Pericytes Regulate Cerebral Perfusion through VEGFR1 in Ischemic Stroke.

Neurons in the penumbra (the area surrounding ischemic tissue that consists of still viable tissue but with reduced blood flow and oxygen transport) may be rescued following stroke if adequate perfusion is restored in time. It has been speculated that post-stroke angiogenesis in the penumbra can reduce damage caused by ischemia. However, the mechanism for neovasculature formation in the brain remains unclear and vascular-targeted therapies for brain ischemia remain suboptimal. Here, we show that VEGFR1 was highly upregulated in pericytes after stroke. Knockdown of VEGFR1 in pericytes led to increased infarct area and compromised post-ischemia vessel formation. Furthermore, in vitro studies confirmed a critical role for pericyte-derived VEGFR1 in both endothelial tube formation and pericyte migration. Interestingly, our results show that pericyte-derived VEGFR1 has opposite effects on Akt activity in endothelial cells and pericytes. Collectively, these results indicate that pericyte-specific expression of VEGFR1 modulates ischemia-induced vessel formation and vascular integrity in the brain.

A novel de novo TSC2 nonsense mutation detected in a pediatric patient with tuberous sclerosis complex.

PURPOSE: Tuberous sclerosis complex (TSC) is an autosomal dominant multisystem disorder characterized by hamartomas in multiple organ systems. The TSC1 and TSC2 genes have been identified as the genetic basis of TSC. Two gene tests were used for definitive genetic diagnosis. METHODS: In our study, the case of a Chinese pediatric patient with seizures, hypomelanotic macules, hyperpigmented patches, multiple parenchymal lesions in the ventricle, and developmental retardation is detailed. Whole-genome sequencing (WGS) and multiplex ligation-dependent probe amplification (MLPA) were employed to detect genetic variations and copy number variations of TSC1 and TSC2. RESULTS: A novel heterozygous nonsense mutation in the TSC2 gene (c.3751A>T, p.Lys1251Ter) was identified in a Chinese pediatric patient suffering from TSC, whose unaffected parents did not carry this mutation. The mutation was classified as "pathogenic" according to the American College of Medical Genetics (ACMG) guidelines. CONCLUSION: WGS was carried out to definitively diagnose and detect variations in the exon and noncoding region of the gene and copy number variations in the whole genome simultaneously. For diseases with complex genetic mechanisms, WGS as the first-line test can be efficient and cost-effective for clinical diagnosis.

Asymmetric Slow-Spike-Wave Patterns with Maximal Discharges Contralateral to MRI Lesions Predict Better Surgical Prognosis in Symptomatic Lennox-Gastaut Syndrome or Lennox-Gastaut Phenotypes.

INTRODUCTION: Lennox-Gastaut syndrome (LGS) is a severe subtype of childhood-onset epileptic encephalopathy with drug-resistant and poor surgical prognosis. However, electroencephalogram (EEG) patterns of symptomatic LGS or LG phenotypes with structural brain lesions including focal abnormalities or asymmetric slow-spike-wave (SSW) patterns remain largely unknown. Due to the contradictory lateralization difference between MRI lesions and EEG pattern in symptomatic LGS or LG phenotypes, it is difficult to determine the precise lateralization of epileptic lesions, which is crucial to better surgical prognosis. This study is aim to ascertain the clinical characteristics of the EEG patterns, and its relationship with MRI lesions and to evaluate its prognostic value of surgical treatment in symptomatic LGS or LG phenotypes. METHODS: Twenty-four symptomatic LGS cases with asymmetric EEG SSW patterns and contralaterally independent or contralaterally dominant MRI lesions were collected, and their clinical features were analyzed retrospectively. RESULTS: In this cohort, most of lesions were perinatal or acquired during the first 6 months of life. The most common etiology was intracerebral hemorrhage. The LGS patients with both asymmetric SSW and focal sporadic epileptic waves (SEW) patterns showed the best surgical outcome with Engel class I level. Asymmetric SSW patterns with maximal discharges contralateral to MRI lesions were frequently observed in most of symptomatic LGS or LG phenotypes. Predominantly diffuse destructive lesions led to an attenuated voltage of ipsilateral scalp EEG producing an asymmetric SSW pattern in those patients with symptomatic LGS or LG phenotypes. CONCLUSIONS: Our study reveals a special SEW EEG pattern in symptomatic LG patients with asymmetric SSW and MRI lesions contralateral to the dominant EEG patterns. Contradictory lateralization difference between MRI and EEG probably arises from the relative voltage attenuation presenting in EEG ipsilateral to huge destructive lesions from early life. Our study suggests that the independent focal SEW activity remaining ipsilateral to the MRI lesion can potentially predict better surgical prognosis in symptomatic LGS or LG phenotypes.

Foxp3 exhibits antiepileptic effects in ictogenesis involved in TLR4 signaling.

Inflammatory processes play critical roles in epileptogenesis, but the exact mechanisms that underlie these processes are still not completely understood. In this study, we investigated the role of forkhead transcription factor 3 (Foxp3), a transcription factor that is involved in T-cell differentiation, in epileptogenesis. In both human epileptic tissues and experimental seizure models, we found significant up-regulation of Foxp3 in neurons and glial cells. Of importance, Foxp3-/- mice were susceptible to kainic acid-induced seizures, whereas overexpression of Foxp3 reduced acute seizure occurrence and decreased chronic seizure recurrence. In addition, in vitro experiments revealed that Foxp3 inhibited neuronal excitability via glial cells and not neurons. The protective effects of Foxp3 were manifested as a reduction in glial cell activation and proinflammatory cytokine production and increased neuronal survival. Moreover, we showed that beneficial effects of Foxp3 involved the attenuation of TLR4 signaling and inflammation, which led to the inactivation of NR2B-containing NMDA receptors. These results suggest that Foxp3 in glial cells may play an antiepileptic role in epileptogenesis and may act as a modulator of TLR4. Taken together, our results indicate that Foxp3 may represent a novel therapeutic target for achieving anticonvulsant effects in patients with epilepsy that is currently resistant to drugs.-Wang, F.-X., Xiong, X.-Y., Zhong, Q., Meng, Z.-Y., Yang, H., Yang, Q.-W. Foxp3 exhibits antiepileptic effects in ictogenesis involved in TLR4 signaling.

TRIF contributes to epileptogenesis in temporal lobe epilepsy during TLR4 activation.

Increasing evidence indicates that inflammatory processes play a crucial role in the etiopathology of epilepsy and seizure disorders. The Toll/IL-1R domain-containing adapter-inducing IFN-ß (TRIF) activated several transcriptions leading to the production of pro-inflammatory cytokines in the central nervous system, which suggests a potential role for TRIF in the epileptogenesis of epilepsy. In this study, we investigated the roles of TRIF in human and mice epileptogenic tissues. Western blot and immunohistochemistry assays showed that the expression of TRIF was significantly upregulated in neurons and glial cells in both human epileptic tissues and mouse models, and positively correlated with seizure frequency. TRIF expression positively correlated with high-mobility group box 1 (HMGB1) expression. In TRIF-deficient mice, electroencephalograms displayed a significant decrease in seizure frequency and duration time, while KA induced seizures compared with wild-type (WT) mice. The number and duration time of spontaneous seizures were also decreased in the chronic KA-induced TRIF-deficient mouse models. In TLR4-deficient hippocampal neurons and mouse models, TRIF expression was lower compared with WT mice during HMGB1 and KA stimulation. Meanwhile, in KA-induced TRIF-deficient mouse models, microglia activation was significantly suppressed; pro-inflammatory factors including IL-1ß, TNF-α, iNOS, HMGB1 and IFN-ß were reduced; and the survival of the neurons in the hippocampus increased compared with WT mice. Our findings suggested that TRIF may be involved in the epileptogenesis of temporal lobe epilepsy, which would make it a potential therapeutic target for the treatment of epilepsy.

Concomitant Asymptomatic Intracranial Atherosclerotic Stenosis Increase the 30-Day Risk of Stroke in Patients Undergoing Symptomatic Intracranial Atherosclerotic Stenosis Stenting.

BACKGROUND: In the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) trial, 19.1% of ischemic strokes occurred out of the territory of previously symptomatic stenosis during the mean follow-up period of 23.4 months. However, it is unknown how many ischemic strokes were due to a previously asymptomatic intracranial atherosclerotic stenosis (ICAS). The objective of this study was to investigate whether the concomitant asymptomatic ICAS influences the outcome of patients undergoing symptomatic ICAS stenting. METHODS: We retrospectively reviewed 576 consecutive patients with nondisabling ischemic stroke (modified Rankin scale score of ≤3) who were treated with symptomatic ICAS (≥70% stenosis) stenting with or without concomitant asymptomatic ICAS. The baseline characteristics and the 30-day primary end points (stroke or death after stenting) were compared by bivariate and multivariable logistic analyses. RESULTS: The 30-day rate of primary end points was 5.2%, which was higher in patients with concomitant asymptomatic ICAS (≥50% stenosis) than in those without asymptomatic ICAS (no stenosis or <50% stenosis) (8.9% versus 3.8%, P = .014). In patients with concomitant asymptomatic ICAS, 25% of ischemic strokes occurred out of the territory of the stented artery, whereas in patients without asymptomatic ICAS, no ischemic stroke occurred out of the territory of the stented artery. Multivariable analysis showed that concomitant asymptomatic ICAS was an independent risk factor for 30-day stroke (odds ratio = 2.37, 95% confidence interval, 1.14-5.63; P = .023). CONCLUSIONS: Concomitant asymptomatic ICAS (≥50% stenosis) might increase the 30-day risk of stroke in patients undergoing symptomatic ICAS stenting.

Toll-Like Receptor 4/MyD88-Mediated Signaling of Hepcidin Expression Causing Brain Iron Accumulation, Oxidative Injury, and Cognitive Impairment After Intracerebral Hemorrhage.

BACKGROUND: Disturbance of brain iron metabolism after intracerebral hemorrhage (ICH) results in oxidative brain injury and cognition impairment. Hepcidin plays an important role in regulating iron metabolism, and we have reported that serum hepcidin is positively correlated with poor outcomes in patients with ICH. However, the roles of hepcidin in brain iron metabolism after ICH remain largely unknown. METHODS: Parabiosis and ICH models combined with in vivo and in vitro experiments were used to investigate the roles of hepcidin in brain iron metabolism after ICH. RESULTS: Increased hepcidin-25 was found in serum and primarily in astrocytes after ICH. The brain iron efflux, oxidative brain injury, and cognition impairment were improved in Hepc-/- ICH mice but aggravated by the human hepcidin-25 peptide in C57BL/6 ICH mice. Data obtained in in vitro studies showed that increased hepcidin inhibited the intracellular iron efflux of brain microvascular endothelial cells but was rescued by a hepcidin antagonist, fursultiamine. Using parabiosis ICH models also shows that increased serum hepcidin prevents brain iron efflux. In addition, Toll-like receptor 4 (TLR4)/MyD88 signaling pathway increased hepcidin expression by promoting interleukin-6 expression and signal transducer and activator of transcription 3 phosphorylation. TLR4-/- and MyD88-/- mice exhibited improvement in brain iron efflux at 7, 14, and 28 days after ICH, and the TLR4 antagonist (6R)-6-[N-(2-chloro-4-fluorophenyl) sulfamoyl] cyclohex-1-ene-1-carboxylate significantly decreased brain iron levels at days 14 and 28 after ICH and improved cognition impairment at day 28. CONCLUSIONS: The results presented here show that increased hepcidin expression caused by inflammation prevents brain iron efflux via inhibition of the intracellular iron efflux of brain microvascular endothelial cells entering into circulation and aggravating oxidative brain injury and cognition impairment, which identifies a mechanistic target for muting inflammation to promote brain iron efflux and to attenuate oxidative brain injury after ICH.

Polyinosinic-polycytidylic acid has therapeutic effects against cerebral ischemia/reperfusion injury through the downregulation of TLR4 signaling via TLR3.

Recent reports have shown that preconditioning with the TLR3 ligand polyinosinic-polycytidylic acid (poly(I:C)) protects against cerebral ischemia/reperfusion (I/R) injury. However, it is unclear whether poly(I:C) treatment after cerebral I/R injury is also effective. We used mouse/rat middle cerebral artery occlusion and cell oxygen-glucose deprivation models to evaluate the therapeutic effects and mechanisms of poly(I:C) treatment. Poly(I:C) was i.p. injected 3 h after ischemia (treatment group). Cerebral infarct volumes and brain edemas were significantly reduced, and neurologic scores were significantly increased. TNF-α and IL-1ß levels were markedly decreased, whereas IFN-ß levels were greatly increased, in the ischemic brain tissues, cerebral spinal fluid, and serum. Injuries to hippocampal neurons and mitochondria were greatly reduced. The numbers of TUNEL-positive and Fluoro-Jade B(+) cells also decreased significantly in the ischemic brain tissues. Poly(I:C) treatment increased the levels of Hsp27, Hsp70, and Bcl2 and decreased the level of Bax in the ischemic brain tissues. Moreover, poly(I:C) treatment attenuated the levels of TNF-α and IL-1ß in serum and cerebral spinal fluid of mice stimulated by LPS. However, the protective effects of poly(I:C) against cerebral ischemia were abolished in TLR3(-/-) and TLR4(-/-)mice. Poly(I:C) downregulated TLR4 signaling via TLR3. Poly(I:C) treatment exhibited obvious protective effects 14 d after ischemia and was also effective in the rat permanent middle cerebral artery occlusion model. The results suggest that poly(I:C) exerts therapeutic effects against cerebral I/R injury through the downregulation of TLR4 signaling via TLR3. Poly(I:C) is a promising new drug candidate for the treatment of cerebral infarcts.

Safety and Efficacy of Wingspan Stenting for Severe Symptomatic Atherosclerotic Stenosis of the Middle Cerebral Artery: Analysis of 278 Continuous Cases.

OBJECTIVE: Our objective is to investigate the safety and long-term efficacy of the Wingspan stent (Boston Scientific, Natick, MA, USA) for treating severe atherosclerotic stenosis of the middle cerebral artery (MCA). METHODS: A total of 278 consecutive patients from our stroke database with clinical symptoms within the prior 90 days and intracranial atherosclerotic stenosis of 70% or above of the MCA were enrolled in this study between September 2012 and November 2014, and these patients were followed until the end of June 2015. The endpoint events included any stroke or death within 30 days after stenting and any subsequent ipsilateral ischemic stroke. RESULTS: Among the 278 enrolled patients, 277 patients (99.6%) successfully underwent stenting. The mean rate of stenosis decreased from 82.5 ± 7.9% to 9.0 ± 3.2% following treatment. Within 30 days after stenting, 12 patients (4.3%) experienced endpoint events, including 8 cases (2.9%) of hemorrhagic stroke and 4 cases (1.4%) of ischemic stroke; 2 perioperative deaths occurred. During 8-33 months of follow-up, 19 patients developed endpoint events. The 1- and 2-year endpoint event rates were 5.8% (95% confidence interval [CI], 5.0%-15.7%) and 7.2% (95% CI, 4.3%-10.1%), respectively. CONCLUSIONS: From this study, we can conclude that the treatment of severe symptomatic atherosclerotic stenosis of the MCA using the Wingspan stent was safe and effective and that the long-term stroke recurrence rate after stenting was low.

Function and mechanism of toll-like receptors in cerebral ischemic tolerance: from preconditioning to treatment.

Increasing evidence suggests that toll-like receptors (TLRs) play an important role in cerebral ischemia-reperfusion injury. The endogenous ligands released from ischemic neurons activate the TLR signaling pathway, resulting in the production of a large number of inflammatory cytokines, thereby causing secondary inflammation damage following cerebral ischemia. However, the preconditioning for minor cerebral ischemia or the preconditioning with TLR ligands can reduce cerebral ischemic injury by regulating the TLR signaling pathway following ischemia in brain tissue (mainly, the inhibition of the TLR4/NF-κB signaling pathway and the enhancement of the interferon regulatory factor-dependent signaling), resulting in TLR ischemic tolerance. Additionally, recent studies found that postconditioning with TLR ligands after cerebral ischemia can also reduce ischemic damage through the regulation of the TLR signaling pathway, showing a significant therapeutic effect against cerebral ischemia. These studies suggest that the ischemic tolerance mediated by TLRs can serve as an important target for the prevention and treatment of cerebral ischemia. On the basis of describing the function and mechanism of TLRs in mediating cerebral ischemic damage, this review focuses on the mechanisms of cerebral ischemic tolerance induced by the preconditioning and postconditioning of TLRs and discusses the clinical application of TLRs for ischemic tolerance.

Toll-like receptor 2/4 heterodimer mediates inflammatory injury in intracerebral hemorrhage.

OBJECTIVE: Inflammatory injury plays a critical role in intracerebral hemorrhage (ICH)-induced secondary brain injury. However, the upstream events that initiate inflammatory responses following ICH remain elusive. Our previous studies suggested that Toll-like receptor 4 (TLR4) may be the upstream signal that triggers inflammatory injury in ICH. In addition, recent clinical findings indicated that both TLR2 and TLR4 may participate in ICH-induced brain injury. However, it is unclear how TLR2 functions in ICH-induced inflammatory injury and how TLR2 interacts with TLR4. METHODS: The role of TLR2 and TLR2/TLR4 heterodimerization in ICH-induced inflammatory injury was investigated in both in vivo and in vitro models of ICH. RESULTS: TLR2 mediated ICH-induced inflammatory injury, which forms a heterodimer with TLR4 in both in vivo and in vitro models of ICH. Hemoglobin (Hb), but not other blood components, triggered inflammatory injury in ICH via assembly of TLR2/TLR4 heterodimers. MyD88 (myeloid differentiation primary response gene 88), but not TRIF (Toll/IR-1 domain-containing adaptor protein inducing interferon-beta), was required for ICH-induced TLR2/TLR4 heterodimerization. Mutation of MyD88 Arg196 abolished the TLR2/TLR4 heterodimerization. INTERPRETATION: Our results suggest that a novel TLR2/TLR4 heterodimer induced by Hb initiates inflammatory injury in ICH. Interfering with the assembly of the TLR2/TLR4 heterodimer may be a novel target for developing effective treatment of ICH.

TLR1 expression in mouse brain was increased in a KA-induced seizure model.

OBJECTIVE: Toll-like receptors (TLRs) that mediate inflammatory responses play an important role in epilepsy; however, whether TLR1 is also involved in epileptogenesis remains unclear. Thus, in this study, we investigated the extent and pattern of TLR1 expression in epileptic tissues. METHODS: One-hundred and thirty-two mice were intra-cerebroventricularly injected with PBS or kainic acid (KA) and were examined at 1, 3, 8 and 24 h. The expression pattern and distribution of TLR1 were examined by reverse-transcriptase polymerase chain reaction (RT-PCR), western blot analysis and immunohistochemistry staining. RESULTS: The mRNA and protein levels of TLR1 were significantly upregulated in the hippocampus and temporal cortex of epileptic mice compared with those of controls. TLR1 expression was increased as early as 1 h following KA treatment and peaked at 8 and 24 h. Immunohistochemistry staining demonstrated that TLR1 was distributed in the CA1-3, dentate gyrus and hilus regions of the hippocampus and different cortical regions. Immunofluorescent staining further revealed that TLR1 was primarily expressed in the neurons, microglia, and astrocytes of epileptogenic tissue. SIGNIFICANCE: These results demonstrate that cortical and hippocampal sub-regional expression of TLR1 is altered during epileptogenesis in a time- and location-specific manner, suggesting a close association with the process of epilepsy.

Serum hepcidin concentrations correlate with serum iron level and outcome in patients with intracerebral hemorrhage.

Iron plays a detrimental role in the intracerebral hemorrhage (ICH)-induced brain damage, while hepcidin is the most important iron-regulated hormone. Here, we investigate the association between serum hepcidin and serum iron, outcome in patients with ICH. Serum samples of 81 cases with ICH were obtained on consecutive days to detect the levels of hepcidin, iron, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). The National Institutes of Health Stroke Scale score (NIHSS) was measured at admission and on days 7 and 30, and the modified Rankin Scale (mRS) score was evaluated at 3 months after ICH. Additionally, the correlations of serum hepcidin with serum iron and the mRS score were analyzed by a generalized linear model. Higher serum hepcidin levels were detected in patients with poor outcomes (P < 0.001), and the mRS score increased by a mean of 1.135 points (95% CI 1.021-1.247, P < 0.001) for every serum hepcidin quartile after adjusting for other prognostic variables. Pearson correlation analysis showed that serum hepcidin was negatively correlated with serum iron (r = -0.5301, P < 0.001), and a significantly lower concentration of serum iron was found in patients with poor outcomes (P = 0.007). Additionally, serum hepcidin was independently correlated with mRS scores of ICH patients (OR 1.115, 95% CI 0.995-1.249, P = 0.021). Our results suggest that serum hepcidin is closely related to the outcome of patients with ICH and may be a biological marker for outcome prediction.

Investigation of the Binding Interaction of Mfsd2a with NEDD4-2 via Molecular Dynamics Simulations.

Major facilitator superfamily domain-containing 2a (Mfsd2a) is a sodium-dependent lysophosphatidylcholine cotransporter that plays an important role in maintaining the integrity of the blood-brain barrier and neurological function. Abnormal degradation of Mfsd2a often leads to dysfunction of the blood-brain barrier, while upregulation of Mfsd2a can retrieve neurological damage. It has been reported that Mfsd2a can be specifically recognized and ubiquitinated by neural precursor cell-expressed developmentally downregulated gene 4 type 2 (NEDD4-2) ubiquitin ligase and finally degraded through the proteasome pathway. However, the structural basis for the specific binding of Mfsd2a to NEDD4-2 is unclear. In this work, we combined deep learning and molecular dynamics simulations to obtain a Mfsd2a structure with high quality and a stable Mfsd2a/NEDD4-2-WW3 interaction model. Moreover, molecular mechanics generalized Born surface area (MM-GBSA) methods coupled with per-residue energy decomposition studies were carried out to analyze the key residues that dominate the binding interaction. Based on these results, we designed three peptides containing the key residues by truncating the Mfsd2a sequences. One of them was found to significantly inhibit Mfsd2a ubiquitination, which was further validated in an oxygen-glucose deprivation (OGD) model in a human microvascular endothelial cell line. This work provides some new insights into the understanding of Mfsd2a and NEDD4-2 interaction and might promote further development of drugs targeting Mfsd2a ubiquitination.

Astrocyte-derived lactate aggravates brain injury of ischemic stroke in mice by promoting the formation of protein lactylation.

Aim: Although lactate supplementation at the reperfusion stage of ischemic stroke has been shown to offer neuroprotection, whether the role of accumulated lactate at the ischemia phase is neuroprotection or not remains largely unknown. Thus, in this study, we aimed to investigate the roles and mechanisms of accumulated brain lactate at the ischemia stage in regulating brain injury of ischemic stroke. Methods and Results: Pharmacological inhibition of lactate production by either inhibiting LDHA or glycolysis markedly attenuated the mouse brain injury of ischemic stroke. In contrast, additional lactate supplement further aggravates brain injury, which may be closely related to the induction of neuronal death and A1 astrocytes. The contributing roles of increased lactate at the ischemic stage may be related to the promotive formation of protein lysine lactylation (Kla), while the post-treatment of lactate at the reperfusion stage did not influence the brain protein Kla levels with neuroprotection. Increased protein Kla levels were found mainly in neurons by the HPLC-MS/MS analysis and immunofluorescent staining. Then, pharmacological inhibition of lactate production or blocking the lactate shuttle to neurons showed markedly decreased protein Kla levels in the ischemic brains. Additionally, Ldha specific knockout in astrocytes (Aldh1l1 CreERT2; Ldha fl/fl mice, cKO) mice with MCAO were constructed and the results showed that the protein Kla level was decreased accompanied by a decrease in the volume of cerebral infarction in cKO mice compared to the control groups. Furthermore, blocking the protein Kla formation by inhibiting the writer p300 with its antagonist A-485 significantly alleviates neuronal death and glial activation of cerebral ischemia with a reduction in the protein Kla level, resulting in extending reperfusion window and improving functional recovery for ischemic stroke. Conclusion: Collectively, increased brain lactate derived from astrocytes aggravates ischemic brain injury by promoting the protein Kla formation, suggesting that inhibiting lactate production or the formation of protein Kla at the ischemia stage presents new therapeutic targets for the treatment of ischemic stroke.

Growth hormone promotes myelin repair after chronic hypoxia via triggering pericyte-dependent angiogenesis.

White matter injury (WMI) causes oligodendrocyte precursor cell (OPC) differentiation arrest and functional deficits, with no effective therapies to date. Here, we report increased expression of growth hormone (GH) in the hypoxic neonatal mouse brain, a model of WMI. GH treatment during or post hypoxic exposure rescues hypoxia-induced hypomyelination and promotes functional recovery in adolescent mice. Single-cell sequencing reveals that Ghr mRNA expression is highly enriched in vascular cells. Cell-lineage labeling and tracing identify the GHR-expressing vascular cells as a subpopulation of pericytes. These cells display tip-cell-like morphology with kinetic polarized filopodia revealed by two-photon live imaging and seemingly direct blood vessel branching and bridging. Gain-of-function and loss-of-function experiments indicate that GHR signaling in pericytes is sufficient to modulate angiogenesis in neonatal brains, which enhances OPC differentiation and myelination indirectly. These findings demonstrate that targeting GHR and/or downstream effectors may represent a promising therapeutic strategy for WMI.

Toll-like receptor 4 antagonist attenuates intracerebral hemorrhage-induced brain injury.

BACKGROUND AND PURPOSE: Accumulating evidence indicates that inflammatory responses cause secondary injury after intracerebral hemorrhage (ICH). We recently demonstrated the involvement of toll-like receptor 4 (TLR4) signaling in these processes. The purpose of the current study was to investigate the protective effect and mechanism of TAK-242 (Ethyl (6R)-6-[N-(2-chloro-4-fluorophenyl) sulfamoyl] cyclohex-1-ene-1 -carboxylate, Takeda), a TLR4 antagonist, in an ICH mouse model. METHODS: TAK-242 was intraperitoneally injected 6 hours after ICH once daily for 5 successive days. We assessed neurological deficit scores; changes in brain water content; and levels of inflammatory factors, DNA damage, and neuronal degeneration in perihematomal region 1, 3, and 5 days after ICH. Peripheral inflammatory cell infiltration was determined using flow cytometry; and the expression of TLR4 downstream signaling molecules was assessed by Western blot. RESULTS: TAK-242 significantly reduced brain water content, neurological deficit scores, and levels of inflammatory factors. The levels of DNA damage and neuronal degeneration were also significantly decreased, as was peripheral inflammatory cell infiltration. The expression of TLR4 downstream signaling molecules, including myeloid differentiation primary response gene 88, toll/IR-1(TIR)-domain-containing adaptor protein inducing interferon-beta IκBα, nuclear factor-κBp65, and phosphorylated nuclear factor-κBp65, was significantly downregulated. CONCLUSIONS: The results suggest that TLR4 antagonist reduced inflammatory injury and neurological deficits in a mouse model of ICH. The mechanism may involve decreased expression of signaling molecules downstream of TLR4.

Toll-like receptor 4 signaling in intracerebral hemorrhage-induced inflammation and injury.

Intracerebral hemorrhage (ICH) is a common type of fatal stroke, accounting for about 15% to 20% of all strokes. Hemorrhagic strokes are associated with high mortality and morbidity, and increasing evidence shows that innate immune responses and inflammatory injury play a critical role in ICH-induced neurological deficits. However, the signaling pathways involved in ICH-induced inflammatory responses remain elusive. Toll-like receptor 4 (TLR4) belongs to a large family of pattern recognition receptors that play a key role in innate immunity and inflammatory responses. In this review, we summarize recent findings concerning the involvement of TLR4 signaling in ICH-induced inflammation and brain injury. We discuss the key mechanisms associated with TLR4 signaling in ICH and explore the potential for therapeutic intervention by targeting TLR4 signaling.

Association between interleukin-1α C(-889)T polymorphism and Alzheimer's disease: a meta-analysis including 12,817 subjects.

Epidemiological studies have evaluated the association between interleukin-1 (IL-1)α C(-889)T polymorphism and Alzheimer's disease (AD), but the results remain inconclusive. This meta-analysis was, therefore, designed to clarify these controversies. Systematic searches of electronic databases Embase, PubMed, and Web of Science as well as hand searching of the references of identified articles and the meeting abstracts were performed. Statistical analyses were performed using software Review Manager (Version 5.1.2) and Stata (Version 11.0). The pooled odds ratios (ORs) with 95 % confidence intervals (95 % CIs) were calculated. A total of 28 publications including 29 studies were involved. There was a significant association between IL-1α C(-889)T polymorphism and AD (for T allele vs. C allele: OR = 1.14, 95 % CI = 1.07-1.21; for T/T vs. C/C: OR = 1.39, 95 % CI = 1.18-1.63; for dominant model: OR = 1.13, 95 % CI = 1.04-1.22; and for recessive model: OR = 1.39, 95 % CI = 1.20-1.60). Significant association was found for Asians, Caucasians, and early-onset Alzheimer's disease (EOAD) but for late-onset Alzheimer's disease (LOAD). This meta-analysis indicates that there is a significant association between IL-1α C(-889)T polymorphism and AD as well as EOAD.