High altitude retinopathy: An overview and new insights.

High altitude retinopathy (HAR) is a common ocular disorder that occurs on ascent to high altitude. There are many clinical symptoms, retinal vascular dilatation, retinal edema and hemorrhage are common. These usually do not or slightly affect vision; rarely, severe cases develop serious or permanent vision loss. At present, the research progress of HAR mainly focuses on hemodynamic changes, blood-retinal barrier damage, oxidative stress and inflammatory response. Although the related studies on HAR are limited, it shows that HAR still belongs to hypoxia, and hypobaric hypoxia plays an aggravating role in promoting the development of the disease. Various studies have demonstrated the correlation of HAR with acute mountain sickness (AMS) and high-altitude cerebral edema (HACE), so a deeper understanding of HAR is important. The slow ascent rates and ascent altitude are the key to preventing any altitude sickness. Research on traditional chinese medicine (TCM) and western medicine has been gradually carried out. Further exploration of the pathogenesis and prevention strategies of HAR will provide better guidance for doctors and high-altitude travelers.

Hyperbaric hydrogen therapy improves secondary brain injury after head trauma.

Background: The pathophysiology of traumatic brain injury (TBI) is caused by the initial physical damage and by the subsequent biochemical damage (secondary brain injury). Oxidative stress is deeply involved in secondary brain injury, so molecular hydrogen therapy may be effective for TBI. Hydrogen gas shows the optimal effect at concentrations of 2% or higher, but can only be used up to 1.3% in the form of a gas cylinder mixed with oxygen gas, which may not be sufficiently effective. The partial pressure of hydrogen increases in proportion to the pressure, so hyperbaric hydrogen therapy (HBH2) is more effective than that at atmospheric pressure. Methods: A total of 120 mice were divided into three groups: TBI + non-treatment group (TBI group; n = 40), TBI + HBH2 group (n = 40), and non-TBI + non-treatment group (sham group; n = 40). The TBI and TBI + HBH2 groups were subjected to moderate cerebral contusion induced by controlled cortical impact. The TBI + HBH2 group received hyperbaric hydrogen therapy at 2 atmospheres for 90 minutes, at 30 minutes after TBI. Brain edema, neuronal cell loss in the injured hippocampus, neurological function, and cognitive function were evaluated. Results: The TBI + HBH2 group showed significantly less cerebral edema (p ≺ 0.05). Residual hippocampal neurons were significantly more numerous in the TBI + HBH2 group on day 28 (p ≺ 0.05). Neurological score and behavioral tests showed that the TBI + HBH2 group had significantly reduced hyperactivity on day 14 (p ≺ 0.01). Conclusion: Hyperbaric hydrogen therapy may be effective for posttraumatic secondary brain injury.

Early complementary acupuncture improves the clinical prognosis of traumatic brain edema: A randomized controlled trial.

BACKGROUND: Traumatic brain edema occurs commonly brain injury, and most manifests as pericontusional edema of brain contusions. On the basis of evidence-based medicine, apart from recommending craniotomy and mannitol, there are few particularly effective measures to prevent and treat traumatic brain edema. It is uncertain whether an early complementary acupuncture treatment would improve long-term outcomes of patients with traumatic brain edema. The aim of this study is to assess the efficacy and the safety of early complementary acupuncture for patients with traumatic brain edema. METHODS: This study is an actively accruing, single-center, single-blinded, 2-arm, randomized controlled trial. Patients with traumatic brain injury, a Glasgow Coma Scale score of 6∼12, and brain edema on computed tomography scan will be divided into 2 groups on the basis of stratified block randomization. All patients will receive conventional treatment, and the study group will undergo additional acupuncture therapy (start within 72 hours after the injury) once a day for 28 days. The primary outcome is the dichotomized Glasgow Outcome Score at 6 months and 12 months after injury, and the secondary outcomes are the Glasgow Coma Scale, the volume of traumatic brain edema, the serum levels of C-reactive protein and interleukin-6, and the Modified Barthel Index. DISCUSSION: This study will provide data regarding the efficacy of early complementary acupuncture for traumatic brain edema. If the study yields positive results, its findings may offer insights into a valuable complementary option of acupuncture for traumatic brain edema that could provide pilot evidence for large, randomized, controlled trials.Trial registration: This trial has been published in the Chinese Clinical Trial Register, http://www.chictr.org.cn/edit.aspx?pid=141208&htm=4 (Identifier: ChiCTR2100053794, registered on December 3, 2021).

Efficacy of Naoxueshu in acute spontaneous intracerebral hemorrhage: a multicenter observational study.

OBJECTIVE: To evaluate the efficacy and safety outcome and related risk factors of Naoxueshu in the treatment of acute SICH. METHODS: Two hundred twenty patients were enrolled in this study. Diagnosis of SICH was based on neuroimaging. All the patients received regular treatment and Naoxueshu oral liquid 10 ml 3 times a day for 14 consecutive days. Surgical intervention was conducted as needed. Efficacy and safety outcomes were evaluated. RESULTS: Hematoma volume decreased significantly 7 days after Naoxueshu treatment (from 27.3 ± 20.0 to 15.1 ± 15.1 ml, P < 0.0001), and it decreased further in 14-day result (6.9 ± 10.4 ml, P < 0.0001). Patients' neurological function was improved remarkably with NIHSS scores from baseline 13 points to 7-day 7 points (P < 0.0001) and 14-day 4 points (P < 0.0001). Cerebral edema was relieved only 14 days after Naoxueshu treatment (from 3 to 2 points, P < 0.0001). No clinically significant change was found in 7-day and 14-day safety results. Female sex was related independently to large 7-day hematoma volume and worse 7-day NIHSS score while it would not affect patients' 14-day outcomes. Rare cause of SICH (B = 17.4, P = 0.009) alone was related to large 14-day hematoma volume. Worse baseline NIHSS score (B = 0.3, P = 0.003) and early use of Naoxueshu (B = 2.9, P = 0.005) were related to worse 7-day and14-day neurological function. CONCLUSION: Naoxueshu oral liquid could relieve hematoma volume and cerebral edema safely; meanwhile, it could improve patients' neurological function. Sex, cause of SICH, and time from onset to receive Naoxueshu should be taken into consideration in the treatment of SICH.

Vitamin D3 Supplement Attenuates Blood-Brain Barrier Disruption and Cognitive Impairments in a Rat Model of Traumatic Brain Injury.

This study was designed to study the effects of vitamin D3 supplementation on the cognitive dysfunction and neurological function of traumatic brain injury (TBI) and the possible underlying mechanisms. To this purpose, different doses of vitamin D3 were intraperitoneally injection to TBI rats for one week before TBI surgery and three consecutive weeks after TBI. Brain edema evaluation was conducted on the third day and Evans blue staining for blood-brain barrier (BBB) permeability on the seventh day after TBI. Rat behavior was assessed by evaluation of neurological scores and morris water maze. It was revealed that vitamin D levels increased in serum after the administration of vitamin D3 for one week. TBI led to neurological deficit, together with brain edema, BBB disruption and inflammation. Vitamin D3 supplement ameliorated neurological deficit and cognitive impairments induced by TBI. Vitamin D3 administration reduced brain edema and impairments of blood-brain barrier induced by TBI, as well as decreased inflammatory response in TBI rat brain. Our results showed that vitamin D3 administration alleviated neurobehavioral deficits and improved brain edema after TBI. Vitamin D3 inhibited inflammatory cytokines and decreased BBB disruption in TBI rats. Vitamin D3 may be used for the treatment of TBI as a protective intervention.

Naoxueshu relieves hematoma after clot removal in acute spontaneous intracerebral hemorrhage.

OBJECTIVES: Surgical treatment is expected to remove clot immediately in acute spontaneous intracerebral hemorrhage (SICH) patients. The aim of this study was to evaluate whether Naoxueshu could enhance the efficacy of clot removal surgery in acute SICH patients. METHODS: One hundred twenty patients who had been diagnosed as SICH according to neuroimaging were enrolled in this study. They received craniotomy, decompressive craniectomy, or minimally invasive surgical evacuation as appropriate and then were randomized into two groups: the Naoxueshu group (NXS group, n = 60) and the control group (n = 60). All the patients received standard medical management while patients in NXS group also took Naoxueshu oral liquid 10 ml with three times a day for seven consecutive days. The primary outcome was the 7-day hematoma volume and secondary outcomes were 7-day National Institutes of Health Stroke Scale (NIHSS) score and 7-day cerebral edema score. RESULTS: After clot removal surgery, hematoma volume in NXS group (9.5 ± 8.0) was significantly decreased than that in Control group (21.3 ± 22.9, p < .0001) 7 days after surgery. Moreover, cerebral edema was also relieved after 7-day's Naoxueshu treatment (2.5 ± 0.9 vs. 2.9 ± 0.7, p = .043). Since patients in NXS group had worse baseline NIHSS score (17.2 ± 8.1 vs. 13.7 ± 10.1, p = .039), it was reasonable to conclude that Naoxueshu treatment could improve patients' neurological function because 7-day NIHSS score of the two groups was similar. CONCLUSION: Naoxueshu oral liquid could relieve hematoma volume and cerebral edema after clot removal surgery in acute SICH patients. Moreover, it had the potential to improve patients' short-term neurological function.

Preventative, but not post-stroke, inhibition of CD36 attenuates brain swelling in hyperlipidemic stroke.

The lack of inclusion of comorbidities in animal models of stroke may underlie the limited development of therapy in stroke. Previous studies in mice deficient of CD36, an immune receptor, indicated its contribution to stroke-induced inflammation and injury in hyperlipidemic conditions. The current study, therefore, tested whether pharmacological inhibition of CD36 provides neuroprotection in hyperlipidemic stroke. The hyperlipidemic mice subjected to stroke showed an exacerbation of infarct size and profound brain swelling. However, post-stroke treatment with CD36 inhibitors did not reduce, and in some cases worsened, acute stroke outcome, suggesting potential benefits of elevated CD36 in the post-stroke brain in a hyperlipidemic condition. On the other hand, chronic treatment of a CD36 inhibitor prior to stroke significantly reduced stroke-induced brain swelling. There was a trend toward infarct reduction, although it did not reach statistical significance. The observed benefit of preventative CD36 inhibition is in line with previously reported smaller infarct volume and swelling in CD36 KO mice. Thus, the current findings suggest that insights gained from the genetic models should be carefully considered before the implementation of pharmacological interventions, as a potential therapeutic strategy may depend on preventative treatment or a post-stroke acute treatment paradigm.

Hyperbaric oxygen therapy in the treatment of malign edema complication after arteriovenous malformation radiosurgery.

A 16-year-old female patient with headache was admitted to our hospital. Radiological examination showed a Spetzler-Martin Grade III arteriovenous malformation (AVM) located at the left frontal lobe. Volume-staged stereotactic radiosurgery (SRS) treatment performed in two fractions at three-month intervals and post-procedural period were uneventful. Eight months later the patient was admitted to our hospital with headache, vomiting, right-sided facial palsy and right upper extremity paresthesia. Radiological examination demonstrated severe vasogenic edema in the left centrum semiovale and temporal region. Due to severe and steroid-resistant malign edema, hyperbaric oxygen (HBO2) therapy was performed as an alternative treatment option. Neurological symptoms resolved completely after HBO2. Radiological examination demonstrated serious improvement of brain edema and mass effect.

Amiloride Alleviates Neurological Deficits Following Transient Global Ischemia and Engagement of Central IL-6 and TNF-α Signal.

BACKGROUND: Central pro-inflammatory cytokine (PIC) signal is involved in neurological deficits after transient global ischemia induced by cardiac arrest (CA). The present study was to examine if blocking acid sensing ion channels (ASICs) using amiloride in the Central Nervous System can alleviate neurological deficits after the induction of CA and further examine the participation of PIC signal in the hippocampus for the effects of amiloride. METHODS: CA was induced by asphyxia and then cardiopulmonary resuscitation was performed in rats. Western blot analysis and ELISA were used to determine the protein expression of ASIC subunit ASIC1 in the hippocampus, and the levels of PICs. As noted, it is unlikely that this procedure is clinically used although amiloride and other pharmacological agents were given into the brain in this study. RESULTS: CA increased ASIC1 in the hippocampus of rats in comparison with control animals. This was associated with the increase in IL-1ß, IL-6 and TNF-α together with Caspase-3 and Caspase-9. The administration of amiloride into the lateral ventricle attenuated the upregulation of Caspase-3/Caspase-9 and this further alleviated neurological severity score and brain edema. Inhibition of central IL-6 and TNF-α also decreased ASIC1 in the hippocampus of CA rats. CONCLUSION: Transient global ischemia induced by CA amplifies ASIC1a in the hippocampus likely via PIC signal. Amiloride administered into the Central Nervous System plays a neuroprotective role in the process of global ischemia. Thus, targeting ASICs (i.e., ASIC1a) is suggested for the treatment and improvement of CA-evoked global cerebral ischemia.

Chrysin ameliorates cerebral ischemia/reperfusion (I/R) injury in rats by regulating the PI3K/Akt/mTOR pathway.

In this study, the effects of chrysin on cerebral ischemia by establishing middle cerebral artery occlusion (MCAO) in rat were investigated. In vivo experiments, the rats were orally administrated with clopidogrel or chrysin once daily for 7 days before the experimental of ischemia and the rats were divided into 5 groups: the sham group, the I/R group, I/R + clopidogrel group, I/R + chrysin (10 mg/kg), I/R + chrysin (20 mg/kg) group. Chrysin significantly ameliorated the I/R rats, evaluated by TTC staining, determination of brain wet to dry weight ratio and neurological deficits. Moreover, in serum and brain tissues of the I/R rats, chrysin also could effectively suppress the release of inflammatory cytokines, including levels of interleukin-6 (IL-6), interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α). In addition, chrysin could improve the SOD activity in the I/R rats. Mechanically, chrysin could activate the PI3K/Akt/mTOR pathway, inhibited inflammation and apoptosis. In oxygen-glucose deprivation and recovery (OGD/R)-induced SH-SY5Y cells in vitro. Chrysin markedly decreased the levels of TNF-α, IL-6 and IL-1ß in supernatant of OGD/R-induced SH-SY5Y cells via activating PI3K/Akt/mTOR pathway. In conclusion, our study demonstrated that chrysin might be a potential therapeutic agent for cerebral ischemia.

A novel lecithin-based delivery form of Boswellic acids as complementary treatment of radiochemotherapy-induced cerebral edema in patients with glioblastoma multiforme: a longitudinal pilot experience.

BACKGROUND: Glioblastoma multiforme (GBM) is an extremely challenging neurological disease for which the development of more effective therapeutic options and of adjuvant/complementary treatment is needed. We investigated the effects of an innovative phytosome-based delivery form of boswellic acids extract (Monoselect AKBA™) on radiochemotherapy-induced cerebral edema in patients with primary GBM. METHODS: Patients with de novo GBM treated with surgery, radiotherapy and chemotherapy with temozolomide were enrolled in this longitudinal study and received boswellia-based product 4500 mg/die for a maximum of 34 weeks. Cerebral edema was assessed at 4, 12, 22 and 34 weeks post-surgery, together with steroids consumption and patients' psychological status. RESULTS: A total of 20 patients were included in the study. The percentage of patients with reduced edema was constant during the study, while the percentage of those with reduced or stable edema tended to increase over time. Of note, two patients achieved a considerable reduction in brain edema, which led to a more favorable and beneficial surgical resection. In addition, a good percentage of patients assumed a stable/reduced steroids dose or were dexamethasone free during the study. Lastly, patients' QoL and psychological state were maintained throughout the study. CONCLUSIONS: Complementary treatment with Monoselect AKBA™ might exert a beneficial effect in reducing radiochemotherapy-induced cerebral edema, thanks to the anti-inflammatory properties of the boswellia serrata extract. The reduction in brain edema might diminish dexamethasone assumption, thus minimizing steroids-induced side effects, and in few cases may allow a complete surgical excision of the tumor mass.

Results of Phosphorus Magnetic Resonance Spectroscopy for Brain Metastases Correlate with Histopathologic Results.

BACKGROUND: Brain metastases (BMs) are classically well-circumscribed lesions. Still, the amount of edema in these neoplasms suggests either mechanisms of infiltration or defense. A better understanding of the mechanisms within the edema of BMs seems reasonable to preoperatively identify areas of potential infiltration and resect them. BMs represent tumors with high energy demand and cell turnover; therefore, they qualify for preoperative investigation with phosphorus-31 magnetic resonance spectroscopy (31PMRS), which reveals information about those characteristics. METHODS: Ten patients with BMs were included in this trial. All underwent preoperative standard magnetic resonance imaging with additional 31PMRS. In all patients, 1 voxel within the contrast-enhancing tumor (CE+), 1 voxel at the border (including CE+ areas and surrounding T2-hyperintensive [T2+] areas), and 1 distant voxel purely including T2+ areas were determined by a neuroradiologist and a neurosurgeon. A frameless stereotactic biopsy was performed after craniotomy. Subsequently, the metabolites of the 31PMRS were analyzed and compared with the histopathologic results. RESULTS: Ratios, reflecting resynthesis (CE+/border/T2+: 1.109 ± 0.192/1.112 ± 0.158/1.083 ± 0.097), hydrolysis (0.303 ± 0.089/0.360 ± 0.122/0.321 ± 0.089), energy demand (4.227 ± 2.35/3.453 ± 1.284/3.599 ± 0.833), and membrane turnover (1.239 ± 0.2611/3.453 ± 1.284/3.599 ± 0.283) were calculated and compared intraindividually with a voxel from the contralateral side (resynthesis/hydrolysis/energy demand/membrane turnover: 1.063 ± 0.085/0.335 ± 0.073/3.317 ± 0.7573/0.784 ± 0.186), respectively. Resynthesis showed a trend toward higher ratios in CE+ and border biopsies without reaching statistical significances. This trend was also seen concerning energy demand. Membrane turnover was significantly higher in CE+, border zone, and also in the T2+ areas compared with controls (P > 0.001). CONCLUSIONS: 31PMRS in BMs provides information on metabolic changes in tumor and surrounding edema. There is proof of enhanced metabolism in tissue without histologic tumor manifestation.

Phenylethanoid glycosides of Phlomis younghusbandii Mukerjee ameliorate acute hypobaric hypoxia-induced brain impairment in rats.

High altitude cerebral edema (HACE), whose development process is associated with oxidative stress and inflammatory response, is a life-threatening condition caused by rapid ascent speed to high altitudes. Phenylethanoid glycosides (PhGCs) are primary active constituents isolated from Phlomis younghusbandii Mukerjee that reportedly exhibit potent anti-oxidant and anti-inflammatory activities. The present study aims to investigate the protective effect of phenylethanoid glycosides (PhGCs) from P. younghusbandii in acute hypobaric hypoxia (AHH) - stimulated HACE rats and its underlying mechanisms. The expression of pro-inflammatory cytokine levels (IL-1ß, TNF-α, and IL-6) was detected by RT-PCR and ELISA at mRNA and protein levels in brain tissues. Western blotting was carried out to measure the major protein levels (IL-1ß, TNF-α, and NF-κB) in brain tissues. The oxidative stress biomarkers (MDA, SOD, and GSH) were evaluated using kits. Results demonstrate that PhGCs significantly improved pathological changes in brain tissues, reduced the brain's water content, and attenuated the production and mRNA expression of pro-inflammatory cytokines. Furthermore, the increased oxidative stress and the decrease in anti-oxidant stress system under the AHH condition were also abrogated reversely through PhGCs treatment by elevating the levels of SOD and GSH and suppressing the accumulation of MDA. Simultaneously, there was also a significant reduction in NF-κB, IL-1ß, and TNF-α protein expression levels in brain tissues, suggesting that blocking the NF-κB signaling pathway activation prevented the production of pro-inflammatory cytokines. Taken together, these findings indicate that PhGCs may afford a protectively intervene in HACE through the suppression of oxidative stress and inflammatory response via the inhibition of the NF-κB signaling pathway, indicating that PhGCs are promising agents for the treatment of acute HACE.

Calcium channel blockade with nimodipine reverses MRI evidence of cerebral oedema following acute hypoxia.

Acute cerebral hypoxia causes rapid calcium shifts leading to neuronal damage and death. Calcium channel antagonists improve outcomes in some clinical conditions, but mechanisms remain unclear. In 18 healthy participants we: (i) quantified with multiparametric MRI the effect of hypoxia on the thalamus, a region particularly sensitive to hypoxia, and on the whole brain in general; (ii) investigated how calcium channel antagonism with the drug nimodipine affects the brain response to hypoxia. Hypoxia resulted in a significant decrease in apparent diffusion coefficient (ADC), a measure particularly sensitive to cell swelling, in a widespread network of regions across the brain, and the thalamus in particular. In hypoxia, nimodipine significantly increased ADC in the same brain regions, normalizing ADC towards normoxia baseline. There was positive correlation between blood nimodipine levels and ADC change. In the thalamus, there was a significant decrease in the amplitude of low frequency fluctuations (ALFF) in resting state functional MRI and an apparent increase of grey matter volume in hypoxia, with the ALFF partially normalized towards normoxia baseline with nimodipine. This study provides further evidence that the brain response to acute hypoxia is mediated by calcium, and importantly that manipulation of intracellular calcium flux following hypoxia may reduce cerebral cytotoxic oedema.

Use of hyperbaric oxygen therapy in pediatric neuro-oncology: a single institutional experience.

INTRODUCTION: Hyperbaric oxygen therapy (HBOT) has been utilized as adjunctive treatment of CNS tumors and for radiation necrosis (RN) with reported success. The safety and efficacy in pediatric patients is less understood. METHODS: Seven patients (ages 10-23 years, six females) were treated with HBOT (3-60 sessions) for either RN (n = 5) or tumor-associated edema (n = 2). Tumor diagnosis included low-grade glioma (n = 4, two with neurofibromatosis type 1), meningioma (n = 1), medulloblastoma (n = 1) and secondary high grade glioma (n = 1). Prior therapies included: surgery (n = 4), chemotherapy (n = 4) and radiation (N = 5: four focal, one craniospinal). Three underwent biopsy: one confirming RN, one high-grade glioma, and one low-grade glioma. Patients were assessed for clinical and radiographic changes post HBOT. RESULTS: Median time to clinical and radiographic presentation was 8.5 months (range 6 months-11 years) in those who had prior radiation. Clinical improvement after HBOT (median: 40 sessions) was observed in four of seven patients. Symptoms were stable in two and worsened in one patient. Radiographic improvement was seen in four patients; three had radiographic disease progression. In the subgroup treated for presumed and biopsy-confirmed RN (n = 5), four of five (80%) had clinical and radiographic improvement. There were no long-term adverse events due to HBOT. CONCLUSIONS: HBOT is safe and well-tolerated in pediatric and young adult patients with CNS tumors. Clinical and radiographic improvements were observed in over half of patients. Clinical trials are needed to establish safety and efficacy of HBOT as adjunct therapy in pediatric CNS tumors.

Omega-3 polyunsaturated fatty acid attenuates traumatic brain injury-induced neuronal apoptosis by inducing autophagy through the upregulation of SIRT1-mediated deacetylation of Beclin-1.

BACKGROUND: Enhancing autophagy after traumatic brain injury (TBI) may decrease the expression of neuronal apoptosis-related molecules. Autophagy-mediated neuronal survival is regulated by the sirtuin family of proteins (SIRT). Omega-3 polyunsaturated fatty acids (ω-3 PUFA) are known to have antioxidative and anti-inflammatory effects. We previously demonstrated that ω-3 PUFA supplementation attenuated neuronal apoptosis by modulating the neuroinflammatory response through SIRT1-mediated deacetylation of the HMGB1/NF-κB pathway, leading to neuroprotective effects following experimental traumatic brain injury (TBI). However, no studies have elucidated if the neuroprotective effects of ω-3 PUFAs against TBI-induced neuronal apoptosis are modulated by SIRT1-mediated deacetylation of the autophagy pathway. METHODS: The Feeney DM TBI model was adopted to induce TBI rats. Modified neurological severity scores, the rotarod test, brain water content, and Nissl staining were employed to determine the neuroprotective effects of ω-3 PUFA supplementation. Immunofluorescent staining and western blot analysis were used to detect Beclin-1 nuclear translocation and autophagy pathway activation. The impact of SIRT1 deacetylase activity on Beclin-1 acetylation and the interaction between cytoplasmic Beclin-1 and Bcl-2 were assessed to evaluate the neuroprotective effects of ω-3 PUFAs and to determine if these effects were dependent on SIRT1-mediated deacetylation of the autophagy pathway in order to gain further insight into the mechanisms underlying the development of neuroprotection after TBI. RESULTS: ω-3 PUFA supplementation protected neurons against TBI-induced neuronal apoptosis via enhancement of the autophagy pathway. We also found that treatment with ω-3 PUFA significantly increased the NAD+/NADH ratio and SIRT1 activity following TBI. In addition, ω-3 PUFA supplementation increased Beclin-1 deacetylation and its nuclear export and induced direct interactions between cytoplasmic Beclin-1 and Bcl-2 by increasing SIRT1 activity following TBI. These events led to the inhibition of neuronal apoptosis and to neuroprotective effects through enhancing autophagy after TBI, possibly due to elevated SIRT1. CONCLUSIONS: ω-3 PUFA supplementation attenuated TBI-induced neuronal apoptosis by inducing the autophagy pathway through the upregulation of SIRT1-mediated deacetylation of Beclin-1.

Ginkgolide B ameliorates NLRP3 inflammasome activation after hypoxic-ischemic brain injury in the neonatal male rat.

INTRODUCTION: Perinatal hypoxic-ischemic (HI) insult is an important cause of brain injury in neonates. The development of novel treatment strategies for neonates with HI brain injury is urgently needed. Ginkgolide B (GB) is a main component of Ginkgo biloba extracts with a long history of use in traditional Chinese medicine. However, it is unknown whether GB could play a protective role in hypoxic stress in immature animals. METHODS: Using neonatal hypoxic-ischemic (HI) brain injury model of rat pups, neurological score, infarct size, and brain edema were evaluated after HI injury. The activation of microglia and the production of IL-1ß and IL-18 were detected by immunohistochemistry and ELISA, respectively. A priming signal (NF-κB P65) and an activation signal (Caspase-1) of NLRP3 inflammasome activation were detected by western blot analyses. RESULTS: GB administrated 30 min prior to ischemia induction can improve neurological disorder, reduce infarct volume and alleviate cerebral edema. Compared with the HI groups, GB inhibited the activation of microglia and decreased the production of IL-1ß and IL-18 in neocortex. Furthermore, GB reduced NLRP3 expression mainly in microglia, and significantly inhibited the expression of Caspase-1 and the nuclear translocation of NF-κB P65, preventing NLRP3 inflammasome activation. CONCLUSIONS: GB ameliorates hypoxic-ischemic brain injury in the neonatal male rat via inhibiting NLRP3 inflammasome activation.

Interventions for the treatment of brain radionecrosis after radiotherapy or radiosurgery.

BACKGROUND: Brain radionecrosis (tissue death caused by radiation) can occur following high-dose radiotherapy to brain tissue and can have a significant impact on a person's quality of life (QoL) and function. The underlying pathophysiological mechanism remains unclear for this condition, which makes establishing effective treatments challenging. OBJECTIVES: To assess the effectiveness of interventions used for the treatment of brain radionecrosis in adults over 18 years old. SEARCH METHODS: In October 2017, we searched the Cochrane Register of Controlled Trials (CENTRAL), MEDLINE, Embase and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) for eligible studies. We also searched unpublished data through Physicians Data Query, www.controlled-trials.com/rct, www.clinicaltrials.gov, and www.cancer.gov/clinicaltrials for ongoing trials and handsearched relevant conference material. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of any intervention directed to treat brain radionecrosis in adults over 18 years old previously treated with radiation therapy to the brain. We anticipated a limited number of RCTs, so we also planned to include all comparative prospective intervention trials and quasi-randomised trials of interventions for brain radionecrosis in adults as long as these studies had a comparison group that reflects the standard of care (i.e. placebo or corticosteroids). Selection bias was likely to be an issue in all the included non-randomised studies therefore results are interpreted with caution. DATA COLLECTION AND ANALYSIS: Two review authors (CC, PB) independently extracted data from selected studies and completed a 'Risk of bias' assessment. For dichotomous outcomes, the odds ratio (OR) for the outcome of interest was reported. For continuous outcomes, treatment effect was reported as mean difference (MD) between treatment arms with 95% confidence intervals (CIs). MAIN RESULTS: Two RCTs and one prospective non-randomised study evaluating pharmacological interventions met the inclusion criteria for this review. As each study evaluated a different drug or intervention using different endpoints, a meta-analysis was not possible. There were no trials of non-pharmacological interventions that met the inclusion criteria.A very small randomised, double-blind, placebo-controlled trial of bevacizumab versus placebo reported that 100% (7/7) of participants on bevacizumab had reduction in brain oedema by at least 25% and reduction in post-gadolinium enhancement, whereas all those receiving placebo had clinical or radiological worsening or both. This was an encouraging finding but due to the small sample size we did not report a relative effect. The authors also failed to provide adequate details regarding the randomisation and blinding procedures Therefore, the certainty of this evidence is low and a larger RCT adhering to reporting standards is needed.An open-label RCT demonstrated a greater reduction in brain oedema (T2 hyperintensity) in the edaravone plus corticosteroid group than in the corticosteroid alone group (MD was 3.03 (95% CI 0.14 to 5.92; low-certainty evidence due to high risk of bias and imprecision); although the result approached borderline significance, there was no evidence of any important difference in the reduction in post-gadolinium enhancement between arms (MD = 0.47, 95% CI - 0.80 to 1.74; low-certainty evidence due to high risk of bias and imprecision).In the RCT of bevacizumab versus placebo, all seven participants receiving bevacizumab were reported to have neurological improvement, whereas five of seven participants on placebo had neurological worsening (very low-certainty evidence due to small sample size and concerns over validity of analyses). While no adverse events were noted with placebo, three severe adverse events were noted with bevacizumab, which included aspiration pneumonia, pulmonary embolus and superior sagittal sinus thrombosis. In the RCT of corticosteroids with or without edaravone, the participants who received the combination treatment were noted to have significantly greater clinical improvement than corticosteroids alone based on LENT/SOMA scale (OR = 2.51, 95% CI 1.26 to 5.01; low-certainty evidence due to open-label design). No differences in treatment toxicities were observed between arms.One included prospective non-randomised study of alpha-tocopherol (vitamin E) versus no active treatment was found but it did not include any radiological assessment. As only one included study was a double-blinded randomised controlled trial, the other studies were prone to selection and detection biases.None of the included studies reported quality of life outcomes or adequately reported details about corticosteroid requirements.A limited number of prospective studies were identified but subsequently excluded as these studies had a limited number of participants evaluating different pharmacological interventions using variable endpoints. AUTHORS' CONCLUSIONS: There is a lack of good certainty evidence to help quantify the risks and benefits of interventions for the treatment of brain radionecrosis after radiotherapy or radiosurgery. In an RCT of 14 patients, bevacizumab showed radiological response which was associated with minimal improvement in cognition or symptom severity. Although it was a randomised trial by design, the small sample size limits the quality of data. A trial of edaravone plus corticosteroids versus corticosteroids alone reported greater reduction in the surrounding oedema with combination treatment but no effect on the enhancing radionecrosis lesion. Due to the open-label design and wide confidence intervals in the results, the quality of this data was also low. There was no evidence to support any non-pharmacological interventions for the treatment of radionecrosis. Further prospective randomised studies of pharmacological and non-pharmacological interventions are needed to generate stronger evidence. Two ongoing RCTs, one evaluating bevacizumab and one evaluating hyperbaric oxygen therapy were identified.

Electroacupuncture: a new approach to open the blood-brain barrier in rats recovering from middle cerebral artery occlusion.

OBJECTIVE: To examine for an opening effect on the blood-brain barrier (BBB) in intact rats and rats with experimental ischaemia-reperfusion (I/R) during the recovery period after various electroacupuncture (EA) treatments with different time courses, and to determine whether there is a time-dependent effect. An additional objective was to determine whether this method could induce the penetration of nerve growth factor (NGF) through the BBB. METHODS: A middle cerebral artery occlusion (MCAO) model was first established. We chose different stimulation time courses and observed the effects of EA treatment (100 Hz frequency; 2 mA intensity) at GV20 and GV26 on the BBB in rats recovering from MCAO 3 weeks after modelling. The rats were injected with 2% Evans blue (EB) saline. The brain water content was measured using a wet/dry weighing method. The degree of penetration of EB was detected using spectrophotometry and laser confocal microscopy. The rats were then injected with NGF, and the concentration of NGF in the brain tissues was measured using ELISA. RESULTS: The increase in the BBB permeability was most notable following the 8 min EA stimulation (P<0.05), which may be advantageous for the targeted delivery of drugs (such as NGF) into the brain. Additionally, this effect did not appear to cause brain oedema (P>0.05) in healthy or MCAO rats. CONCLUSIONS: EA treatment for a certain stimulation time at GV20 and GV26 in MCAO rats can increase BBB permeability.