Menaquinone-4 Alleviates Neurological Deficits Associated with Intracerebral Hemorrhage by Preserving Corticospinal Tract in Mice.

Menaquinone-4 (MK-4) is an isoform of vitamin K2 that has been shown to exert various biological actions besides its functions in blood coagulation and bone metabolism. Here we examined the effect of MK-4 on a mouse model of intracerebral hemorrhage (ICH). Daily oral administration of 200 mg/kg MK-4 starting from 3 h after induction of ICH by intrastriatal collagenase injection significantly ameliorated neurological deficits. Unexpectedly, MK-4 produced no significant effects on various histopathological parameters, including the decrease of remaining neurons and the increase of infiltrating neutrophils within the hematoma, the increased accumulation of activated microglia/macrophages and astrocytes around the hematoma, as well as the injury volume and brain swelling by hematoma formation. In addition, ICH-induced increases in nitrosative/oxidative stress reflected by changes in the immunoreactivities against nitrotyrosine and heme oxygenase-1 as well as the contents of malondialdehyde and glutathione were not significantly affected by MK-4. In contrast, MK-4 alleviated axon tract injury in the internal capsule as revealed by neurofilament-H immunofluorescence. Enhanced preservation of the corticospinal tract by MK-4 was also confirmed by retrograde labeling of neurons in the primary motor cortex innervating the spinal cord. These results suggest that MK-4 produces therapeutic effect on ICH by protecting structural integrity of the corticospinal tract.

Combination of tea catechins and ornithine effectively activates the urea cycle: an in vitro and human pilot study.

PURPOSE: Accumulation of ammonia causes central and peripheral fatigue. This study aimed to investigate the synergistic effect of tea catechins and low-dose ornithine in activating the urea cycle to reduce blood ammonia levels during exercise. METHODS: We used hepatocyte-like cells derived from human-induced pluripotent stem (iPS) cells to assess the effect of tea catechins combined with ornithine on urea cycle activity. The urea production and expression of key genes involved in the metabolism of urea were investigated. We then examined the synergistic improvement in ammonia metabolism by tea catechins in combination with ornithine in a human pilot study. RESULTS: Tea catechins combined with ornithine increased urea cycle activity in hepatocyte-like cells derived from human iPS cells. Intake of 538.6 mg of tea catechins with 1592 mg of ornithine for 2 consecutive days during exercise loading suppressed the exercise-induced increase in the blood ammonia concentration as well as stabilized blood glucose levels. CONCLUSION: Controlling the levels of ammonia, a toxic waste produced in the body, is important in a variety of situations, including exercise. The present study suggests that a heterogeneous combination of polyphenols and amino acids efficiently suppresses elevated ammonia during exercise in humans by a mechanism that includes urea cycle activation. TRIAL REGISTRATION: This study was registered in the University Hospital Medical Information Network Clinical Trial Registry (No. UMIN000035484, dated January 8, 2019).

Mouse Model of Anti-Obesity Effects of Blautia hansenii on Diet-Induced Obesity.

Reportedly, a relationship exists between intestinal microflora and obesity-related lifestyle diseases. Blautia spp. a major intestinal microbiota, accounts for 3-11% of human intestinal microflora. Epidemiological reports have described that people with more visceral fat have less Blautia hansenii in their intestinal tract irrespective of age or gender. However, the effect of oral administration of heat-sterilized Blautia hansenii on obesity has not been clarified. Therefore, the aim of this study was to evaluate the effects of dietary Blautia hansenii administration on obesity in high-fat-diet-induced obesity in a mouse model. Heat-sterilized cells of Blautia hansenii were used. C57BL/6J mice (normal mice, n = 7) were fed with each experimental diet for nine weeks. Diets for experimentation were: normal-fat (NF) diets, high-fat (HF) diets, and high-fat + Blautia hansenii (HF + Blautia) diets. The HF + Blautia group was administered about 1 × 109 (CFU/mouse/day) of Blautia hansenii. During the periods of experimentation, body weight, food intake, water consumption, and fecal weight were recorded, and glucose tolerance tests were performed. Subsequently, the white adipose tissue (WAT) weight and serum components were measured. Short-chain fatty acid contents in the feces and cecum were analyzed. Furthermore, changes in the intestinal microflora were analyzed using meta-genomics analysis. Results showed that the total weight of WAT in the HF + Blautia group was significantly lower (13.2%) than that of the HF group. Moreover, the HF + Blautia group exhibited better glucose tolerance than the HF group. Productivity of short-chain fatty acids in the intestinal tract was at a significantly (p < 0.05) low level in the HF group; on the other hand, it recovered in the HF + Blautia group. Furthermore, there was a higher ratio of Blautia (p < 0.05) in the intestinal tracts of the HF + Blautia group than in the HF group. These results suggest that Blautia hansenii administration suppresses obesity induced by a high-fat diet.

Association of the COVID-19 pandemic with changes in objectively measured sedentary behaviour and adiposity.

BACKGROUND: Several studies have reported that the coronavirus disease (COVID-19) pandemic has increased sedentary behaviour and obesity; however, these analyses used self-reported data, and the association between sedentary behaviour and visceral fat and adipocytokines during the COVID-19 pandemic remains unclear. We aimed to investigate the association of the COVID-19 pandemic with objectively measured sedentary behaviour and these obesity-related factors. METHODS: Longitudinal analysis was conducted on 257 Japanese participants who underwent health check-ups in 2018 before and in 2020 during the COVID-19 pandemic. For both time points, sedentary behaviour was measured using an accelerometer for at least 7 days, visceral fat area (VFA) was measured using abdominal bioelectrical impedance analysis, and blood adiponectin level was measured using latex agglutination turbidimetric immunoassay. Multiple linear regression was performed to determine the association between sedentary behaviour and these outcomes. RESULTS: Compared with data in 2018, sedentary behaviour and VFA were significantly increased (P < 0.001, P = 0.006) whereas adiponectin level was significantly decreased (P < 0.001) in 2020. Increased sedentary behaviour was significantly associated with an increase in VFA (ß = 3.85, 95% CI 1.22-6.49, P = 0.004) and a decrease in adiponectin level (ß = -0.04, 95% CI -0.06 to -0.01, P = 0.005). However, the association of sedentary behaviour with adiponectin level was not significant after considering the effects of VFA. CONCLUSIONS: The COVID-19 pandemic was associated with objectively measured sedentary behaviour and obesity-related factors in Japanese adults. Additionally, an increase in sedentary behaviour was associated with an increase in VFA, whereas the association of sedentary behaviour with adiponectin was partly mediated by VFA. These results suggest that avoiding increasing sedentary time is important to prevent visceral adiposity thereby ameliorating adiponectin, especially during behavioural limitations such as the COVID-19 pandemic.

Therapeutic effect of allicin in a mouse model of intracerebral hemorrhage.

Natural compounds with sulfur moiety produce various biological actions that may be beneficial for the therapies of several devastative disorders of the central nervous system. Here we investigated potential therapeutic effect of allicin, an organosulfur compound derived from garlic, in a mouse model of intracerebral hemorrhage (ICH) based on intrastriatal collagenase injection. Daily intraperitoneal administration of allicin (50 mg/kg) from 3 h after induction of ICH afforded neuroprotective effects, as evidenced by the increase of surviving neurons in the hematoma, reduction of axonal transport impairment, and prevention of axon tract injury. In addition, allicin inhibited accumulation of activated microglia/macrophages around the hematoma and infiltration of neutrophils within the hematoma. Allicin also suppressed ICH-induced mRNA upregulation of pro-inflammatory factors such as interleukin 6 and C-X-C motif ligand 2 in the brain, suggesting its anti-inflammatory effect. Moreover, ICH-induced increase of malondialdehyde as well as decrease of total glutathione in the brain was attenuated by allicin. Finally, allicin-treated mice showed better recovery of sensorimotor functions after ICH than vehicle-treated mice. These results indicate that allicin produces a therapeutic effect on ICH pathology via alleviation of neuronal damage, inflammatory responses and oxidative stress in the brain.

Distinct Pharmacological Profiles of Monosulfide and Trisulfide in an Experimental Model of Intracerebral Hemorrhage in Mice.

Hydrogen sulfide and polysulfides are increasingly recognized as bioactive signaling molecules to produce various actions and regulate (patho)physiological processes. Here we examined the effects of sodium sulfide (Na2S) and sodium trisulfide (Na2S3) on an experimental model of intracerebral hemorrhage (ICH) in mice. Na2S or Na2S3 (25 µmol/kg, intraperitoneally (i.p.)) was administered 30 min before ICH induction by intrastriatal injection of collagenase. We found that Na2S significantly ameliorated sensorimotor functions of mice after ICH. Histopathological examinations revealed that Na2S inhibited neuron loss in the striatum, prevented axon degeneration in the internal capsule, and ameliorated axonal transport dysfunction in the striatum and the cerebral cortex where the edge of hematoma was located. Although Na2S did not suppress accumulation of activated microglia/macrophages in the peri-hematoma region, it suppressed ICH-induced upregulation of inflammatory mediators such as C-X-C motif ligand 2. On the other hand, Na2S3 did not ameliorate ICH-induced sensorimotor dysfunction. Although the effect of Na2S3 on several parameters such as axon degeneration and axonal transport dysfunction was comparable to that of Na2S, Na2S3 did not significantly inhibit neuron loss and upregulation of inflammatory mediators. These results suggest that the regulation of multiple pathological events is involved in the effect of Na2S leading to amelioration of neurological symptoms associated with ICH.

Mature Adult Mice With Exercise-Preconditioning Show Better Recovery After Intracerebral Hemorrhage.

Background and Purpose: Physical exercise offers therapeutic potentials for several central nervous system disorders, including stroke and cardiovascular diseases. However, it is still mostly unknown whether and how exercise preconditioning affects the prognosis of intracerebral hemorrhage (ICH). In this study, we examined the effects of preconditioning on ICH pathology in mature adult mice using treadmill exercise. Methods: Male C57BL/6J (25-week old) mice were subjected to 6 weeks of treadmill exercise followed by ICH induction. Outcome measurements included various neurological function tests at multiple time points and the assessment of lesion volume at 8 days after ICH induction. In addition, plasma soluble factors and phagocytotic microglial numbers in the peri-lesion area were also measured to determine the mechanisms underlying the effects of exercise preconditioning. Results: The 6-week treadmill exercise preconditioning promoted recovery from ICH-induced neurological deficits in mice. In addition, mice with exercise preconditioning showed smaller lesion volumes and increased numbers of phagocytotic microglia. Furthermore, the levels of several soluble factors, including endostatin, IGFBP (insulin-like growth factor-binding protein)-2 and -3, MMP (matrix metallopeptidase)-9, osteopontin, and pentraxin-3, were increased in the plasma samples from ICH mice with exercise preconditioning compared with ICH mice without exercise. Conclusions: These results suggest that mice with exercise preconditioning may suffer less severe injury from hemorrhagic stroke, and therefore, a habit of physical exercise may improve brain health even in middle adulthood.

Increased plasma plasmin-α2-plasmin inhibitor complex levels correlate with postoperative rebleeding after endoscopic surgery for spontaneous intracerebral hemorrhage.

BACKGROUND: Postoperative rebleeding (PR) is one of the most severe complications of endoscopic surgery, often performed to remove spontaneous intracerebral hemorrhage (sICH). However, the risk factors for PR remain unclear. OBJECTIVE: This study retrospectively investigated whether increased preoperative plasma plasmin-α2-plasmin inhibitor complex (PIC) levels, indicating activation of fibrinolysis, are associated with PR. METHODS: A total of 101 patients underwent endoscopic surgery to evacuate sICH at our institution from January 2010 to June 2019, and 79 patients who underwent examinations of plasma PIC levels at admission with available radiographical data were included. Correlations between PR and increased plasma PIC levels were retrospectively evaluated. RESULTS: PR occurred in eight patients (10.1%), and high PIC levels (≥ 4 or 6 µg/ml) were significantly associated with PR. The sensitivities employing high PIC levels of ≥ 4 µg/ml and ≥ 6 µg/ml were both 0.63, and the specificities using the same PIC levels were 0.86 and 0.92, respectively. Multivariable analyses showed that high plasma PIC levels of ≥ 4 µg/ml (odds ratio (OR), 12.77; 95% confidence interval (CI), 1.65-98.77; p = 0.02) or ≥ 6 µg/ml (OR, 18.33; 95% CI, 2.32-144.82; p = 0.006) were independent predictors of PR. CONCLUSIONS: This study found that increased plasma PIC levels were associated with PR following the endoscopic evacuation of sICHs, indicating that increased plasma PIC levels could be potentially used to predict PR. Further studies are needed to establish new surgical strategies and adjuvant treatments to improve surgical outcomes in patients with sICH prone to PR.

Plaque Characteristics of Patients with Symptomatic Mild Carotid Artery Stenosis.

BACKGROUND: Carotid revascularization may be considered for severe stenosis, but its use for symptomatic mild stenosis (<50%) with vulnerable plaque or ulcer remains uncertain. The characteristics of patients with symptomatic mild stenosis who underwent revascularization are reviewed. METHODS: The subjects of this study were 18 patients with symptomatic mild stenosis (<50%) on angiography from among 175 patients who underwent revascularization in our department. The plaques were evaluated by black-blood magnetic resonance imaging (BB-MRI) and ultrasonography (US) and classified into 2 types: type 1 (n = 15), a lesion with an ulcer or mobile plaque or thrombosis on angiography or US; and type 2 (n = 3), a lesion without any of the above. Fourteen patients underwent carotid endarterectomy (CEA), and 4 patients underwent carotid artery stenting. RESULTS: The stenosis on angiography was 27.2% ± 10.7 (5%-41%), and the area carotid artery stenosis rate on US was 69.8 ± 14.5% (44.5%-97%). The stenosis rate of these 2 methods was not at all correlated. In type 1 plaque that underwent CEA, 10 of 11 patients had vulnerable plaque by histopathology, and 1 patient had thrombus on the plaque by operative findings. In type 2 plaque that underwent CEA, all patients had vulnerable plaque by histopathology. During the follow-up period, none of the patients had restenosis or stroke. CONCLUSIONS: The findings of US and BB-MRI in patients with symptomatic mild stenosis (<50%) on angiography are important for determining treatment. If BB-MRI or US shows the findings of vulnerable plaque in mild stenosis, surgical treatment may be considered for these patients.

Synthesis of perfluoroalkylated pentacenes and evaluation of their fundamental physical properties.

Symmetrical and unsymmetrical pentacenes carrying two perfluoroalkyl (Rf) chains, at the 6 and 13 positions, were synthesized from easily available pentacene-6,13-quinone via facile three or four step reactions. After extensive evaluation, it was clearly found that the control of both the electron density of the aromatic rings on the pentacene core and molecular alignment in the crystalline state nicely affected their physical properties. Thus, we successfully prove in this article that (1) their anti-oxidation ability was significantly enhanced due to a decrease in the HOMO and LUMO energy and (2) a distinct difference in charge-transporting properties was observed between the symmetrical and unsymmetrical pentacenes.

[A Case of an Orbital Angioleiomyoma].

A 70-year-old woman presented with a 4-year history of painless conjunctival congestion and proptosis of the right eye. Computed tomography and magnetic resonance imaging revealed a 48-mm lesion in the right medial orbit. As the symptoms progressed, the tumor was resected by performing fronto-orbital craniotomy. Histopathological examination revealed a vascular tumor surrounded by smooth muscle fibers and immunohistochemistry demonstrated tumor positivity for smooth muscle actin and desmin. The tumor was diagnosed as an angioleiomyoma, and no recurrence has been observed as of 5 years postoperatively. Angioleiomyomas in the orbit are extremely rare;thus, we have reported this case with reference to the literature.

Endogenous GIP ameliorates impairment of insulin secretion in proglucagon-deficient mice under moderate beta cell damage induced by streptozotocin.

AIMS/HYPOTHESIS: The action of incretin hormones including glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) is potentiated in animal models defective in glucagon action. It has been reported that such animal models maintain normoglycaemia under streptozotocin (STZ)-induced beta cell damage. However, the role of GIP in regulation of glucose metabolism under a combination of glucagon deficiency and STZ-induced beta cell damage has not been fully explored. METHODS: In this study, we investigated glucose metabolism in mice deficient in proglucagon-derived peptides (PGDPs)-namely glucagon gene knockout (GcgKO) mice-administered with STZ. Single high-dose STZ (200 mg/kg, hSTZ) or moderate-dose STZ for five consecutive days (50 mg/kg × 5, mSTZ) was administered to GcgKO mice. The contribution of GIP to glucose metabolism in GcgKO mice was also investigated by experiments employing dipeptidyl peptidase IV (DPP4) inhibitor (DPP4i) or Gcg-Gipr double knockout (DKO) mice. RESULTS: GcgKO mice developed severe diabetes by hSTZ administration despite the absence of glucagon. Administration of mSTZ decreased pancreatic insulin content to 18.8 ± 3.4 (%) in GcgKO mice, but ad libitum-fed blood glucose levels did not significantly increase. Glucose-induced insulin secretion was marginally impaired in mSTZ-treated GcgKO mice but was abolished in mSTZ-treated DKO mice. Although GcgKO mice lack GLP-1, treatment with DPP4i potentiated glucose-induced insulin secretion and ameliorated glucose intolerance in mSTZ-treated GcgKO mice, but did not increase beta cell area or significantly reduce apoptotic cells in islets. CONCLUSIONS/INTERPRETATION: These results indicate that GIP has the potential to ameliorate glucose intolerance even under STZ-induced beta cell damage by increasing insulin secretion rather than by promoting beta cell survival.

Eed/Sox2 regulatory loop controls ES cell self-renewal through histone methylation and acetylation.

Transcription factors and epigenetic modulators are involved in the maintenance of self-renewal in embryonic stem (ES) cells. Here, we demonstrate the existence of a regulatory loop in ES cells between Sox2, an indispensable transcription factor for self-renewal, and embryonic ectoderm development (Eed), an epigenetic modulator regulating histone methylation. We found that Sox2 and Eed positively regulate each other's expression. Interestingly, Sox2 overexpression suppressed the induction of differentiation-associated genes in Eed-deficient ES cells without restoring histone methylation. This Sox2-mediated suppression was prevented by knockdown of the histone acetyltransferase (HAT), Tip60 or Elp3, and Sox2 stimulated expression of these HATs. Furthermore, forced expression of either HAT resulted in repression of differentiation-associated genes in Eed-deficient cells. These results suggest that Sox2 overcame the phenotype of Eed-deficient ES cells by promoting histone acetylation. We also found that knockout of Eed and knockdown of these HATs synergistically enhanced the upregulation of differentiation-associated genes in ES cells. Taken together, our results suggest that the Eed/Sox2 regulatory loop contributes to the maintenance of self-renewal in ES cells by controlling histone methylation and acetylation.

Nurr1 overexpression in the primary motor cortex alleviates motor dysfunction induced by intracerebral hemorrhage in the striatum in mice.

Hemorrhage-induced injury of the corticospinal tract (CST) in the internal capsule (IC) causes severe neurological dysfunction in both human patients and rodent models of intracerebral hemorrhage (ICH). A nuclear receptor Nurr1 (NR4A2) is known to exert anti-inflammatory and neuroprotective effects in several neurological disorders. Previously we showed that Nurr1 ligands prevented CST injury and alleviated neurological deficits after ICH in mice. To prove direct effect of Nurr1 on CST integrity, we examined the effect of Nurr1 overexpression in neurons of the primary motor cortex on pathological consequences of ICH in mice. ICH was induced by intrastriatal injection of collagenase type VII, where hematoma invaded into IC. Neuron-specific overexpression of Nurr1 was induced by microinjection of synapsin I promoter-driven adeno-associated virus (AAV) vector into the primary motor cortex. Nurr1 overexpression significantly alleviated motor dysfunction but showed only modest effect on sensorimotor dysfunction after ICH. Nurr1 overexpression also preserved axonal structures in IC, while having no effect on hematoma-associated inflammatory events, oxidative stress, and neuronal death in the striatum after ICH. Immunostaining revealed that Nurr1 overexpression increased the expression of Ret tyrosine kinase and phosphorylation of Akt and ERK1/2 in neurons in the motor cortex. Moreover, administration of Nurr1 ligands 1,1-bis(3'-indolyl)-1-(p-chlorophenyl)methane or amodiaquine increased phosphorylation levels of Akt and ERK1/2 as well as expression of glial cell line-derived neurotrophic factor and Ret genes in the cerebral cortex. These results suggest that the therapeutic effect of Nurr1 on striatal ICH is attributable to the preservation of CST by acting on cortical neurons.

Student athlete well-being framework: an empirical examination of elite college student athletes.

The current study proposes a multidimensional student athlete well-being framework (SAWBF). The authors used 12 items to capture SAWBF comprised of four well-being dimensions (i.e., physical, hedonic, psychological, and social well-being). To empirically assess the reliability and validity of the framework, data from elite collegiate student athletes in Japan (N = 546) were procured. The results indicated sufficient convergent and discriminant validities of SAWBF. The authors also assessed predictive validity correlations of the framework by focusing on the oft-supported well-being outcome-organizational citizenship behavior, which were also found to be associated with SAWBF. The findings indicated the usefulness of SAWBF; and coaches and staff members can utilize the framework to multi-dimensionally understand well-being status of their student athletes, potentially boosting adaptive behaviors.

Acyclic retinoid peretinoin reduces hemorrhage-associated brain injury in vitro and in vivo.

Peretinoin is an acyclic retinoid that stimulates retinoic acid receptors (NR1Bs) and produces therapeutic effects on hepatocellular cancer. We have previously shown that NR1B agonists such as Am80 and all trans-retinoic acid suppress pathogenic events in intracerebral hemorrhage. The present study addressed the actions of peretinoin and Am80 against cytotoxicity of a blood protease thrombin on cortico-striatal slice cultures obtained from neonatal rat brains. Application of 100 U/ml thrombin to the slice cultures for 72 h caused cell death in the cortical region and tissue shrinkage in the striatal region. Peretinoin (50 µM) and Am80 (1 µM) counteracted these cytotoxic effects of thrombin, and the effect of peretinoin and Am80 was blocked by LE540, an NR1B antagonist. A broad-spectrum kinase inhibitor K252a (3 µM) attenuated the cytoprotective effect of peretinoin in the cortical region, whereas a specific protein kinase A inhibitor KT5720 (1 µM) attenuated the protective effect of peretinoin in the cortical and the striatal regions. On the other hand, nuclear factor-κB (NF-κB) inhibitors such as pyrrolidine dithiocarbamate (50 µM) and Bay11-7082 (10 µM) prevented thrombin-induced shrinkage of the striatal region. Peretinoin and Am80 as well as Bay11-7082 blocked thrombin-induced nuclear translocation of NF-κB in striatal microglia and loss of striatal neurons. We also found that daily administration of peretinoin reduced histopathological injury and alleviated motor deficits in a mouse model of intracerebral hemorrhage. These results indicate that NR1B agonists including peretinoin may serve as a therapeutic option for hemorrhagic brain injury.

Influence of COVID-19 Crisis on Motivation and Hiking Intention of Gen Z in China: Perceived Risk and Coping Appraisal as Moderators.

People's lives have drastically changed since the outbreak of COVID-19. One concern during the pandemic has been the level of inactivity among people. Compared to various generations (e.g., baby boomers, generation alpha), Generation Z (Gen Z) traditionally spends much less time in outdoor spaces. Due to the pandemic, their inactiveness is assumed to be even more severe. Hiking, an outdoor activity, has become a possible remedy for young people to exercise in a safer sport environment compared to traditional facility-based activities. Although various studies have supported the link between motivations and hiking intention, the relationship may be altered based on psychological influences unique to the pandemic situations-perceived risk and coping appraisals. The current study was conducted to investigate the relationship between Gen Z's motivations and hiking intention and moderating roles of perceived risk and coping appraisals in a pandemic environment. Data were collected from Gen Z between 18 and 24 in China (N = 407). The validity and reliability of all the constructs were assessed by confirmatory factor analysis (CFA), average variance extracted (AVE), and composite reliability. For testing hypotheses, PROCESS Macro 4.0 was used. The findings proposed that the appraisals of the pandemic situation (i.e., perceived risk and coping ability) moderated the relationship between two of the motivations-intellectual and destination motivations-and hiking intention. As a result, organizers of outdoor sports programs can implement viable strategies and take valid measurements to minimize the fear and worries among people in the time of the crisis.

A Nurr1 ligand C-DIM12 attenuates brain inflammation and improves functional recovery after intracerebral hemorrhage in mice.

We have previously reported that amodiaquine, a compound that binds to the ligand-binding domain of a nuclear receptor Nurr1, attenuates inflammatory responses and neurological deficits after intracerebral hemorrhage (ICH) in mice. 1,1-Bis(3'-indolyl)-1-(p-chlorophenyl)methane (C-DIM12) is another Nurr1 ligand that recognizes a domain of Nurr1 different from the ligand-binding domain. In the present study, mice were treated daily with C-DIM12 (50 or 100 mg/kg, p.o.) or amodiaquine (40 mg/kg, i.p.), or twice daily with 1400 W (20 mg/kg, i.p.), an inducible nitric oxide synthase (iNOS) inhibitor, from 3 h after ICH induction by microinjection of collagenase into the striatum. C-DIM12 improved the recovery of neurological function and prevented neuron loss in the hematoma, while suppressed activation of microglia/macrophages and expression of inflammatory mediators interleukin-6 and CC chemokine ligand 2. In addition, C-DIM12 as well as amodiaquine preserved axonal structures in the internal capsule and axonal transport function. We also found that C-DIM12 and amodiaquine suppressed the increases of iNOS mRNA expression after ICH. Moreover, 1400 W improved neurological function and prevented neuron loss, activation of microglia/macrophages and axonal transport dysfunction. These results suggest that suppression of iNOS induction contributes to several features of the therapeutic effects of Nurr1 ligands.

Hydroxychloroquine improves motor function and affords neuroprotection without inhibition of inflammation and autophagy in mice after intracerebral hemorrhage.

We examined the effect of an immunomodulator hydroxychloroquine, also known as a Nurr1 ligand and an autophagy inhibitor, on a mouse model of intracerebral hemorrhage (ICH). Daily administration of hydroxychloroquine (100 mg/kg, i.p.) from 3 h after induction of ICH alleviated neurological deficits of mice, increased the number of surviving neurons in the hematoma and prevented fragmentation of axon structures in the internal capsule. Unexpectedly, hydroxychloroquine did not inhibit either upregulation of pro-inflammatory mediators or autophagic responses in the brain. Hence, hydroxychloroquine may produce therapeutic effects on ICH primarily via neuroprotection including preservation of the axon tract integrity.

Intra-abdominal hemorrhage due to segmental arterial mediolysis of an ovarian artery pseudoaneurysm and concomitant aneurysmal subarachnoid hemorrhage: illustrative case.

BACKGROUND: Aneurysmal subarachnoid hemorrhage (SAH) is one of the most severe neurosurgical diseases in which systemic management is important from the acute phase to the chronic phase. The authors reported a case of aneurysmal SAH associated with intra-abdominal hemorrhage possibly caused by segmental arterial mediolysis (SAM). OBSERVATIONS: A 60-year-old woman collapsed suddenly at home. On arrival at our hospital, she was comatose and her head computed tomography (CT) showed SAH, probably from an anterior cerebral artery aneurysm. Simultaneous body CT to screen for pneumonia associated with COVID-19 incidentally detected an intra-abdominal hematoma and the bleeding point. Emergent ventriculostomy was conducted first. Because abdominal angiography detected a ruptured pseudoaneurysm of an ovarian artery, emergency embolization was subsequently performed for hemostasis. However, she deteriorated again, and her pupils became fully dilated. The patient died on day 3 of hospitalization. LESSONS: Patients with aneurysmal SAH rarely have intra-abdominal hemorrhage in the acute stage and may have a fatal outcome. Intra-abdominal hemorrhage should be suspected in the setting of unstable vital signs, and prompt treatment is necessary.