Jay Malaguit

The efficacy and safety of cilostazol for the secondary prevention of ischemic stroke in acute and chronic phases in Asian population- an updated meta-analysis

BackgroundsWhile previous meta-analysis have investigated the efficacy of cilostazol in the secondary prevention of ischemic stroke, they were criticized for their methodology, which confused the acute and chronic phases of stroke. We present a new systematic review, which differs from previous meta-analysis by distinguishing between the different phases of stroke, and includes two new randomized, controlled trials (RCTs).MethodsAll RCTs investigating the effect of cilostazol on secondary prevention of ischemic stroke were obtained. Outcomes were analyzed by Review Manager, including recurrence of cerebral infarction (ROCI), hemorrhage stroke or subarachnoid hemorrhage (HSSH), all-cause death (ACD), and modified Rankin Scale score (mRS). The Grading of Recommendations Assessment, Development and Evaluation (GRADE) assessed the quality of the evidence.Results5491 patients from six studies were included in the current study. In secondary prevention of ischemic stroke in chronic phase, cilostazol was associated with a 47% reduction in ROCI (relative risk [RR] 0.53, 95% confidence interval [CI] 0.34 to 0.81, p = 0.003), while no significant difference in HSSH and ACD compared with placebo; and 71% reduction in HSSH (RR 0.29, 95% CI 0.15 to 0.56, p = 0.0002) compared with aspirin, but not in ROCI and ACD. In the secondary prevention of ischemic stroke in acute phase, cilostazol did not show any effect in the ROCI, HSSH, ACD and mRS compared to placebo or aspirin. The quality of the evidence from chronic phase was high or moderate, and those from acute phase were moderate or low when analyzed by GRADE approach.ConclusionCilostazol provided a protective effect in the secondary prevention of the chronic phase of ischemic stroke.

Pathophysiology and the Monitoring Methods for Cardiac Arrest Associated Brain Injury

Cardiac arrest (CA) is a well-known cause of global brain ischemia. After CA and subsequent loss of consciousness, oxygen tension starts to decline and leads to a series of cellular changes that will lead to cellular death, if not reversed immediately, with brain edema as a result. The electroencephalographic activity starts to change as well. Although increased intracranial pressure (ICP) is not a direct result of cardiac arrest, it can still occur due to hypoxic-ischemic encephalopathy induced changes in brain tissue, and is a measure of brain edema after CA and ischemic brain injury. In this review, we will discuss the pathophysiology of brain edema after CA, some available techniques, and methods to monitor brain oxygen, electroencephalography (EEG), ICP (intracranial pressure), and microdialysis on its measurement of cerebral metabolism and its usefulness both in clinical practice and possible basic science research in development. With this review, we hope to gain knowledge of the more personalized information about patient status and specifics of their brain injury, and thus facilitating the physicians’ decision making in terms of which treatments to pursue.

Intranasal Administration of Interferon Beta Attenuates Neuronal Apoptosis via the JAK1/STAT3/BCL-2 Pathway in a Rat Model of Neonatal Hypoxic-Ischemic Encephalopathy

Neonatal hypoxic-ischemic encephalopathy (HIE) is an injury that often leads to detrimental neurological deficits. Currently, there are no established therapies for HIE and it is critical to develop treatments that provide protection after HIE. The objective of this study was to investigate the ability of interferon beta (IFNβ) to provide neuroprotection and reduce apoptosis after HIE. Postnatal Day 10 rat pups were subjected to unilateral carotid artery ligation followed by 2.5 hr of exposure to hypoxia (8% O2). Intranasal administration of human recombinant IFNβ occurred 2 hr after HIE and infarct volume, body weight, neurobehavioral tests, histology, immunohistochemistry, brain water content, blood–brain barrier permeability, enzyme-linked immunosorbent assay, and Western blot were all used to evaluate various parameters. The results showed that both IFNβ and the Type 1 interferon receptor expression decreases after HIE. Intranasal administration of human recombinant IFNβ was able to be detected in the central nervous system and was able to reduce brain infarction volumes and improve neurological behavior tests 24 hr after HIE. Western blot analysis also revealed that human recombinant IFNβ treatment stimulated Stat3 and Bcl-2 expression leading to a decrease in cleaved caspase-3 expression after HIE. Positive Fluoro-Jade C staining also demonstrated that IFNβ treatment was able to decrease neuronal apoptosis. Furthermore, the beneficial effects of IFNβ treatment were reversed when a Stat3 inhibitor was applied. Also an intraperitoneal administration of human recombinant IFNβ into the systemic compartment was unable to confer the same protective effects as intranasal IFNβ treatment.

Dihydrolipoic Acid Inhibits Lysosomal Rupture and NLRP3 Through Lysosome-Associated Membrane Protein-1/Calcium/Calmodulin-Dependent Protein Kinase II/TAK1 Pathways After Subarachnoid Hemorrhage in Rat

Background and Purpose— The NLRP3 (nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3) inflammasome is a crucial component of the inflammatory response in early brain injury after subarachnoid hemorrhage (SAH). In this study, we investigated a role of dihydrolipoic acid (DHLA) in lysosomal rupture, NLRP3 activation, and determined the underlying pathway. Methods— SAH was induced by endovascular perforation in male Sprague–Dawley rats. DHLA was administered intraperitoneally 1 hour after SAH. Small interfering RNA for lysosome-associated membrane protein-1 and CaMKII&agr; (calcium/calmodulin-dependent protein kinase II &agr;) was administered through intracerebroventricular 48 hours before SAH induction. SAH grade evaluation, short- and long-term neurological function testing, Western blot, and immunofluorescence staining experiments were performed. Results— DHLA treatment increased the expression of lysosome-associated membrane protein-1 and decreased phosphorylated CaMKII&agr; and NLRP3 inflammasome, thereby alleviating neurological deficits after SAH. Lysosome-associated membrane protein-1 small interfering RNA abolished the neuroprotective effects of DHLA and increased the level of phosphorylated CaMKII&agr;, p-TAK1 (phosphorylated transforming growth factor-&bgr;-activated kinase), p-JNK (phosphorylated c-Jun-N-terminal kinase), and NLRP3 inflammasome. CaMKII&agr; small interfering RNA downregulated the expression of p-TAK1, p-JNK, and NLRP3 and improved the neurobehavior after SAH. Conclusions— DHLA treatment improved neurofunction and alleviated inflammation through the lysosome-associated membrane protein-1/CaMKII/TAK1 pathway in early brain injury after SAH. DHLA may provide a promising treatment to alleviate early brain injury after SAH.

Osteopontin-Rac1 on Blood-Brain Barrier Stability Following Rodent Neonatal Hypoxia-Ischemia

Osteopontin (OPN) is a neuroprotective molecule that is upregulated following rodent neonatal hypoxic-ischemic (nHI) brain injury. Because Rac1 is a regulator of blood-brain barrier (BBB) stability, we hypothesized a role for this in OPN signaling. nHI was induced by unilateral ligation of the right carotid artery followed by hypoxia (8 % oxygen for 2 h) in P10 Sprague-Dawley rat pups. Intranasal (iN) OPN was administered at 1 h post-nHI. Groups consisted of: (1) Sham, (2) Vehicle, (3) OPN, and (4) OPN + Rac1 inhibitor (NSC23766). Evans blue dye extravasation (BBB permeability) was quantified 24 h post-nHI, and brain edema at 48 h. Increased BBB permeability and brain edema following nHI was ameliorated in the OPN treatment group. However, those rat pups receiving OPN co-treatment with the Rac1 inhibitor experienced no improvement compared with vehicle. OPN protects the BBB following nHI, and this was reversed by Rac1 inhibitor (NSC23766).

CpG-ODN exerts a neuroprotective effect via the TLR9/pAMPK signaling pathway by activation of autophagy in a neonatal HIE rat model

ABSTRACT Hypoxic Ischemic Encephalopathy (HIE) is an injury caused to the brain due to prolonged lack of oxygen and blood supply which results in death or long‐term disabilities. The main aim of this study was to investigate the role of Cytosine‐phospho‐guanine oligodeoxynucleotide (CpG‐ODN) in autophagy after HIE. Ten‐day old (P10) rat pups underwent right common carotid artery ligation followed by 2.5 h of hypoxia as previously described by Rice‐Vannucci. At 1 h post HIE, rats were intranasally administered with recombinant CpG‐ODN. Time‐course expression levels of endogenous key proteins, TLR9, pAMPK/AMPK, LC3II/I, and LAMP1 involved in CpG‐ODNs protective effects were measured using western blot. Short (48 h) and long (4 w) term neurobehavior studies were performed using righting reflex, negative geotaxis, water maze, foot fault and Rota rod tests. Brain samples were collected after long term for histological analysis. Furthermore, to elucidate the pathway via which CpG‐ODN confers protection, TLR9 and AMPK inhibitors were used. Time course results showed that the expression of TLR9, pAMPK/AMPK, LC3II/I, LAMP1 increased after HIE. Neurobehavioral studies showed that HIE induced a significant delay in development and resulted in cognitive and motor function deficits. However, CpG‐ODN ameliorated HIE‐induced outcomes and improved long term neurological deficits. In addition, CpG‐ODN increased expression of pAMPK/AMPK, p‐ULK1/ULK1, P‐AMBRA1/AMBRA1, LC3II/I and LAMP1 while inhibition of TLR9 and AMPK reversed those effects. In summary, CpG‐ODN increased HIE‐induced autophagy and improved short and long term neurobehavioral outcomes which may be mediated by the TLR9/pAMPK signaling pathway after HIE. Graphical abstract Figure. No Caption available. HighlightsAdministration of exogenous CpG‐ODN significantly increased autophagy and improved neurological deficits.Autophagy plays a major role in early brain injury after HIE.TLR9/AMPK/ULK/AMBRA pathway is one of the pathways activated which leads to autophagy in early brain injury.Induction of autophagy immediately after injury may be the key to treat HIE.

Changes in Brain Swelling and Infarction Volume over Four Days After Hypoxia Ischemia in Neonatal Rats

The leading cause of morbidity and mortality in infants is hypoxia-ischemia (HI). The current therapies for HI have limited success, in part due to a lack of understanding of HI pathophysiology and underlying mechanisms. Herein, a neonatal rat model of HI was used to examine the changes in brain swelling and infarct volume over 4 days after HI. Forty-four P10 rat pups were sacrificed at 2, 3, or 4 days post-HI. After sacrifice, the brains were removed, sliced, and stained with TTC (2,3,5-triphenyl-2H-tetrazolium chloride). Images of TTC-stained brains were used for measurement of the ipsilateral hemisphere brain volumes and infarct volumes, calculated using standard equations. The hemispheric brain volumes of HI animals in all groups was lower than that of sham animals and decreased as the post-HI sacrifice time increased. The infarct volume of HI animals was larger than that of sham animals. Infarct volumes tended to decrease over the days post-HI. The change in infarct volume is likely the result of a combination of brain growth and repair mechanisms. However, changes in the hemispheric brain volume may include tissue growth and repair mechanism, so also may be a limitation of the current algorithm used for calculating ipsilateral hemisphere brain volume.

Intranasal Osteopontin for Rodent Germinal Matrix Hemorrhage

Germinal matrix hemorrhage (GMH) is the most common and devastating neurological problem of premature infants. Current treatment is largely ineffective and GMH has been nonpreventable. Osteopontin (OPN) is an endogenous protein that has been shown to be neuroprotective, however, it has not been tested in GMH. P7 neonatal rats were subjected to stereotactic ganglionic eminence collagenase infusion. Groups were as follows: (1) sham, (2) GMH + vehicle, (3) GMH + intranasal OPN. Seventy-two hours later, the animals were evaluated using righting reflex, blood-brain barrier (BBB) permeability by Evans blue dye leakage, brain water content, and hemoglobin assay. Intranasal OPN improved outcomes after GMH by attenuation of brain swelling, BBB function, re-bleeding, and neurological outcomes. OPN may play an important role in enhancing neuroprotective brain signaling following GMH. These observed effects may offer novel possibilities for therapy in this patient population.

Intratumoral Hemorrhage in a Patient With Cerebellar Hemangioblastoma: A Case Report and Review

AbstractSpontaneous hemorrhage is rarely associated with hemangioblastomas. Intratumoral hemorrhage occurring in cerebellar hemangioblastomas is more rare.A 25-year-old man was admitted to our hospital with headache. We found a round cystic lesion with solid part in the right cerebellum. The lesion was resected. The final pathological diagnosis was hemangioblastomas. The radiological features of this case were similar to normal hemangioblastomas, whereas our histological examination showed the occurrence of the intratumoral hemorrhage.If the hemangioblastoma ruptures in our case, the outcome of the patient will be worse. It is difficult to identify the intratumoral hemorrhage of hemangioblastomas and quite dangerous if it is diagnosed late. Diagnosing an intratumoral hemorrhage of hemangioblastomas still needs a further discussion. Genetic screening may help us make an early diagnosis. Furthermore, the mechanism about intratumoral hemorrhage of hemangioblastomas remains unknown. The mutation of D6Mit135 gene on chromosome 6 may be responsible for the vascular dilation and hemorrhage induction in the hemangioblastomas. Tumor size, upregulation of vascular endothelial growth factor, spinalradicular location, and solid type are also factors relating to the hemorrhage of hemangioblastomas.The purpose of reporting our case is 2-fold: to remind clinicians to consider the possibility of internal hemorrhaging while diagnosing this disease, and provide a starting point to discuss mechanisms regarding the intratumoral hemorrhage of hemangioblastomas.

Role of PPAR-β/δ/miR-17/TXNIP pathway in neuronal apoptosis after neonatal hypoxic-ischemic injury in rats

Abstract Activation of peroxisome proliferator–activated receptor beta/delta (PPAR‐&bgr;/&dgr;), a nuclear receptor acting as a transcription factor, was shown to be protective in various models of neurological diseases. However, there is no information about the role of PPAR‐&bgr;/&dgr; as well as its molecular mechanisms in neonatal hypoxia‐ischemia (HI). In the present study, we hypothesized that PPAR‐&bgr;/&dgr; agonist GW0742 can activate miR‐17‐5p, consequently inhibiting TXNIP and ASK1/p38 pathway leading to attenuation of apoptosis. Ten‐day‐old rat pups were subjected to right common carotid artery ligation followed by 2.5 h hypoxia. GW0742 was administered intranasally 1 and 24 h post HI. PPAR‐&bgr;/&dgr; receptor antagonist GSK3787 was administered intranasally 1 h before and 24 h after HI, antimir‐17‐5p and TXNIP CRISPR activation plasmid were administered intracerebroventricularly 24 and 48 h before HI, respectively. Brain infarct area measurement, neurological function tests, western blot, reverse transcription quantitative real‐time polymerase chain reaction (RT‐qPCR), Fluoro‐Jade C and immunofluorescence staining were conducted. GW0742 reduced brain infarct area, brain atrophy, apoptosis, and improved neurological function at 72 h and 4 weeks post HI. Furthermore, GW0742 treatment increased PPAR‐&bgr;/&dgr; nuclear expression and miR‐17‐5p level and reduced TXNIP in ipsilateral hemisphere after HI, resulting in inhibition of ASK1/p38 pathway and attenuation of apoptosis. Inhibition of PPAR‐&bgr;/&dgr; receptor and miR‐17‐5p and activation of TXNIP reversed the protective effects. For the first time, we provide evidence that intranasal administration of PPAR‐&bgr;/&dgr; agonist GW0742 attenuated neuronal apoptosis at least in part via PPAR‐&bgr;/&dgr;/miR‐17/TXNIP pathway. GW0742 could represent a therapeutic target for treatment of neonatal hypoxic ischemic encephalopathy (HIE). Graphical abstract Figure. No Caption available. HighlightsPPAR‐&bgr;/&dgr; nuclear expression is decreased after neonatal brain injury (HI).GW0742 induces PPAR‐&bgr;/&dgr; nuclear expression in neurons.GW0742 has a protective effect on brain infarction and neurobehavior after HI.GW0742 protective effect is mediated by PPAR‐&bgr;/&dgr;, miR‐17‐5p and TXNIP.PPAR‐&bgr;/&dgr; activation attenuates apoptosis after HI.