurodevelopmental functions, methylation-sensitive developmental transcription factor motifs, and human NDD DMRs identified from brain and placenta. Brain and cffDNA methylation levels from a large region overlapping mir-663 correlated with maternal obesity, metabolic and immune markers, and infant behavior. A DUX4 hippocampal co-methylation network correlated with maternal obesity, infant behavior, infant hippocampal lipidomic and metabolomic profiles, and maternal blood measurements of DUX4 cffDNA methylation, cytokines, and metabolites. We conclude that in this model, maternal obesity was associated with changes in the infant brain and behavior, and these differences were detectable in pregnancy through integrative analyses of cffDNA methylation with immune and metabolic factors.

Impact of Maternal Obesity on the Gestational Metabolome and Infant Metabolome, Brain, and Behavioral Development in Rhesus Macaques.

Maternal gestational obesity is associated with elevated risks for neurodevelopmental disorder, including autism spectrum disorder. However, the mechanisms by which maternal adiposity influences fetal developmental programming remain to be elucidated. We aimed to understand the impact of maternal obesity on the metabolism of both pregnant mothers and their offspring, as well as on metabolic, brain, and behavioral development of offspring by utilizing metabolomics, protein, and behavioral assays in a non-human primate model. We found that maternal obesity was associated with elevated inflammation and significant alterations in metabolites of energy metabolism and one-carbon metabolism in maternal plasma and urine, as well as in the placenta. Infants that were born to obese mothers were significantly larger at birth compared to those that were born to lean mothers. Additionally, they exhibited significantly reduced novelty preference and significant alterations in their emotional response to stress situations. These changes coincided with differences in the phosphorylation of enzymes in the brain mTOR signaling pathway between infants that were born to obese and lean mothers and correlated with the concentration of maternal plasma betaine during pregnancy. In summary, gestational obesity significantly impacted the infant systemic and brain metabolome and adaptive behaviors.

Loss of body weight in old 5xFAD mice and the alteration of gut microbiota composition.

The cause of age-related body weight loss in Alzheimer's disease (AD) is unclear. We compared the differences in food intake, malabsorption, locomotor activity, and gut microbiota composition between 5xFAD mice, a useful model of AD, and wild-type (WT) mice to investigate the mechanisms underlying lower body weight in 5xFAD mice. Fifteen-month-old male 5xFAD mice and age-matched WT mice were divided into four groups: a control diet (CD) or a high-fat diet (HFD). After feeding CD or HFD for eight to nine weeks, 5xFAD mice had a significantly lower body weight than WT mice regardless of diet (p < 0.05). Additionally, the 5xFAD mice did not show a reduction in food intake compared to the WT mice regardless of diet. To evaluate malabsorption, we performed a fecal fat test. There was no obvious fecal fat in both the 5xFAD mice and WT mice. However, 5xFAD mice showed greater locomotor activity than WT mice in the Y-maze test. The comprehensive analysis of gut microbiota composition showed that 15-month-old 5xFAD mice had more Proteobacteria population and fewer Actinobacteria and Bifidobacteriales populations than WT mice. To investigate the effects of fructooligosaccharides (FOS), we administrated FOS to 15-month-old 5xFAD mice. FOS administration decreased Proteobacteria and increased Actinobacteria population, although that did not change Bifidobacteriales population. Moreover, cognitive impairment and body weight of 5xFAD mice were not changed by FOS administration. In conclusion, loss of body weight in 15-month-old 5xFAD mice might be partially derived from excess energy output by hyperactivity. Moreover, 15-month-old 5xFAD mice might have unique alteration of gut microbiota composition and the potential resistance to FOS.

Neurosurgical Treatment of Patients with Posterior Fossa Acute Subdural Hematoma Right after Cardiac Surgery.

As posterior fossa acute subdural hematoma (ASDH) right after cardiac surgery is extremely rare, the clinical course and optimal treatment strategy remain undetermined. We performed a retrospective analysis of patients with posterior fossa ASDH right after cardiac surgery requiring neurosurgical treatment at our institution over a 7-year period and, in this study, discussed the neurosurgical strategy and clinical course. Collected data included clinical history, laboratory results, time course, symptoms, neurosurgical treatment, outcome at discharge, and imaging studies. All six patients were women who had no history of head trauma and had received antithrombotic therapy during the perioperative period of cardiac surgery. All patients showed lower platelets count and were diagnosed with ASDH within 3 days (longest time 64 h) right after cardiac surgery. After discontinuation of anticoagulation therapy and administration of reversal agents, they underwent emergency hematoma evacuation craniotomy (n = 5) or burr hole drainage surgery (n = 1), which were performed in the prone (n = 4) or lateral (n = 2) positions. Four of these patients showed favorable outcomes, and two showed poor outcomes. One of the poor-outcome patients received three antithrombotic therapies, and another developed rapidly progressive ASDH. Posterior fossa ASDH associated with antithrombotic therapy right after cardiac surgery is frequently found in women, and emergent neurosurgical treatment with anticoagulation discontinuation and reversal agent administration can be performed safely. Burr hole drainage surgery might be acceptable in nonsevere cases. By contrast, we must pay attention to cases receiving both anticoagulant and antiplatelet drugs and rapid progression cases.

Central sympathetic nerve activation in subarachnoid hemorrhage.

Subarachnoid hemorrhage (SAH) is a life-threatening condition, and although its two main complications-cerebral vasospasm (CVS)/delayed cerebral ischemia (DCI) and early brain injury (EBI)-have been widely studied, prognosis has not improved over time. The sympathetic nerve (SN) system is important for the regulation of cardiovascular function and is closely associated with cerebral vessels and the regulation of cerebral blood flow and cerebrovascular function; thus, excessive SN activation leads to a rapid breakdown of homeostasis in the brain. In the hyperacute phase, patients with SAH can experience possibly lethal conditions that are thought to be associated with SN activation (catecholamine surge)-related arrhythmia, neurogenic pulmonary edema, and irreversible injury to the hypothalamus and brainstem. Although the role of the SN system in SAH has long been investigated and considerable evidence has been collected, the exact pathophysiology remains undetermined, mainly because the relationships between the SN system and SAH are complicated, and many SN-modulating factors are involved. Thus, research concerning these relationships needs to explore novel findings that correlate with the relevant concepts based on past reliable evidence. Here, we explore the role of the central SN (CSN) system in SAH pathophysiology and provide a comprehensive review of the functional CSN network; brain injury in hyperacute phase involving the CSN system; pathophysiological overlap between the CSN system and the two major SAH complications, CVS/DCI and EBI; CSN-modulating factors; and SAH-related extracerebral organ injury. Further studies are warranted to determine the specific roles of the CSN system in the brain injuries associated with SAH.

"Motion-specific Headache": A Predictor for Diagnosis and Favorable Prognosis after Surgery in Young Patients with Chiari Malformation Type 1.

As headache is known as one of the most common symptoms in the patients with Chiari malformation type 1 (CM1), it is difficult to find out CM1-related headache among the symptoms because headache itself is commonly seen. Herein, we retrospectively review the cases of six CM1 patients complaining only of headache by which they complained of deterioration in daily life activities. The symptom of headache worsened during anteflexion (n = 2; 33%), retroflexion (n = 1; 17%), jumping (n = 3; 50%), going up the stairs (n = 1; 17%), and running (n = 1; 17%). Mean age at the onset was 15.7 years old (ranging 11-18) and four out of six were female. These inductive factors were clearly different from "Valsalva-like maneuvers," although the mechanism might originate from dynamic tonsil changes. We named these headaches as "motion-specific." These headaches radiated to the posterior side. MRI revealed that the extent of tonsillar ectopia was 11.3 mm, while syringomyelia was observed in three out of six patients (50%). All patients underwent surgical treatment, with the "motion-specific headache" completely disappearing 12.5 days thereafter. Although headaches are common, "motion-specific headache" may be a good candidate symptom to distinguish CM1 patients, especially among teenagers with headaches, and a good predictor for favorable outcomes after surgical treatment.

Efficacy of a Novel Prophylactic Barbiturate Therapy for Severe Traumatic Brain Injuries: Step-down Infusion of a Barbiturate with Normothermia.

This study aimed to examine the beneficial effects of a novel prophylactic barbiturate therapy, step-down infusion of barbiturates, using thiamylal with normothermia (NOR+sdB), on the poor outcome in the patients with severe traumatic brain injuries (sTBI), in comparison with mild hypothermia (MD-HYPO). From January 2000 to March 2019, 4133 patients with TBI were admitted to our hospital. The inclusion criteria were: a Glasgow coma scale (GCS) score of ≤8 on admission, age between 20 and 80 years, intracranial hematoma requiring surgical evacuation of the hematoma with craniotomy and/or external decompression, and patients who underwent management of body temperature and assessed their outcome at 6-12 months. Finally, 43 patients were included in the MD-HYPO (n = 29) and NOR+sdB (n = 14) groups. sdB was initiated intraoperatively or immediately after the surgical treatment. There were no significant differences in patient characteristics, including age, sex, past medical history, GCS on admission, type of intracranial hematoma, and length of hospitalization between the two groups. Although NOR+sdB could not improve the patient's poor outcome either at discharge from the intensive care unit (ICU) or at 6-12 months after admission, the treatment inhibited composite death at discharge from the ICU. The mean value of the maximum intracranial pressure (ICP) in the NOR+sdB group was <20 mmHg throughout the first 120 h. NOR+sdB prevented composite death in the ICU in patients with sTBI, and we may obtain novel insights into the beneficial role of prophylactic barbiturate therapy from suppression of the elevated ICP during the first 120 h.

Sympathetic hyperactivity, hypertension, and tachycardia induced by stimulation of the ponto-medullary junction in humans.

OBJECTIVE: The purpose of this study is to investigate changes in autonomic activities and systemic circulation generated by surgical manipulation or electrical stimulation to the human brain stem. METHODS: We constructed a system that simultaneously recorded microsurgical field videos and heart rate variability (HRV) that represent autonomic activities. In 20 brain stem surgeries recorded, HRV features and sites of surgical manipulation were analyzed in 19 hypertensive epochs, defined as the periods with transient increases in the blood pressure. We analyzed the period during electrical stimulation to the ponto-medullary junction, performed for the purpose of monitoring a cranial nerve function. RESULTS: In the hypertensive epoch, HRV analysis showed that sympathetic activity predominated over the parasympathetic activity. The hypertensive epoch was more associated with surgical manipulation of the area in the caudal pons or the rostral medulla oblongata compared to controls. During the period of electrical stimulation, there were significant increases in blood pressures and heart rates, accompanied by sympathetic overdrive. CONCLUSIONS: Our results provide physiological evidence that there is an important autonomic center located adjacent to the ponto-medullary junction. SIGNIFICANCE: A large study would reveal a candidate target of neuromodulation for disorders with autonomic imbalances such as drug-resistant hypertension.

The endogenous and exogenous brain-derived neurotrophic factor plays pivotal roles in the pathogenesis of stroke onset in high salt-loaded hypertensive rats.

Brain-derived neurotrophic factor (BDNF) is known to have neuroprotective effects on multiple neurovascular diseases especially poststroke recovery. On the other hand, BDNF reported to increase blood pressure (BP) which is one of the major risk factors for stroke onset. To clarify the conflicting effects on stroke onset, we examined the expression of endogenous BDNF in relation to stroke onset. In addition, we explored the effect of exogenous central BDNF against stroke onset and all-cause mortality as the primary endpoint and BP as the secondary object in hypertensive rats with high-salt diet. In experiment 1, male spontaneously hypertensive stroke-prone rats (SHRSP) were fed a 0.3% (n = 8) or an 8% (n = 22) sodium diet (Na) through 28 days. The SHRSP with 8% Na showed significant increase of stroke onset, all-cause mortality, upregulation of reactive astrocytes, and disruption of blood-brain barrier. BDNF in the rats with 8% Na was significantly upregulated and mainly expressed in reactive astrocytes, whereas phosphorylated tropomyosin-related kinase B did not change by the rich BDNF. In experiment 2, male SHRSP were treated with continuous intracerebroventricular injection of 2.1 µg/day BDNF (n = 10) or the vehicle (Phosphate buffer saline; n = 10) and fed an 8% Na through 24 days. Exogenous central BDNF induced significant increase of BP and heart rate, and exhibited higher stroke onset and all-cause mortality compared with vehicle group. The present study demonstrated that endogenous BDNF were significantly produced in reactive astrocytes in relation to stroke onset regardless of neuroprotection. In addition, exogenous central BDNF increased BP which might be associated with sympathetic nerve activity and provided unfavorable effects on the prognosis of hypertensive rats. As BDNF is still potentially a good candidate for the treatment of neurovascular diseases, we suggest that hypertensive patients need care for the elevation of BP in the clinical trials of BDNF.

Long-term effects of western diet consumption in male and female mice.

Long-term consumption of a diet with excessive fat and sucrose (Western diet, WD) leads to an elevated risk of obesity and metabolic syndrome in both males and females. However, there are sexual dimorphisms in metabolism which are apparent when considering the prevalence of complications of metabolic syndrome, such as non-alcoholic fatty liver disease. This study aimed to elucidate the impact of a WD on the metabolome and the gut microbiota of male and female mice at 5, 10, and 15 months to capture the dynamic and comprehensive changes brought about by diet at different stages of life. Here we show that there are important considerations of age and sex that should be considered when assessing the impact of diet on the gut microbiome and health.