Prophylactic supplement with melatonin prevented the brain injury after cardiac arrest in rats.

Prophylactic pharmacotherapy for health care in patients with high risk of cardiac arrest (CA) is an elusive and less explored strategy. Melatonin has possibilities used as a daily nutraceutical to trigger the cellular adaptation. We sought to find the effects of long-term daily prophylactic supplement with melatonin on the victim of CA. Rats were divided into sham, CA, and melatonin + CA (Mel + CA) groups. The rats in the Mel + CA group received daily IP injection of melatonin 100 mg/kg for 14 days. CA was induced by 8 min asphyxia and followed by manual cardiopulmonary resuscitation. The endpoint was 24 h after resuscitation. Survival, neurological outcome, and hippocampal mitochondrial integrity, dynamics and function were assessed. Survival was significantly higher in the Mel + CA group than the CA group (81 vs. 42%, P = 0.04). Compared to the CA group, neurological damage in the CA1 region and the level of cytochrome c, cleaved caspase-3 and caspase-9 in the Mel + CA group were decreased (P < 0.05). Mitochondrial function and integrity were protected in the Mel + CA group compared to the CA group, according to the results of mitochondrial swelling, ΔΨm, ROS production, oxygen consumption rate, and respiratory control rate (P < 0.05). Melatonin increased SIRT3 and downregulated acetylated CypD. The mitochondrial dynamics and autophagy were improved in the Mel + CA group (P < 0.05). Long-term daily prophylactic supplement with melatonin buy the time from brain injury after CA.

[Protective effect of breviscapine against brain injury induced by intrauterine inflammation in preterm rats and its mechanism]. / ç¯ç›èŠ±ç´ å¯¹å®«å† ç‚Žç—‡è‡´æ—©äº§å¤§é¼ è„‘æŸä¼¤çš„ä¿æŠ¤ä½œç”¨åŠå ¶æœºåˆ¶æŽ¢è®¨.

OBJECTIVES: To study the protective effect of breviscapine against brain injury induced by intrauterine inflammation in preterm rats and its mechanism. METHODS: A preterm rat model of brain injury caused by intrauterine inflammation was prepared by intraperitoneal injections of lipopolysaccharide in pregnant rats. The pregnant rats and preterm rats were respectively randomly divided into 5 groups: control, model, low-dose breviscapine (45 mg/kg), high-dose breviscapine (90 mg/kg), and high-dose breviscapine (90 mg/kg)+ML385 [a nuclear factor erythroid 2-related factor 2 (Nrf2) inhibitor, 30 mg/kg] (n=10 each). The number and body weight of the live offspring rats were measured for each group. Hematoxylin-eosin staining was used to observe the pathological morphology of the uterus and placenta of pregnant rats and the pathological morphology of the brain tissue of offspring rats. Immunofluorescent staining was used to measure the co-expression of ionized calcium binding adaptor molecule-1 (IBA-1) and nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) in the cerebral cortex of offspring rats. ELISA was used to measure the levels of interleukin-6 (IL-6), interleukin-8 (IL-8), and interleukin-1ß (IL-1ß) in the brain tissue of offspring rats. Western blotting was used to measure the expression of Nrf2 pathway-related proteins in the brain tissue of offspring rats. RESULTS: Pathological injury was found in the uterus, and placenta tissue of the pregnant rats and the brain tissue of the offspring rats, and severe microglia pyroptosis occurred in the cerebral cortex of the offspring rats in the model group. Compared with the control group, the model group had significant reductions in the number and body weight of the live offspring rats and the protein expression levels of Nrf2 and heme oxygenase-1 (HO-1) in the brain tissue of the offspring rats (P<0.05), but significant increases in the relative fluorescence intensity of the co-expression of IBA-1 and NLRP3, the levels of the inflammatory factors IL-6, IL-8, and IL-1ß, and the protein expression levels of NLRP3 and caspase-1 in the brain tissue of the offspring rats (P<0.05). Compared with the model group, the breviscapine administration groups showed alleviated pathological injury of the uterus and placenta tissue of the pregnant rats and the brain tissue of the offspring rats, significant increases in the number and body weight of the live offspring rats and the protein expression levels of Nrf2 and HO-1 in the brain tissue of the offspring rats (P<0.05), and significant reductions in the relative fluorescence intensity of the co-expression of IBA-1 and NLRP3, the levels of the inflammatory factors IL-6, IL-8, and IL-1ß, and the protein expression levels of NLRP3 and caspase-1 in the brain tissue of the offspring rats (P<0.05). The high-dose breviscapine group had a significantly better effect than the low-dose breviscapine (P<0.05). ML385 significantly inhibited the intervention effect of high-dose breviscapine (P<0.05). CONCLUSIONS: Breviscapine can inhibit inflammatory response in brain tissue of preterm rats caused by intrauterine inflammation by activating the Nrf2 pathway, and it can also inhibit microglial pyroptosis and alleviate brain injury.

Protective effect of breviscapine against brain injury induced by intrauterine inflammation in preterm rats and its mechanism / 中国当代儿科杂志

OBJECTIVES@#To study the protective effect of breviscapine against brain injury induced by intrauterine inflammation in preterm rats and its mechanism.@*METHODS@#A preterm rat model of brain injury caused by intrauterine inflammation was prepared by intraperitoneal injections of lipopolysaccharide in pregnant rats. The pregnant rats and preterm rats were respectively randomly divided into 5 groups: control, model, low-dose breviscapine (45 mg/kg), high-dose breviscapine (90 mg/kg), and high-dose breviscapine (90 mg/kg)+ML385 [a nuclear factor erythroid 2-related factor 2 (Nrf2) inhibitor, 30 mg/kg] (n=10 each). The number and body weight of the live offspring rats were measured for each group. Hematoxylin-eosin staining was used to observe the pathological morphology of the uterus and placenta of pregnant rats and the pathological morphology of the brain tissue of offspring rats. Immunofluorescent staining was used to measure the co-expression of ionized calcium binding adaptor molecule-1 (IBA-1) and nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) in the cerebral cortex of offspring rats. ELISA was used to measure the levels of interleukin-6 (IL-6), interleukin-8 (IL-8), and interleukin-1β (IL-1β) in the brain tissue of offspring rats. Western blotting was used to measure the expression of Nrf2 pathway-related proteins in the brain tissue of offspring rats.@*RESULTS@#Pathological injury was found in the uterus, and placenta tissue of the pregnant rats and the brain tissue of the offspring rats, and severe microglia pyroptosis occurred in the cerebral cortex of the offspring rats in the model group. Compared with the control group, the model group had significant reductions in the number and body weight of the live offspring rats and the protein expression levels of Nrf2 and heme oxygenase-1 (HO-1) in the brain tissue of the offspring rats (P<0.05), but significant increases in the relative fluorescence intensity of the co-expression of IBA-1 and NLRP3, the levels of the inflammatory factors IL-6, IL-8, and IL-1β, and the protein expression levels of NLRP3 and caspase-1 in the brain tissue of the offspring rats (P<0.05). Compared with the model group, the breviscapine administration groups showed alleviated pathological injury of the uterus and placenta tissue of the pregnant rats and the brain tissue of the offspring rats, significant increases in the number and body weight of the live offspring rats and the protein expression levels of Nrf2 and HO-1 in the brain tissue of the offspring rats (P<0.05), and significant reductions in the relative fluorescence intensity of the co-expression of IBA-1 and NLRP3, the levels of the inflammatory factors IL-6, IL-8, and IL-1β, and the protein expression levels of NLRP3 and caspase-1 in the brain tissue of the offspring rats (P<0.05). The high-dose breviscapine group had a significantly better effect than the low-dose breviscapine (P<0.05). ML385 significantly inhibited the intervention effect of high-dose breviscapine (P<0.05).@*CONCLUSIONS@#Breviscapine can inhibit inflammatory response in brain tissue of preterm rats caused by intrauterine inflammation by activating the Nrf2 pathway, and it can also inhibit microglial pyroptosis and alleviate brain injury.

Supplementation with dietary omega-3 PUFA mitigates fetal brain inflammation and mitochondrial damage caused by high doses of sodium nitrite in maternal rats.

OBJECTIVE: Food safety and nutrition during pregnancy are important concerns related to fetal brain development. In the present study, we aimed to explore the effects of omega-3 polyunsaturated fatty acids (PUFA ω-3) on exogenous sodium nitrite intervention-induced fetal brain injury in pregnant rats. METHODS: During pregnancy, rats were exposed to water containing sodium nitrite (0.05%, 0.15%, and 0.25%) to establish a fetal rat brain injury model. Inflammatory factors and oxidative stress levels were detected using enzyme-linked immunosorbent assay (ELISA) or flow cytometry. Subsequently, animals were divided into three groups: control, model, and 4% PUFA ω-3. Pregnancy outcomes were measured and recorded. Hematoxylin-eosin (H&E) staining and immunohistochemistry (IHC) were utilized to observe brain injury. ELISA, quantitative real-time PCR (qRT-PCR), western blot, flow cytometry, and transmission electron microscopy (TEM) were adopted to measure the levels of inflammatory factors, the NRF1/HMOX1 signaling pathway, and mitochondrial and oxidative stress damage. RESULTS: With the increase of sodium nitrite concentration, the inflammatory factors and oxidative stress levels increased. Therefore, the high dose group was set as the model group for the following experiments. After PUFA ω-3 treatment, the fetal survival ratio, average body weight, and brain weight were elevated. The cells in the PUFA ω-3 group were more closely arranged and more round than the model. PUFA ω-3 treatment relieved inflammatory factors, oxidative stress levels, and mitochondria damage while increasing the indicators related to brain injury and NRF1/HMOX1 levels. CONCLUSIONS: Sodium nitrite exposure during pregnancy could cause brain damage in fetal rats. PUFA ω-3 might help alleviate brain inflammation, oxidative stress, and mitochondrial damage, possibly through the NRF1/HMOX1 signaling pathway. In conclusion, appropriately reducing sodium nitrite exposure and increasing PUFA omega-3 intake during pregnancy may benefit fetal brain development. These findings could further our understanding of nutrition and health during pregnancy.

Dose-Dependent Neuroprotective Effects of Bovine Lactoferrin Following Neonatal Hypoxia-Ischemia in the Immature Rat Brain.

Injuries to the developing brain due to hypoxia-ischemia (HI) are common causes of neurological disabilities in preterm babies. HI, with oxygen deprivation to the brain or reduced cerebral blood perfusion due to birth asphyxia, often leads to severe brain damage and sequelae. Injury mechanisms include glutamate excitotoxicity, oxidative stress, blood-brain barrier dysfunction, and exacerbated inflammation. Nutritional intervention is emerging as a therapeutic alternative to prevent and rescue brain from HI injury. Lactoferrin (Lf) is an iron-binding protein present in saliva, tears, and breast milk, which has been shown to have antioxidant, anti-inflammatory and anti-apoptotic properties when administered to mothers as a dietary supplement during pregnancy and/or lactation in preclinical studies of developmental brain injuries. However, despite Lf's promising neuroprotective effects, there is no established dose. Here, we tested three different doses of dietary maternal Lf supplementation using the postnatal day 3 HI model and evaluated the acute neurochemical damage profile using 1H Magnetic Resonance Spectroscopy (MRS) and long-term microstructure alterations using advanced diffusion imaging (DTI/NODDI) allied to protein expression and histological analysis. Pregnant Wistar rats were fed either control diet or bovine Lf supplemented chow at 0.1, 1, or 10 g/kg/body weight concentration from the last day of pregnancy (embryonic day 21-E21) to weaning. At postnatal day 3 (P3), pups from both sexes had their right common carotid artery permanently occluded and were exposed to 6% oxygen for 30 min. Sham rats had the incision but neither surgery nor hypoxia episode. At P4, MRS was performed on a 9.4 T scanner to obtain the neurochemical profile in the cortex. At P4 and P25, histological analysis and protein expression were assessed in the cortex and hippocampus. Brain volumes and ex vivo microstructural analysis using DTI/NODDI parameters were performed at P25. Acute metabolic disturbance induced in cortical tissue by HIP3 was reversed with all three doses of Lf. However, data obtained from MRS show that Lf neuroprotective effects were modulated by the dose. Through western blotting analysis, we observed that HI pups supplemented with Lf at 0.1 and 1 g/kg were able to counteract glutamatergic excitotoxicity and prevent metabolic failure. When 10 g/kg was administered, we observed reduced brain volumes, increased astrogliosis, and hypomyelination, pointing to detrimental effects of high Lf dose. In conclusion, Lf supplementation attenuates, in a dose-dependent manner, the acute and long-term cerebral injury caused by HI. Lf reached its optimal effects at a dose of 1 g/kg, which pinpoints the need to better understand effects of Lf, the pathways involved and possible harmful effects. These new data reinforce our knowledge regarding neuroprotection in developmental brain injury using Lf through lactation and provide new insights into lactoferrin's neuroprotection capacities and limitation for immature brains.

Transvenous Diaphragm Neurostimulation Mitigates Ventilation-associated Brain Injury.

Rationale: Mechanical ventilation (MV) is associated with hippocampal apoptosis and inflammation, and it is important to study strategies to mitigate them. Objectives: To explore whether temporary transvenous diaphragm neurostimulation (TTDN) in association with MV mitigates hippocampal apoptosis and inflammation after 50 hours of MV. Methods: Normal-lung porcine study comparing apoptotic index, inflammatory markers, and neurological-damage serum markers between never-ventilated subjects, subjects undergoing 50 hours of MV plus either TTDN every other breath or every breath, and subjects undergoing 50 hours of MV (MV group). MV settings in volume control were Vt of 8 ml/kg, and positive end-expiratory pressure of 5 cm H2O. Measurements and Main Results: Apoptotic indices, microglia percentages, and reactive astrocyte percentages were greater in the MV group in comparison with the other groups (P < 0.05). Transpulmonary pressure at baseline and at study end were both lower in the group receiving TTDN every breath, but lung injury scores and systemic inflammatory markers were not different between the groups. Serum concentrations of four neurological-damage markers were lower in the group receiving TTDN every breath than in the MV group (P < 0.05). Heart rate variability declined significantly in the MV group and increased significantly in both TTDN groups over the course of the experiments. Conclusions: Our study found that mechanical ventilation is associated with hippocampal apoptosis and inflammation, independent of lung injury and systemic inflammation. Also, in a porcine model, TTDN results in neuroprotection after 50 hours, and the degree of neuroprotection increases with greater exposure to TTDN.

Angelica gigas root ameliorates ischaemic stroke-induced brain injury in mice by activating the PI3K/AKT/mTOR and MAPK pathways.

CONTEXT: Traditionally, the root of Angelica gigas Nakai (Umbelliferae), has long been used to treat ischaemic diseases and is considered safe in humans. OBJECTIVE: To investigate the neuroprotective effects of a methanol extract of A. gigas root (AGmex) on the middle cerebral artery occlusion (MCAO)-induced brain injury in mice, and the underlying mechanisms. MATERIALS AND METHODS: Two hours of transient MCAO (tMCAO) was induced in C57BL/6 mice (MCAO control group and AGmex groups), AGmex was administered to the AGmex group at 300-3,000 mg/kg bw at 1, 1, and 24 h before tMCAO or at 1000 mg/kg bw at 1 h before and after tMCAO. Infarction volumes, tissue staining, and western blotting were used to investigate the mechanism underlying the neuroprotective effects of AGmex. RESULTS: The median effective dose (ED50) could not be measured because the AGmex treatment did not reduce the infarction volume caused by 2 h of tMCAO to within 50%; however, pre-treatment with AGmex twice at 1,000 mg/kg bw before tMCAO significantly reduced the infarction volumes. The proteins related to cell growth, differentiation, and death were upregulated by this treatment, and the major recovery mechanisms appeared to involve the attenuation of the mitochondrial function of Bcl-2/Bax and activation of the PI3K/AKT/mTOR and MAPK signalling pathways in ischaemic neurons. CONCLUSIONS: This study provides evidence supporting the use of A. gigas root against ischaemic stroke and suggests a novel developmental starting point for the treatment of ischaemic stroke.

Preventing Brain Injury in the Preterm Infant-Current Controversies and Potential Therapies.

Preterm birth is associated with a high risk of morbidity and mortality including brain damage and cerebral palsy. The development of brain injury in the preterm infant may be influenced by many factors including perinatal asphyxia, infection/inflammation, chronic hypoxia and exposure to treatments such as mechanical ventilation and corticosteroids. There are currently very limited treatment options available. In clinical trials, magnesium sulfate has been associated with a small, significant reduction in the risk of cerebral palsy and gross motor dysfunction in early childhood but no effect on the combined outcome of death or disability, and longer-term follow up to date has not shown improved neurological outcomes in school-age children. Recombinant erythropoietin has shown neuroprotective potential in preclinical studies but two large randomized trials, in extremely preterm infants, of treatment started within 24 or 48 h of birth showed no effect on the risk of severe neurodevelopmental impairment or death at 2 years of age. Preclinical studies have highlighted a number of promising neuroprotective treatments, such as therapeutic hypothermia, melatonin, human amnion epithelial cells, umbilical cord blood and vitamin D supplementation, which may be useful at reducing brain damage in preterm infants. Moreover, refinements of clinical care of preterm infants have the potential to influence later neurological outcomes, including the administration of antenatal and postnatal corticosteroids and more accurate identification and targeted treatment of seizures.

The poly-ADP ribose polymerase-1/apoptosis-inducing factor pathway may help mediate the protective effect of electroacupuncture on early brain injury after subarachnoid hemorrhage.

Subarachnoid hemorrhage (SAH) is a clinically common, acute, critical cerebrovascular disease associated with high mortality. Here, we investigated the effects of electroacupuncture on early brain injury after SAH. We successfully established a Sprague-Dawley rat model of the SAH model, and randomly divided the rats into four groups: sham-operated group, SAH group, positive control group, and electroacupuncture group. Electroacupuncture effectively decreased the number of transferase UTP nick end labeling-positive cells and extent of DNA fragmentation compared with the control, indicating a decrease in apoptosis. Moreover, electroacupuncture decreased the expression of proteins involved in the poly-ADP ribose polymerase-1/apoptosis-inducing factor (PARP-1/AIF) pathway in vivo, and the difference was statistically significant (P < 0.05). Treatment with electroacupuncture resulted in a significant improvement in neurological function. It inhibited the increase in blood-brain barrier permeability by regulating the protein expression of matrix metalloproteinase-9, occludin, and claudin-5. Additionally, electroacupuncture limited the development of cerebral edema and microglial activation in early brain injury after SAH. In conclusion, electroacupuncture can ameliorate early brain injury after SAH, and this may occur via inhibition of the PARP-1/AIF pathway.

The green tea polyphenolic catechin epigallocatechin gallate and neuroprotection.

Epigallocatechin gallate is the most abundant composition of the tea catechins and is thought to be responsible for the majority of biological activity of green tea extracts such as antioxidant, anti-inflammatory, and antiapoptotic effects. Meanwhile, EGCG has been shown to be some of the neuroprotective effects against neural injuries and neurodegenerative diseases. This paper summarizes current knowledge on neuroprotective effects of EGCG and their molecular mechanisms responsible for the neuroprotection in various models of neurodegenerative and neural injury.

Electroacupuncture protects rats from ischemic brain injury via coffilin in mice.

BACKGROUND: This study aimed to study the expression level of cofilin after electroacupuncture (EA) pretreatment, using ischemic brain injury model in mice. In addition, infarct volume and neurological functions were measured to understand whether electroacupuncture stimulation could restore the functions of the brain. METHODS: Total of 36 mice was randomly divided into three groups: sham group, middle cerebral artery occlusion model (MACO), and middle cerebral artery occlusion model pretreated with EA (MACO + EA). Mice were stimulated at "Baihui (G20)" and "Dazhui (G14)" 24 hours before focal cerebral ischemia. Infarct volume and neuronal function of brain tissue were scored among different experimental groups. The expression level of cofilin and phosphocofilin of brain tissue were evaluated by using Western blot analysis. TUNEL assay was performed to determine the degree of cell apoptosis. RESULTS: Compared with the sham group, the level of cofilin was dramatically reduced in the MACO group. EA pretreatment could reduce the protein level of cofilin, while EA therapy could also upregulate the protein level of phosphocofilin. Improved neuronal function, smaller infarct volume, and reduced neuronal apoptosis were observed among the mice underwent EA before middle artery occlusion. CONCLUSION: Our results from Western blot analysis and TUNEL assay might suggest that the upregulation of cofilin was concerned with the EA protects rats from ischemic brain injury. Cofilin might be a potential target for developing drugs against brain ischemia.

Curcumin Prevents Cerebellar Hypoplasia and Restores the Behavior in Hyperbilirubinemic Gunn Rat by a Pleiotropic Effect on the Molecular Effectors of Brain Damage.

Bilirubin toxicity to the central nervous system (CNS) is responsible for severe and permanent neurologic damage, resulting in hearing loss, cognitive, and movement impairment. Timely and effective management of severe neonatal hyperbilirubinemia by phototherapy or exchange transfusion is crucial for avoiding permanent neurological consequences, but these therapies are not always possible, particularly in low-income countries. To explore alternative options, we investigated a pharmaceutical approach focused on protecting the CNS from pigment toxicity, independently from serum bilirubin level. To this goal, we tested the ability of curcumin, a nutraceutical already used with relevant results in animal models as well as in clinics in other diseases, in the Gunn rat, the spontaneous model of neonatal hyperbilirubinemia. Curcumin treatment fully abolished the landmark cerebellar hypoplasia of Gunn rat, restoring the histological features, and reverting the behavioral abnormalities present in the hyperbilirubinemic rat. The protection was mediated by a multi-target action on the main bilirubin-induced pathological mechanism ongoing CNS damage (inflammation, redox imbalance, and glutamate neurotoxicity). If confirmed by independent studies, the result suggests the potential of curcumin as an alternative/complementary approach to bilirubin-induced brain damage in the clinical scenario.

Dexmedetomidine inhibits neuronal apoptosis by inducing Sigma-1 receptor signaling in cerebral ischemia-reperfusion injury.

Dexmedetomidine is known to alleviate cerebral ischemia-reperfusion injury (CIRI). We established a rat model of CIRI, which exhibited higher neurological deficit scores and a greater number of apoptotic cells in the cerebral ischemic penumbra than controls. Dexmedetomidine reversed the neuronal apoptosis and improved neurological function in this model. We then examined Sigma-1 receptor (Sig-1R) expression on the endoplasmic reticulum (ER) in brain tissues at different reperfusion time points. Sig-1R expression increased with CIRI and decreased with increasing reperfusion times. After 24 hours of reperfusion, dexmedetomidine upregulated Sig-1R expression, and ER stress proteins (GRP78, CHOP, JNK and Caspase-3) were detected in brain tissues with Western blotting. Moreover, GRP78 expression followed a pattern similar to Sig-1R. Dexmedetomidine induced GRP78 expression but inhibited CHOP, Caspase-3 and phosphorylated-JNK expression in brain tissues. A Sig-1R-specific inhibitor reduced GRP78 expression and partially inhibited the upregulation of GRP78 by dexmedetomidine. The inhibitor also increased CHOP and Caspase-3 expression and partially reversed the inhibitory effects of dexmedetomidine on these pro-apoptotic ER stress proteins. These results suggest that dexmedetomidine at least partially inhibits ER stress-induced apoptosis by activating Sig-1R, thereby attenuating brain damage after 24 hours of ischemia-reperfusion.

M2 microglia-derived exosomes protect the mouse brain from ischemia-reperfusion injury via exosomal miR-124.

Rationale: Microglia play a critical role in modulating cell death and neurobehavioral recovery in response to brain injury either by direct cell-cell interaction or indirect secretion of trophic factors. Exosomes secreted from cells are well documented to deliver bioactive molecules to recipient cells to modulate cell function. Here, we aimed to identify whether M2 microglia exert neuroprotection after ischemic attack through an exosome-mediated cell-cell interaction. Methods: M2 microglia-derived exosomes were intravenously injected into the mouse brain immediately after middle cerebral artery occlusion. Infarct volume, neurological score, and neuronal apoptosis were examined 3 days after ischemic attack. Exosome RNA and target protein expression levels in neurons and brain tissue were determined for the mechanistic study. Results: Our results showed that the M2 microglia-derived exosomes were taken up by neurons in vitro and in vivo. M2 microglia-derived exosome treatment attenuated neuronal apoptosis after oxygen-glucose deprivation (p<0.05). In vivo results showed that M2 microglia-derived exosome treatment significantly reduced infarct volume and attenuated behavioral deficits 3 days after transient brain ischemia (p<0.05), whereas injection of miR-124 knockdown (miR-124k/d) M2 microglia-derived exosomes partly reversed the neuroprotective effect. Our mechanistic study further demonstrated that ubiquitin-specific protease 14 (USP14) was the direct downstream target of miR-124. Injection of miR-124k/d M2 exosomes plus the USP14 inhibitor, IU1, achieved comparable neuroprotective effect as injection of M2 exosomes alone. Conclusions: We demonstrated that M2 microglia-derived exosomes attenuated ischemic brain injury and promoted neuronal survival via exosomal miR-124 and its downstream target USP14. M2 microglia-derived exosomes represent a promising avenue for treating ischemic stroke.

Preventing childhood and lifelong disability: Maternal dietary supplementation for perinatal brain injury.

The majority of brain injuries that lead to cerebral palsy, developmental disability, and mental health disorders have their onset in utero. These lifelong conditions come with great economic and emotional burden as they impact function in nearly all domains of affected individuals' lives. Unfortunately, current therapeutic options are limited. There remains a focus on rescue, rehabilitation, and regeneration after the injury has occurred, rather than aiming to prevent the initial injury. Prevention would imply treating the mother during pregnancy to alter the fetal environment and in turn, treat the fetus. Fear of harming the developing fetus remains as a result of errors of the past such as the release of thalidomide. In this review, we outline evidence from animal studies and clinical trials that have explored maternal dietary supplementation with natural health products (including nutraceuticals and functional foods) for perinatal brain injury prevention. Namely, we discuss magnesium sulphate, creatine, choline, melatonin, resveratrol and broccoli sprouts/sulforaphane. Although clinical trials have only been completed in this realm for magnesium sulphate, results in animal models have been promising, suggesting that this is a productive avenue for further research. Natural health products may provide safe, effective, affordable, and easily accessible prevention of fetal brain injury and resulting lifelong disabilities.

Acteoside Attenuates Oxidative Stress and Neuronal Apoptosis in Rats with Focal Cerebral Ischemia-Reperfusion Injury.

Acteoside (ACT) has been shown to exert antioxidant and neuroprotective effects in neurodegenerative diseases. However, the effect of ACT on cerebral ischemia-reperfusion (I/R) injury is not yet clear. In this study, we found that ACT administration reduced infarct volume and brain edema, and improved neurological deficits, as indicated by the decreased modified neurological severity score. Administration of ACT strikingly reduced oxidative stress, accompanied by decreased levels of reactive oxygen species and malondialdehyde and increased levels of superoxide dismutase and catalase in a rat model of middle cerebral artery occlusion/reperfusion (MCAO/R). Furthermore, ACT administration reduced the number of terminal deoxynucleotidyl transferase uridine 5'-triphosphate (UTP) nick-end labeling-positive cells in the cerebral cortex of ischemic side of MCAO/R rats, accompanied by downregulation of B cell lymphoma 2 (Bcl-2) associated X protein and cleaved caspase-3 proteins and upregulation of Bcl-2 protein. Additionally, ACT treatment inhibited the protein kinase R/eukaryotic initiation factor-2α stress pathway in the brains of MCAO/R rats. Our results demonstrated that ACT attenuates oxidative stress and neuronal apoptosis in MCAO/R rats, suggesting that ACT may serve as a novel therapeutic candidate for the treatment of I/R brain injury.

Tetramethylpyrazine Protects Against Early Brain Injury and Inhibits the PERK/Akt Pathway in a Rat Model of Subarachnoid Hemorrhage.

Neuronal apoptosis is a potentially fatal pathological process that occurs in early brain injury (EBI) after subarachnoid hemorrhage (SAH). There is an urgent need to identify effective therapeutics to alleviate neuronal apoptosis. Tetramethylpyrazine (TMP), as an important component of the Chinese traditional medicinal herb Ligusticum wallichii, has been widely used in China to treat cerebral ischemic injury and confer neuroprotection. In the present work, we investigate whether TMP can reduce EBI following SAH in rats, specifically via inactivating the PERK/Akt signaling cascade. One hundred twenty-five male Sprague-Dawley rats were used in the present study. TMP was administered by intravenous (i.v.) injection, and the Akt inhibitor MK2206 was injected intracerebroventricularly (i.c.v.). SAH grade, neurological scores, and brain water content were measured 24 h after SAH. Neuronal apoptosis was visualized by Fluoro-Jade C (FJC) staining. Western blotting was used to measure the levels of PERK, p-PERK, eIF2α, p-eIF2α, Akt, p-Akt, Bcl-2, Bax, and cleaved caspase-3. Our results showed that TMP effectively reduced neuronal apoptosis and improved neurobehavioral deficits 24 h after SAH. Administration of TMP reduced the abundance of p-PERK and p-eIF2α. In addition, TMP increased the p-Akt level and the Bcl-2/Bax ratio and decreased the level of cleaved caspase-3. The selective Akt inhibitor MK2206 abolished the anti-apoptotic effect of TMP at 24 h after SAH. Collectively, these results indicate that Akt-related anti-apoptosis through the PERK pathway is a major, potent mechanism of EBI. Further investigation of this pathway may provide a basis for the development of TMP as a clinical treatment.

Pretreatment with taurine prevented brain injury and exploratory behaviour associated with administration of anticancer drug cisplatin in rats.

The neurotoxicity associated with cisplatin treatment is one of the major side effects compromising the efficacy of the anti-cancer treatment. The present study investigated the possible protective effects of taurine, an intracellular amino acid, on cisplatin-induced brain injury and exploratory behaviour using five groups of ten female rats each. Group I received drinking water only. Group II orally received taurine alone at 200 mg/kg whereas Group III received cisplatin alone intraperitoneally at 10 mg/kg. Groups IV and V were treated with taurine at 100 and 200 mg/kg respectively for sixteen consecutive days and a single intraperitoneal injection of cisplatin on day 13 to induce neurotoxicity. Endpoint analyses using video-tracking software revealed that cisplatin administration alone caused neurobehavioral deficits evinced by marked decrease in the total distance travelled, average speed, total time mobile, total mobile episode, number of crossing and absolute turn angle. Furthermore, cisplatin alone significantly suppressed brain antioxidant defense mechanisms, elevated nitric oxide and lipid peroxidation levels whereas it increased acetylcholinesterase activity in the treated rats. However, rats pretreated with taurine exhibited significant improvement in behavioural performance and brain antioxidant status with concomitant decrease in acetylcholinesterase activity and oxidative stress indices when compared with cisplatin alone group. Histologically, taurine pretreatment prevented cisplatin-induced neuronal death in the cerebral and cerebellar cortices, caudo-putamen and hippocampus as well as abrogated cisplatin-mediated decrease in the dendritic arborization and mean diameter of the somata of pyramidal neurons in the treated rats. In conclusion, taurine may be a possible protective supplement to reduce cisplatin-induced side-effects including neurotoxicity in patients undergoing cisplatin treatment.

Estrogen receptor-ß of microglia underlies sexual differentiation of neuronal protection via ginsenosides in mice brain.

AIMS: Streptococcus pneumoniae infection in acute bacterial meningitis can lead to widespread brain damage and mortality. Inflammatory responses by immune cells in the brain are thought to determine the degree of brain injury. Yet, the mechanisms underlying host responses to pneumococcal meningitis are largely unknown. To explore host responses as a potential therapeutic target for preventing brain injury after pneumococcal meningitis. METHODS: We evaluated signaling mechanisms that minimize neuronal damage caused by pneumococcal infection; specifically, we assessed pathways related to neuronal survival after enhancing estrogen receptor-ß (ER-ß) expression using a natural therapeutic substance known as ginsenoside Rb1 and Rg3 enhanced ginseng. RESULTS: Tissue damage caused by bacterial infection was reduced in Rb1/Rg3-treated mice as a result of microglial activation and the inhibition of apoptosis. Furthermore, Rb1 upregulated the expression of brain-derived neurotrophic factor (BDNF) as well as anti-apoptotic factors including Bcl-2 and Bcl-xL. Using BV2 microglial cells in vitro, Rb1 treatment inhibited microglial apoptosis in a manner associated with JAK2/STAT5 phosphorylation. CONCLUSION: After S. pneumoniae infection in mice, particularly in female mice, Rb1-containing ginseng increased bacterial clearance and survival. These findings inform our understanding of the host immune response to pneumococcal meningitis.

Patchouli alcohol protects against ischemia/reperfusion-induced brain injury via inhibiting neuroinflammation in normal and obese mice.

Almost all of the candidate drugs for ischemic stroke failed to be translated from bench to beside. One important reason is that animals used in experimental studies cannot mimic ischemic patients due to lack of comorbidities like hypertension, diabetes and obesity. Therefore, it is better to test candidate drugs not only in normal animals but also in animals with comorbidities. Patchouli alcohol (PA), a natural tricyclic sesquiterpene in the traditional Chinese herb Pogostemonisherba, is well recognized for its anti-inflammation function in various inflammatory diseases. And as inflammation plays a very important role in cerebral ischemia/reperfusion (I/R) injury process and determines the ultimate brain damage, we hypothesized that PA could protect against cerebral I/R injury through its anti-inflammation ability. In this study, the effects of PA on cerebral I/R injury were evaluated in normal mice and obese mice. In normal mice with cerebral I/R injury, PA treatment reduced the infarct volume and neurological deficits in a dose- and time-dependent manner. PA treatment alleviated BBB dysfunction, inhibited mRNA and protein levels of TNF-α and IL-1ß and modulated the activation of MAPKs signaling pathways. Moreover, PA also reduced infarct volume, alleviated the BBB dysfunction and inhibited inflammation in ob/ob mice with cerebral I/R injury. In conclusion, we demonstrated for the first time that PA could protect against cerebral I/R injury not only in normal mice but also in obese mice via inhibiting inflammation, suggesting that PA can be a potential drug for clinical treatment of ischemic stroke.