Brain Ischemia-reperfusion Injury Research Articles

Per- and post-remote ischemic conditioning attenuates ischemic brain injury via inhibition of the TLR4/MyD88 signaling pathway in aged rats.

Remote ischemic conditioning (RIC), as an emerging protective method, might be used clinically to prevent ischemia-reperfusion injury (IRI) in ischemic stroke. In this study, we aim to investigate whether RIC performed either during brain ischemia or after reperfusion has a protective effect and further explore the mechanistic basis for the protective effects of RIC against IRI in an aged rat model. We investigated brain IRI in 16-18months old SD rats. Animals underwent: (i) sham laparotomy, (ii) brain IRI, (iii) brain IRI + RIC during ischemia (IRI + RIperC), or (iv) brain IRI + RIC after reperfusion (IRI + RIpostC). RIC consists of three cycles of 10min of hind limb ischemia followed by 10min reperfusion. After 24h of reperfusion, the infarct size, neurological deficit scores and brain oedema were assessed in all groups. The levels of IL-1β, IL-6, TNF-α were measured by ELISA. The mRNA and protein expressions of TLR4, MyD88, TRAF6 and NF-κB were detected by RT-PCR and western blot. Both RIperC and RIpostC treatment attenuated the IRI-induced neuronal injury, reflected by reductions in the infarct size, neurological deficit scores and brain oedema. RIperC and RIpostC also can decrease the concentration of IL-1β, IL-6, TNF-α in IRI. From the results of RT-PCR and western blot, we found that RIC decreased the mRNA and protein expression of TLR4, MyD88, TRAF6 and NF-κB compared to that in the IRI group. The present study suggested that RIC protected aged rats against IRI, and this protective effect might be mediated by inhibiting the TLR-4/MyD88/TRAF-6/NF-κB signaling pathway.

The selective alpha7 nicotinic acetylcholine receptor agonist AR-R17779 does not affect ischemia-reperfusion brain injury in mice.

Inflammation plays a central role in stroke-induced brain injury. The alpha7 nicotinic acetylcholine receptor (α7nAChR) can modulate immune responses in both the periphery and the brain. The aims of the present study were to investigate α7nAChR expression in different brain regions and evaluate the potential effect of the selective α7nAChR agonist AR-R17779 on ischemia–reperfusion brain injury in mice. Droplet digital PCR (ddPCR) was used to evaluate the absolute expression of the gene encoding α7nAChR (Chrna7) in hippocampus, striatum, thalamus and cortex in adult, naïve mice. Mice subjected to transient middle cerebral artery occlusion (tMCAO) or sham surgery were treated with α7nAChR agonist AR-R17779 (12 mg/kg) or saline once daily for 5 days. Infarct size and microglial activation 7 days after tMCAO were analyzed using immunohistochemistry. Chrna7 expression was found in all analyzed brain regions in naïve mice with the highest expression in cortex and hippocampus. At sacrifice, white blood cell count was significantly decreased in AR-R17779 treated mice compared with saline controls in the sham groups, although, no effect was seen in the tMCAO groups. Brain injury and microglial activation were evident 7 days after tMCAO. However, no difference was found between mice treated with saline or AR-R17779. In conclusion, α7nAChR expression varies in different brain regions and, despite a decrease in white blood cells in sham mice receiving AR-R17779, this compound does not affect stroke-induced brain injury.

Long non-coding RNA THRIL inhibits miRNA-24-3p to upregulate neuropilin-1 to aggravate cerebral ischemia-reperfusion injury through regulating the nuclear factor κB p65 signaling.

Purpose: The aim of this study was to investigate the role of the tumor necrosis factor and HNRNPL related immunoregulatory long non-coding RNA (THRIL) in cerebral ischemia-reperfusion injury.Methods: A rat middle cerebral artery occlusion/ischemia-reperfusion (MCAO/IR) model and an oxygen glucose deprivation/reoxygenation (OGD/R) cell model were constructed. THRIL was knocked down using siTHRIL. Neurological deficit score was detected based on the criteria of Zea-Longa. Brain region 2,3,5-Triphenyltetrazolium (TTC) staining and quantitative analysis of cerebral infarction volume, RT-qPCR, and fluorescence immunostaining were performed for assessing THRIL expression. MTT assay was used to detect the cell proliferation ability after transfection, TUNEL assay was applied to detect apoptosis, and western blot and ELISA detected related protein expression. A dual luciferase reporter system and RIP assay were used to confirm the target relationship.Results: THRIL was upregulated in both in vitro and in vivo models of brain ischemia-reperfusion injury. Knockdown of THRIL attenuated OGD/R neuronal apoptosis and OGD/R-induced inflammation. THRIL targeted and regulated the expression of miR-24-3p/neuropilin-1 (NRP1) axis. THRIL silencing significantly improved the neurological functioning of rats in the MCAO/R model by miR-24-3p/NRP1/NF-κB p65 signaling pathway.Conclusion: THRIL could aggravate cerebral ischemia-reperfusion injury by competitively binding to miR-24-3p to promote the upregulation of NRP1 and further promoted the activation of the NF-κB p65 signaling pathway.

MircoRNA-29a in Astrocyte-derived Extracellular Vesicles Suppresses Brain Ischemia Reperfusion Injury via TP53INP1 and the NF-κB/NLRP3 Axis.

Brain ischemia reperfusion injury (BIRI) is defined as a series of brain injury accompanied by inflammation and oxidative stress. Astrocyte-derived extracellular vesicles (EVs) are importantly participated in BIRI with involvement of microRNAs (miRs). Our study aimed to discuss the functions of miR-29a from astrocyte-derived EVs in BIRI treatment. Thus, astrocyte-derived EVs were extracted. Oxygen and glucose deprivation (OGD) cell models and BIR rat models were established. Then, cell and rat activities and pyroptosis-related protein levels in these two kinds of models were detected. Functional assays were performed to verify inflammation and oxidative stress. miR-29a expression in OGD cells and BIR rats was measured, and target relation between miR-29a and tumor protein 53-induced nuclear protein 1 (TP53INP1) was certified. Rat neural function was tested. Astrocyte-derived EVs improved miR-29a expression in N9 microglia and rat brains. Astrocyte-derived EVs inhibited OGD-induced injury and inflammation in vitro, reduced brain infarction, and improved BIR rat neural functions in vivo. miR-29a in EVs protected OGD-treated cells and targeted TP53INP1, whose overexpression suppressed the protective function of EVs on OGD-treated cells. miR-29a alleviated OGD and BIRI via downregulating TP53INP1 and the NF-κB/NLRP3 pathway. Briefly, our study demonstrated that miR-29a in astrocyte-derived EVs inhibits BIRI by downregulating TP53INP1 and the NF-κB/NLRP3 axis.

Role of pERK1/2-NFκB signaling in the neuroprotective effect of thalidomide against cerebral ischemia reperfusion injury in rats

In the present investigation, we tested the hypothesis that suppression of the phospho-extracellular signal regulated kinase (pERK1/2)-nuclear factor kappa (NFκ)-B signaling, subsequent to tumor necrosis factor-α (TNF-α) inhibition, underlies thalidomide (TLM) mediated neuroprotection. Male Wistar rats (250–280 g) were divided into five groups: (1) sham; (2) negative control receiving TLM (5μg/1μl/site) and 3 groups of ischemia-reperfusion (IR) injury rats pretreated with: (3) vehicle (DMSO 100%); (4) TLM (5μg/1μl/site) or (5) PD98059 (0.16μg/1μl/site). IR rats were subjected to occlusion of both common carotid arteries for 45 min followed by reperfusion for 24 h. Drugs and/or vehicles were administered by unilateral intrahippocampal injection after removal of the carotid occlusion and at the beginning of the reperfusion period. IR rats exhibited significant infarct size, histopathological damage, memory impairment, motor incoordination and hyperactivity. Unilateral intra-hippocampal TLM ameliorated these behavioral deficits along with the following ex vivo hippocampal effects: (i) abrogation of the IR-evoked elevations in hippocampal TNF-α, pERK1/2, NFκB, BDNF, iNOS contents and (ii) partial restoration of the reduced anti-inflammatory cytokine IL-10 and p-nNOS S852. These neurochemical effects, which were replicated by the pERK1/2 inhibitor PD98059, likely underlie the reductions in c-Fos and caspase-3 levels as well as the anti-apoptotic effect of TLM in the IR model. These results suggest a crucial anti-inflammatory role for pERK1/2 inhibition in the salutary neuronal and behavioral effects of TLM in a model of brain IR injury.

Microglia exosomal miRNA-137 attenuates ischemic brain injury through targeting Notch1.

Microglia are the resident immune cells in the central nervous system and play an essential role in brain homeostasis and neuroprotection in brain diseases. Exosomes are crucial in intercellular communication by transporting bioactive miRNAs. Thus, this study aimed to investigate the function of microglial exosome in the presence of ischemic injury and related mechanism. Oxygen-glucose deprivation (OGD)-treated neurons and transient middle cerebral artery occlusion (TMCAO)-treated mice were applied in this study. Western blotting, RT-PCR, RNA-seq, luciferase reporter assay, transmission electron microscope, nanoparticle tracking analysis, immunohistochemistry, TUNEL and LDH assays, and behavioral assay were applied in mechanistic and functional studies. The results demonstrated that exosomes derived from microglia in M2 phenotype (BV2-Exo) were internalized by neurons and attenuated neuronal apoptosis in response to ischemic injury in vitro and in vivo. BV2-Exo also decreased infarct volume and behavioral deficits in ischemic mice. Exosomal miRNA-137 was upregulated in BV2-Exo and participated in the partial neuroprotective effect of BV2-Exo. Furthermore, Notch1 was a directly targeting gene of exosomal miRNA-137. In conclusion, these results suggest that BV2-Exo alleviates ischemia-reperfusion brain injury through transporting exosomal miRNA-137. This study provides novel insight into microglial exosomes-based therapies for the treatment of ischemic brain injury.

Effects of Sulforaphane in brain ischemic reperfusion injury in rats

Effects of Sulforaphane in brain ischemic reperfusion injury in rats

Perioperative Dexmedetomidine attenuates brain ischemia reperfusion injury possibly via up-regulation of astrocyte Connexin 43

BackgroundAstrocyte Connexin 43 (Cx43) is essential for the trophic and protective support of neurons during brain ischemia reperfusion (I/R) injury. It is believed that dexmedetomidine participates in Cx43-mediated effects. However, its mechanisms remained unclear. This study aims to address the relationship and regulation among them.MethodsAdult male Sprague-Dawley rats were allocated to the 90-min right middle cerebral arterial occlusion with or without dexmedetomidine pretreatment (5 μg/kg). Neurological functions were evaluated and brain lesions, as well as inflammatory factors (IL-1β, IL-6, TNF-α), were assessed. Ischemic penumbral cortex was harvested to determine the expression of astrocyte Cx43. Primary astrocytes were cultured to evaluate the effect of dexmedetomidine on Cx43 after oxygen-glucose deprivation.ResultsDexmedetomidine pretreatment attenuated neurological injury, brain lesions and expression of inflammatory factors (IL-1β, IL-6, TNF-α) after brain ischemia (P < 0.05). Astrocyte Cx43 was down-regulated by brain I/R injury, both in vivo and in vitro, which were reversed by dexmedetomidine (P < 0.05). This effect was mediated by the phosphorylation of Akt and GSK-3β. Further studies with LY294002 (PI3K inhibitor) or SB216763 (GSK-3β inhibitor) confirmed the effect of dexmedetomidine on astrocyte Cx43.ConclusionsPerioperative dexmedetomidine administration attenuates neurological injury after brain I/R injury, possibly through up-regulation of astrocyte Cx43. Activation of PI3K-Akt-GSK-3β pathway might contribute to this protective effect.

Neuroprotective Effects of Molecular Hydrogen: A Critical Review.

Molecular hydrogen (H2) is a physiologically inert gas. However, during the last 10years, increasing evidence has revealed its biological functions under pathological conditions. More specifically, H2 has protective effects against a variety of diseases, particularly nervous system disorders, which include ischemia/reperfusion injury, traumatic injury, subarachnoid hemorrhage, neuropathic pain, neurodegenerative diseases, cognitive dysfunction induced by surgery and anesthesia, anxiety, and depression. In addition, H2 plays protective roles mainly through anti-oxidation, anti-inflammation, anti-apoptosis, the regulation of autophagy, and preservation of mitochondrial function and the blood-brain barrier. Further, H2 is easy to use and has neuroprotective effects with no major side-effects, indicating that H2 administration is a potential therapeutic strategy in clinical settings. Here we summarize the H2 donors and their pharmacokinetics. Meanwhile, we review the effectiveness and safety of H2 in the treatment of various nervous system diseases based on preclinical and clinical studies, leading to the conclusion that H2 can be a simple and effective clinical therapy for CNS diseases such as ischemia-reperfusion brain injury, Parkinson's disease, and diseases characterized by cognitive dysfunction. The potential mechanisms involved in the neuroprotective effect of H2 are also analyzed.

Cannabinoid CB1 receptor agonist ACEA alleviates brain ischemia/reperfusion injury via CB1\u2013Drp1 pathway

Activation of the cannabinoid CB1 receptor induces neuroprotection against brain ischemia/reperfusion injury (IRI); however, the mechanism is still unknown. In this study, we used oxygen-glucose deprivation/reoxygenation (OGD/R)-induced injury in neuronal cells and middle cerebral artery occlusion (MCAO)-induced brain IRI in rats to mimic ischemic brain injury, and hypothesized that the CB1 receptor agonist arachidonyl-2-chloroethylamide (ACEA) would protect ischemic neurons by inhibiting mitochondrial fission via dynamin-related protein 1 (Drp1). We found that OGD/R injury reduced cell viability and mitochondrial function, increased lactate dehydrogenase (LDH) release, and increased cell apoptosis, and mitochondrial fission. Notably, ACEA significantly abolished the OGD/R-induced neuronal injuries described above. Similarly, ACEA significantly reversed MCAO-induced increases in brain infarct volume, neuronal apoptosis and mitochondrial fission, leading to the recovery of neurological functions. The neuroprotective effects of ACEA were obviously blocked by coadministration of the CB1 receptor antagonist AM251 or by the upregulation of Drp1 expression, indicating that ACEA alleviates brain IRI via the CB1–Drp1 pathway. Our findings suggest that the CB1 receptor links aberrant mitochondrial fission to brain IRI, providing a new therapeutic target for brain IRI treatment.

Platelets as Mediators of Neuroinflammation and Thrombosis.

Beyond platelets function in hemostasis, there is emerging evidence to suggest that platelets contribute crucially to inflammation and immune responses. Therefore, considering the detrimental role of inflammatory conditions in severe neurological disorders such as multiple sclerosis or stroke, this review outlines platelets involvement in neuroinflammation. For this, distinct mechanisms of platelet-mediated thrombosis and inflammation are portrayed, focusing on the interaction of platelet receptors with other immune cells as well as brain endothelial cells. Furthermore, we draw attention to the intimate interplay between platelets and the complement system as well as between platelets and plasmatic coagulation factors in the course of neuroinflammation. Following the thorough exposition of preclinical approaches which aim at ameliorating disease severity after inducing experimental autoimmune encephalomyelitis (a counterpart of multiple sclerosis in mice) or brain ischemia-reperfusion injury, the clinical relevance of platelet-mediated neuroinflammation is addressed. Thus, current as well as future propitious translational and clinical strategies for the treatment of neuro-inflammatory diseases by affecting platelet function are illustrated, emphasizing that targeting platelet-mediated neuroinflammation could become an efficient adjunct therapy to mitigate disease severity of multiple sclerosis or stroke associated brain injury.

Histological Structure of Dentate Gyrus in Global Cerebral Ischemia/Reperfusion Injury and Role of Nitraetes in Protection

Background: Ischemia-reperfusion injury is a hell mark of stroke that happens if blood supply is returned back after a period of ischemia. However, the benefit from restored blood supply by reperfusion can cause bad effect compared to permanent occlusion. Objectives: This study aimed to analyze morphological alterations in dentate gyrus tissue during ischemia and its effects on histology of cells and to understand mechanisms of brain ischemia-reperfusion injury to develop effective therapy. Results: Many experiments proved that the mechanisms of ischemia-reperfusion injury include complement activation, leukocyte infiltration, oxidative stress, platelet adhesion and aggregation and mitochondrial-mediated mechanisms leading to blood-brain-barrier (BBB) disruption, which leads to brain edema. Conclusion: In summary, over the past few years there have been significant advancement in our understanding of molecular and cellular mechanisms of ischemia-reperfusion injury in the brain. The major mechanisms of reperfusion injury are clear but are still far from being clinically successful. Thus, further investigations on brain reperfusion injury mechanisms are wanted. Also, role of nitrates in protection for ischemia-reperfusion brain injury.

Histological Structure of Dentate Gyrus in Global Cerebral Ischemia/Reperfusion Injury and Role of Nitraetes in Protection

Background: Ischemia-reperfusion injury is a hell mark of stroke that happens if blood supply is returned back after a period of ischemia. However, the benefit from restored blood supply by reperfusion can cause bad effect compared to permanent occlusion. Objectives: This study aimed to analyze morphological alterations in dentate gyrus tissue during ischemia and its effects on histology of cells and to understand mechanisms of brain ischemia-reperfusion injury to develop effective therapy. Results: Many experiments proved that the mechanisms of ischemia-reperfusion injury include complement activation, leukocyte infiltration, oxidative stress, platelet adhesion and aggregation and mitochondrial-mediated mechanisms leading to blood-brain-barrier (BBB) disruption, which leads to brain edema. Conclusion: In summary, over the past few years there have been significant advancement in our understanding of molecular and cellular mechanisms of ischemia-reperfusion injury in the brain. The major mechanisms of reperfusion injury are clear but are still far from being clinically successful. Thus, further investigations on brain reperfusion injury mechanisms are wanted. Also, role of nitrates in protection for ischemia-reperfusion brain injury.

LncRNA SNHG3 promotes autophagy-induced neuronal cell apoptosis by acting as a ceRNA for miR-485 to up-regulate ATG7 expression

Long non-coding RNAs (lncRNAs) are bound up with various human diseases. However, their roles in brain ischemia-reperfusion (I/R) injury remain largely unknown. This study aimed to reveal the potential mechanism of LncRNA SNHG3 on autophagy-induced neuronal cell apoptosis in the brain I/R injury. LncRNA SNHG3 and miR-485 or autophagy markers LC3II/I and Beclin-1 expressions were detected by qRT-PCR or Western blot and the apoptosis of N2a cells was analyzed by flow cytometry. Besides, the interactions between LncRNA SNHG3 and miR-485, miR-485 and ATG7 were validated by RNA pull-down and dual-luciferase reporter system assays. After the Oxygen and Glucose Deprivation (OGD) treatment of N2a cells transfected with pcDNA-SNHG3, pcDNA-SNHG3 + miR-485 mimic for 6h, 1mM autophagy inhibitor 3-MA was added and reoxygenated for 24h, the effect of LncRNA SNHG3 on the autophagy-induced neuronal cell apoptosis was measured by Western blot and flow cytometry. LncRNA SNHG3 was highly expressed in the mouse model of transient middle cerebral artery occlusion and cell model of Oxygen and Glucose Deprivation/Reperfusion, while miR-485 was lowly expressed. Furthermore, miR-485 negatively regulated the luciferase activities of LncRNA SNHG3 and ATG7. After the OGD treatment of N2a cells transfected with pcDNA-SNHG3, pcDNA-SNHG3 + miR-485 mimic for 6h, 1mM 3-MA was added and reoxygenated for 24h, the overexpression of LncRNA SNHG3 raised the ratio of LC3-II/LC3-I and Beclin-1 expression and boosted the apoptosis of N2a cells, while these effects were reversed after the transfection of miR-485 mimic. In general, our data expounded that the interference with LncRNA SNHG3 improved brain I/R injury by up-regulating miR-485 and down-regulating ATG7 to restrain autophagy and neuronal cell apoptosis.

&lt;p&gt;Melatonin Plays a Protective Role by Regulating miR-26a-5p-NRSF and JAK2-STAT3 Pathway to Improve Autophagy, Inflammation and Oxidative Stress of Cerebral Ischemia-Reperfusion Injury&lt;/p&gt;

BackgroundMelatonin (MT) has potential protective effect on cerebral ischemia-reperfusion injury (CIRI), but its underlying regulatory mechanism has not been identified.PurposeThis study aimed to explore the role of miR-26a-5p-neuron-restrictive silencing factor (NRSF/REST), Janus kinase-2 (JAK2)-signal transducer and activator of transcription-3 (STAT3) pathway in the protection mechanism of MT against CIRI in vivo and in vitro.MethodsSprague Dawley rats were induced with ischemia-reperfusion (IR) in vivo model; PC12 cells were induced with oxygen-glucose deprivation/reperfusion (OGD/R) in vitro model; and MT intervention was conducted before the model was established. The effect of MT on autophagy factors (LC3II/LC3I, P62), inflammatory factors (TNF-α, IL-6, IL-10) and oxidative stress indexes (MDA, GSHPx, SOD) was explored, and then the above three indexes were determined by real-time quantitative PCR, ELISA, and detection kit corresponding to oxidative stress indexes. The neuroprotective effect of MT pretreatment on brain IR injury was evaluated by neurological deficit scores and TUNEL method. The levels of miR-26a-5p and NRSF were detected by real-time quantitative PCR and Western blot, and the interaction between them was evaluated by dual luciferase report. The role of JAK2-STAT3 pathway in MT protection mechanism was verified by pathway blocker (AG490) and Western blot.ResultsMT pretreatment can significantly reduce neurological deficit score and neuronal apoptosis, inhibit CIRI autophagy, inflammation and oxidative stress in vivo and in vitro, reduce LC3II/LC3I, TNF-α, IL-6, MDA and increase P62, IL-10, GSHPx, SOD. Further analysis identifies that downregulating miR-26a-5p or upregulating NRSF can eliminate the protective effect of MT, and NRSF is the direct target of miR-26a-5p. The protective effect of MT can also be eliminated under AG490 intervention.ConclusionMT plays a protective role by regulating miR-26a-5p-NRSF and JAK2-STAT3 pathway to improve CIRI autophagy, inflammation and oxidative stress.

Vagotomy Improves Hypoxic Pulmonary Vasoconstriction in Rats Subjected to Brain Ischemia-Reperfusion Injury.

Background: Pulmonary dysfunction is one of the critical complications of a stroke. However, it remains unclear whether the mechanism is caused by either neurogenic or inflammatory reactions. The present study aimed to determine the effect of cerebral ischemia-reperfusion injury and the role of the vagus nerve on hypoxic pulmonary vasoconstriction (HPV) in rats.Methods: This study was performed at Shiraz University of Medical Sciences, Shiraz, Iran, 2018. Male Sprague Dawley rats (n=56) were divided into four groups, namely the sham, vagotomy (Vag), 1 hour of ischemia followed by 23 hours of reperfusion without vagotomy (I/R) and with vagotomy (I/R+Vag). Neurological deficit scores and total infarct volumes of brains were measured in the I/R and I/R+Vag groups. Pulmonary artery pressure and lung weight were continuously registered during ventilation with normoxic and hypoxic gases in the isolated lungs. The blood gas parameters and the lung malondialdehyde (MDA) level of each group were also evaluated. ANOVA, with Tukey’s post hoc test and t test, was used to compare the variables in the experimental groups.Results: The infarct volume of the brains in the I/R and I/R+Vag groups were similar. HPV in the I/R group was lower than those in the sham and Vag groups, while vagotomy reversed this response in the I/R+Vag group (P=0.004). In the I/R group, PO2 and pH were lower, and PCO2 was higher than those in the sham and Vag groups. The lung MDA level in the I/R group was higher than that in the Vag group (P=0.019).Conclusion: Brain ischemia-reperfusion injury decreased HPV independent of increased MDA in the lung, whereas vagotomy improved HPV by repairing the blood-gas barrier and oxygen sensing.

Heterogeneity in brain distribution of activated microglia and astrocytes in a rat ischemic model of Alzheimer's disease after 2 years of survival.

The present study was designed to follow neuroinflammation after ischemic brain injury in the long-term survival rat model. Immunohistochemistry was performed 2 years after 10 min global brain ischemia due to cardiac arrest. For the visualization of the cellular inflammatory reaction microglial marker Iba1 and astrocyte marker GFAP were used. In post-ischemic animals our study revealed significant activation of astrocytes in all tested brain regions (hippocampal CA1 and CA3 areas and dentate gyrus, motor and somatosensory cortex, striatum and thalamus), while microglial activation was only found in CA1 and CA3 areas, and the motor cortex. In the specifically sensitive brain areas microglia and astrocytes showed simultaneously significant activation, while in the resistant brain areas only astrocytes were activated. Thus, there was clear evidence of less intensive neuroinflammation in brain areas resistant to ischemia. Such neuroinflammatory processes are backed by microglia and astrocytes activity even up to 2 years after ischemia-reperfusion brain injury. Our study thus revealed a chronic effect of global cerebral ischemia on the neuroinflammatory reaction in the rat brain even 2 years after the insult.

Shared Genomic and Proteomic Contribution of Amyloid and Tau Protein Characteristic of Alzheimer's Disease to Brain Ischemia.

Post-ischemic brain damage is associated with the deposition of folding proteins such as the amyloid and tau protein in the intra- and extracellular spaces of brain tissue. In this review, we summarize the protein changes associated with Alzheimer’s disease and their gene expression (amyloid protein precursor and tau protein) after ischemia-reperfusion brain injury and their role in the post-ischemic injury. Recent advances in understanding the post-ischemic neuropathology have revealed dysregulation of amyloid protein precursor, α-secretase, β-secretase, presenilin 1 and 2, and tau protein genes after ischemic brain injury. However, reduced expression of the α-secretase in post-ischemic brain causes neurons to be less resistant to injury. In this review, we present the latest evidence that proteins associated with Alzheimer’s disease and their genes play a key role in progressive brain damage due to ischemia and reperfusion, and that an ischemic episode is an essential and leading supplier of proteins and genes associated with Alzheimer’s disease in post-ischemic brain. Understanding the underlying processes of linking Alzheimer’s disease-related proteins and their genes in post-ischemic brain injury with the risk of developing Alzheimer’s disease will provide the most significant goals for therapeutic development to date.

Potential sphingosine-1-phosphate-related therapeutic targets in the treatment of cerebral ischemia reperfusion injury

Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid that regulates lymphocyte trafficking, glial cell activation, vasoconstriction, endothelial barrier function, and neuronal death pathways in the brain. Research has increasingly implicated S1P in the pathology of cerebral ischemia reperfusion (IR) injury. As a high-affinity agonist of S1P receptor, fingolimod exhibits excellent neuroprotective effects against ischemic challenge both in vivo and in vitro. By summarizing recent progress on how S1P participates in the development of brain IR injury, this review identifies potential therapeutic targets for the treatment of brain IR injury.

Development of a Neuroprotective Erythropoietin Modified with a Novel Carrier for the Blood-Brain Barrier.

Extremely high doses of erythropoietin (EPO) has been used for neuroprotection in ischemia-reperfusion brain injury to deliver sufficient amounts of EPO across the blood-brain barrier (BBB); however, harmful outcomes were observed afterward. We aimed to test the ability of HBHAc (heparin-binding haemagglutinin adhesion c), an intracellular delivery peptide for macromolecules, as an EPO carrier across the BBB. The cellular internalization and transcytosis ability of HBHAc-modified EPO (EPO-HBHAc) were evaluated in bEnd.3 cells and in the bEnd.3/CTX TNA2 co-culture BBB model, respectively. Subsequently, the NMDA-induced-toxicity model and ischemia-reperfusion rat model were used to understand the neuronal protective activity of EPO-HBHAc. The biodistribution of EPO-HBHAc was demonstrated in rats by the quantification of EPO-HBHAc in the brain, plasma, and organs by ELISA. Our results demonstrate that EPO-HBHAc exhibited significantly higher cellular internalization in dose- and time-dependent manners and better transcytosis ability than EPO. In addition, the transported EPO-HBHAc in the co-culture transwell system maintained the neuronal protective activity when primary rat cortical neurons underwent NMDA-induced toxicity. The calculated cerebral infarction area of rats treated with EPO-HBHAc was significantly reduced compared to that of rats treated with EPO (29.9 ± 7.0% vs 48.9 ± 7.9%) 24h after occlusion in 3VO rat experiments. Moreover, the EPO amount in both CSF and damaged cortex from the EPO-HBHAc group was 4.0-fold and 3.0-fold higher than the EPO group, respectively. These results suggest that HBHAc would be a favorable tool for EPO brain delivery and would further extend the clinical applications of EPO in neuroprotection.