Research progress on the mechanism of action and clinical application of remote ischemic post-conditioning for acute ischemic stroke.

Remote ischemic post-conditioning (RIPostC) can reduce cerebral ischemia reperfusion injury (IRI) by inducing endogenous protective effects, the distal limb ischemia post-treatment and in situ ischemia post-treatment were classified according to the site of intervention. And in the process of clinical application distal limb ischemia post-treatment is more widely used and more conducive to clinical translation. Therefore, in this paper, we review the mechanism of action and clinical application of RIPostC in cerebral ischemia, hoping to provide reference help for future experimental directions and clinical translation.

Understanding the Molecular Mechanisms of H2's Regulatory Effect on miR-29s for Brain Protection during Deep Hypothermic Circulatory Arrest.

INTRODUCTION: Research regarding post-operative brain protection after deep hypothermic circulatory arrest (DHCA) has gained attracted significant attention. We previously demonstrated that hydrogen can significantly reverse DHCA-induced brain damage. METHOD: In the current research, we have established the DHCA model successfully using a modified four-vessel occlusion method and injected miR-29s compounds into the hippocampal tissue of rats. RESULT: We were surprised to find hydrogen increased miR-29s expression in the hippocampal tissue of a DHCA rat model. The administration of agomiR-29s counteracted DHCA-induced hippocampal tissue injury, while the antamiR-29s had the opposite effects. CONCLUSION: Based on the above facts, the brain protection mechanism of hydrogen in DHCAtreated rats may be related to the upregulation of miR-29s, which can exert its beneficial effects by alleviating apoptosis, inflammation, and oxidation.

The Catastrophe of Intracerebral Hemorrhage Drives the Capillary-Hemorrhage Dementias, Including Alzheimer's Disease.

This review advances an understanding of several dementias, based on four premises. One is that capillary hemorrhage is prominent in the pathogenesis of the dementias considered (dementia pugilistica, chronic traumatic encephalopathy, traumatic brain damage, Alzheimer's disease). The second premise is that hemorrhage introduces four neurotoxic factors into brain tissue: hypoxia of the tissue that has lost its blood supply, hemoglobin and its breakdown products, excitotoxic levels of glutamate, and opportunistic pathogens that can infect brain cells and induce a cytotoxic immune response. The third premise is that where organisms evolve molecules that are toxic to itself, like the neurotoxicity ascribed to hemoglobin, amyloid- (A), and glutamate, there must be some role for the molecule that gives the organism a selection advantage. The fourth is the known survival-advantage roles of hemoglobin (oxygen transport), of A (neurotrophic, synaptotrophic, detoxification of heme, protective against pathogens) and of glutamate (a major neurotransmitter). From these premises, we propose 1) that the brain has evolved a multi-factor response to intracerebral hemorrhage, which includes the expression of several protective molecules, including haptoglobin, hemopexin and A; and 2) that it is logical, given these premises, to posit that the four neurotoxic factors set out above, which are introduced into the brain by hemorrhage, drive the progression of the capillary-hemorrhage dementias. In this view, A expressed at the loci of neuronal death in these dementias functions not as a toxin but as a first responder, mitigating the toxicity of hemoglobin and the infection of the brain by opportunistic pathogens.

Effects of Dexmedetomidine on Cognitive Function, Oxidative Stress and Brain Protection in Patients Undergoing Craniocerebral Surgery

Background: The protective mechanism of dexmedetomidine on the brains of patients undergoing craniocerebral surgery remains unclear. The aim of this study was to examine the impact of dexmedetomidine on cognitive function, oxidative stress, and brain protection in such patients. Methods: Fifty-four patients who underwent craniocerebral surgery at our hospital from January 2020 to June 2023 were retrospectively selected as study subjects. They were divided into two groups: the control group (n = 27) and the study group (n = 27), based on different auxiliary anesthesia protocols. Patients in the study group received dexmedetomidine before anesthesia induction, using a midline intravenous pump to assist anesthesia, while the control group received an equivalent amount of normal saline. The remaining anesthesia induction and maintenance protocols were consistent for both groups. Cognitive function was assessed using the Mini Mental State Examination (MMSE) before and 1 day after surgery for both groups. Oxidative stress indicators, including malondialdehyde (MDA), glutathione peroxidase (GSH-Px), and superoxide dismutase (SOD) levels in the serum of both groups, were measured using enzyme-linked immunosorbent assay (ELISA). Additionally, changes in postoperative brain injury indicators, namely neuron-specific enolase (NSE) and central nervous system-specific protein (S100β), were detected and compared in the serum of both groups. Concurrently, postoperative adverse reactions were recorded for both groups. Results: The MMSE scale scores of both groups of patients 24 hours after surgery were significantly lower than those before surgery. However, the MMSE scale scores of the study group patients were notably higher than those in the control group, with a statistically significant difference (p < 0.05). One hour after surgery, the serum levels of MDA, GSH-Px, and SOD in both groups of patients were significantly elevated compared to pre-surgery levels. ... (AU)

Abordaje y tratamiento del ictus isquémico en la fase aguda / Management of acute ischemic stroke

El ictus isquémico es una enfermedad neurológica grave que precisa una atención urgente. Al ser una enfermedad dependiente del tiempo, la asistencia debe ser coordinada y eficaz para que ofrezca el tratamiento adecuado de la forma más precoz posible. El tratamiento de la fase aguda incluye unas medidas generales para garantizar la estabilidad hemodinámica del paciente, el uso de terapias de reperfusión (trombolíticos intravenosos y tratamiento endovascular mediante trombectomía mecánica) y la contribución a la protección cerebral mediante el control de presión arterial, glucemia, temperatura y oxigenación, así como prevenir complicaciones cerebrales y sistémicas. Se debe planificar de manera precoz el tratamiento rehabilitador del paciente. Para evitar las recurrencias precoces se recomienda tratamiento antitrombótico según la etiología del ictus y el control de los factores de riesgo vascular. Todas estas medidas tienen como objetivo revertir los síntomas iniciales, evitar que progrese la lesión, mejorar la situación funcional del paciente y evitar recurrencias (AU)

Ischemic stroke is a serious neurological condition that requires urgent attention. As a time-dependent disease, acute stroke management must be coordinated and effective to provide the best treatment as early as possible. The treatment of the acute phase of ischemic stroke includes general measures to ensure patient hemodynamic stability, the use of reperfusion therapies (intravenous thrombolytics and mechanical thrombectomy), improving cerebral protection by monitoring the homeostasis of certain variables as blood pressure, glycemia, temperature, or oxygenation, as well as preventing cerebral and systemic complications. Also, it is necessary an early planning of comprehensive rehabilitation. To prevent early recurrences, control of vascular risk factors and antithrombotic treatment is recommended. The management of patients with acute ischemic stroke aims to reverse initial symptoms, to prevent further brain damage, improve functional outcomes and avoid ischemic recurrences (AU)

Twelve protections evolved for the brain, and their roles in extending its functional life.

As human longevity has increased, we have come to understand the ability of the brain to function into advanced age, but also its vulnerability with age, apparent in the age-related dementias. Against that background of success and vulnerability, this essay reviews how the brain is protected by (by our count) 12 mechanisms, including: the cranium, a bony helmet; the hydraulic support given by the cerebrospinal fluid; the strategically located carotid body and sinus, which provide input to reflexes that protect the brain from blood-gas imbalance and extremes of blood pressure; the blood brain barrier, an essential sealing of cerebral vessels; the secretion of molecules such as haemopexin and (we argue) the peptide Aß to detoxify haemoglobin, at sites of a bleed; autoregulation of the capillary bed, which stabilises metabolites in extracellular fluid; fuel storage in the brain, as glycogen; oxygen storage, in the haemoprotein neuroglobin; the generation of new neurones, in the adult, to replace cells lost; acquired resilience, the stress-induced strengthening of cell membranes and energy production found in all body tissues; and cognitive reserve, the ability of the brain to maintain function despite damage. Of these 12 protections, we identify 5 as unique to the brain, 3 as protections shared with all body tissues, and another 4 as protections shared with other tissues but specialised for the brain. These protections are a measure of the brain's vulnerability, of its need for protection. They have evolved, we argue, to maintain cognitive function, the ability of the brain to function despite damage that accumulates during life. Several can be tools in the hands of the individual, and of the medical health professional, for the lifelong care of our brains.

TIPE2 ameliorates neuroinflammation and cognitive impairment in sepsis-associated encephalopathy through regulating RhoA/ROCK2-NF-κB signaling pathway.

Sepsis-associated encephalopathy (SAE) is an acute brain dysfunction induced by systemic inflammation caused by sepsis and is one of the most common types of encephalopathy in intensive care units. Deteriorative neuroinflammation is closely related to the development of brain injury, which often transforms into common pathological manifestations in patients with severe sepsis. Therefore, taking necessary preventive and protective measures for potential brain injury and promptly reducing neuroinflammatory injury is necessary to improve the long-term prognoses of patients. Tumor necrosis factor-α-induced protein 8-like 2 (TIPE2) can play a significant protective role in septic lung injury, but studies on its expression and role in neurological diseases are rare. In the present study, we found that TIPE2 can expressed in microglia and ameliorate brain injury caused by SAE by suppressing neuroinflammation. The RhoA/ROCK2 pathway is the central coordinator of tissue injury response, and the activation of RhoA participates in the lipopolysaccharide-induced activation of the nuclear factor kappa B (NF-κB) signaling pathway. The activation of RhoA and phosphorylation of NF-κB was enhanced after TIPE2 deficiency. Importantly, TIPE2 negatively regulates inflammatory responses in vivo and in vitro and plays a protective role in SAE by inhibiting the activation of RhoA/ROCK2-NF-κB signaling pathways. The ultimate aim of our proposed project is to provide a theoretical basis for the development of a novel strategy for the early prevention and therapy of SAE.

[Management of acute ischemic stroke]. / Abordaje y tratamiento del ictus isquémico en la fase aguda.

Ischemic stroke is a serious neurological condition that requires urgent attention. As a time-dependent disease, acute stroke management must be coordinated and effective to provide the best treatment as early as possible. The treatment of the acute phase of ischemic stroke includes general measures to ensure patient hemodynamic stability, the use of reperfusion therapies (intravenous thrombolytics and mechanical thrombectomy), improving cerebral protection by monitoring the homeostasis of certain variables as blood pressure, glycemia, temperature, or oxygenation, as well as preventing cerebral and systemic complications. Also, it is necessary an early planning of comprehensive rehabilitation. To prevent early recurrences, control of vascular risk factors and antithrombotic treatment is recommended. The management of patients with acute ischemic stroke aims to reverse initial symptoms, to prevent further brain damage, improve functional outcomes and avoid ischemic recurrences.

Validation of a new model of selective antegrade cerebral perfusion with circulatory arrest in rats.

BACKGROUND: Selective antegrade cerebral perfusion (SACP) is adopted as an alternative to deep hypothermic circulatory arrest (DHCA) during aortic arch surgery. However, there is still no preclinical evidence to support the use of SACP associated with moderate hypothermia (28-30°C) instead of DHCA (18-20°C). The present study aims to develop a reliable and reproducible preclinical model of cardiopulmonary bypass (CPB) with SACP applicable for assessing the best temperature management. MATERIALS AND METHODS: A central cannulation through the right jugular vein and the left carotid artery was performed, and CPB was instituted.Animals were randomized into two groups: normothermic circulatory arrest without or with cerebral perfusion (NCA vs SACP). EEG monitoring was maintained during CPB. After 10 min of circulatory arrest, rats underwent 60 min of reperfusion. After that, animals were sacrificed, and brains were collected for histology and molecular biology analysis. RESULTS: Power spectral analysis of the EEG signal showed decreased activity in both cortical regions and lateral thalamus in all rats during the circulatory arrest. Only SACP determined complete recovery of brain activity and higher power spectral signal compared to NCA (p < 0.05). Histological damage scores and western blot analysis of inflammatory and apoptotic proteins like caspase-3 and Poly-ADP ribose polymerase (PARP) were significantly lower in SACP compared to NCA. Vascular endothelial growth factor (VEGF) and RNA binding protein 3 (RBM3) involved in cell-protection mechanisms were higher in SACP, showing better neuroprotection (p < 0.05). CONCLUSIONS: SACP by cannulation of the left carotid artery guarantees good perfusion of the whole brain in this rat model of CPB with circulatory arrest. The present model of SACP is reliable, repeatable, and not expensive, and it could be used in the future to achieve preclinical evidence for the best temperature management and to define the best cerebral protection strategy during circulatory arrest.

Effects of different doses of dopamine receptor agonist pramipexole on neurobehaviors and changes of mitochondrial membrane potentials in rats with global cerebral ischemia-reperfusion injury.

OBJECTIVE: To explore the effects of different doses of dopamine receptor agonist pramipexole on neurobehaviors and changes of mitochondrial membrane potential in rats with global cerebral ischemia-reperfusion injury. METHODS: A total of 75 SPF Sprague-Dawley male rats were randomly divided into sham group (n=20), model group (n=20), pramipexole administration group (n=35). The rat model of global cerebral ischemia-reperfusion injury was prepared by the modified Pulsinelli's four-vessel occlusion method. Pramipexole administration group was administered intraperitoneally in rats with global cerebral ischemia-reperfusion injury at different doses of pramipexole 0.25 mg/kg, 0.5 mg/kg, 1 mg/kg, 2 mg/kg, once a day for 14 consecutive days. Based on the results of modified neurological severity scores, open field test and morphology by Nissl's staining to determine the optimal dose of pramipexole. Mitochondrial membrane potential in the optimal dose of pramipexole administration group were measured by the JC-1 fluorescent probe staining method. RESULTS: 1. Different doses of pramipexole 0.25 mg/kg, 0.5 mg/kg, 1 mg/kg, and 2 mg/kg, were used as drug administration in rats with global cerebral ischemia-reperfusion injury for 14 consecutive days, and we found that all four doses of pramipexole could improve the modified neurological severity scores of rats with global cerebral ischemia-reperfusion injury to varying degrees, but only 0.5 mg/kg pramipexole at 1, 3, 7 and 14 days consistently reduced modified neurological severity scores and improved neurological function in rats with global cerebral ischemia-reperfusion injury. In the open-field test, only 0.5 mg/kg pramipexole increased the number of entries into the central zone, duration spent in the central zone, total distance travelled in the open field and average velocity, which improved the spontaneous activities and reduced anxiety and depression of rats with global cerebral ischemia-reperfusion injury. 2. Different doses of pramipexole 0.25 mg/kg, 0.5 mg/kg, 1 mg/kg, and 2 mg/kg for 14 consecutive days significantly increased the number of surviving neurons in the hippocampal CA1 subfield in rats with global cerebral ischemia-reperfusion injury to varying degrees. Based on these results, we tentatively found that 0.5 mg/kg pramipexole may be the optimal dose in all of the above. 3. We found that 0.5 mg/kg pramipexole significantly increased the mitochondrial membrane potential in rats after global cerebral ischemia-reperfusion injury. CONCLUSION: Different doses of dopamine receptor agonist pramipexole improved neurological function of rats with global cerebral ischemia-reperfusion injury to varying degrees, and 0.5 mg/kg pramipexole may be the optimal dose in all of the above. Pramipexole may produce neuroprotective effects by protecting neurons in the hippocampus and improving the mitochondrial membrane potential after global cerebral ischemia-reperfusion injury.

Clinical value of regional cerebral oxygen saturation combined with electrophysiological blood pressure monitoring in patients with carotid artery stenosis and coronary heart disease during carotid endarterectomy / 中国医师进修杂志

Objective:To investigate the effect of regional cerebral oxygen saturation (rSO 2) combined with neurophysiological blood pressure monitoring on brain protection and myocardial protection during carotid endarterectomy (CEA) in patients with carotid stenosis and coronary heart disease. Methods:One hundred patients with carotid artery stenosis complicated with coronary heart disease treated in Jinhua Central Hospital from June 2021 to June 2022 were randomly divided into control group and experimental group. All patients were scheduled to undergo CEA. Fifty patients in the control group were administered with empirically increasing basic blood pressure by 20% - 30%, and 50 patients in the experimental group were administered with blood pressure under the guidance of rSO 2 combined with motor evoked potentials (MEPs) and somatosensory evoked potentials (EPS). The neurological function indexes of the two groups [neuron specific enolase (NSE), central nerve specific protein (S100-β)], myocardial function indicators [cardiac troponin I (cTnI), B-type natriuretic peptide (BNP)], clinical indicators (eye opening time, extubation time, recovery room stay time, hospital stay) and the incidence of postoperative complications [delirium (POD), cognitive dysfunction (POCD), neurological impairment] were compard between the two groups. Results:Two sets of postoperative NSE and S100-β both increased ( P<0.05), but NSE and S100 in the experimental group after surgery were lower than those in the control group: (0.82 ± 0.14) μg/L vs. (1.18 ± 0.28) μg/L, (290.13 ± 27.25) mg/L vs. (301.98 ± 28.56) mg/L, the differences were statistically significant ( P<0.05). After surgery, cTnI and BNP increased in both groups ( P<0.05), but the cTnI and BNP in the experimental group were lower than those in the control group: (2.87 ± 0.74)] μg/L vs. (3.36 ± 0.83) μg/L, (3.01 ± 0.85) μg/L vs. (3.89 ± 0.92) μg/L, the differences were statistically significant ( P<0.05). The opening time, extubation time, recovery room stay time, and hospitalization time in the experimental group were shorter than those in the control group: (16.79 ± 3.15) min vs. (20.55 ± 3.83) min, (29.38 ± 4.66) min vs. (40.14 ± 4.57) min, (66.82 ± 15.80) min vs. (89.35 ± 24.78) min, (11.24 ± 4.89) d vs. (14.56 ± 6.74) d, there were statistical differences ( P<0.05). The incidence of postoperative complications in the experimental group was lower than that in the control group: 12.00% (6/50) vs. 28.00% (14/50), there was statistical difference ( P<0.05). Conclusions:The application of rSO 2 combined with neurophysiological blood pressure monitoring in CEA of patients with carotid artery stenosis and coronary heart disease has a good effect, which has brain protection and myocardial protection, can shorten the recovery time of anesthesia and hospitalization time, and reduce the incidence of postoperative complications.

Protective Effects of Sophoraflavanone G by Inhibiting TNF-α-Induced MMP-9-Mediated Events in Brain Microvascular Endothelial Cells.

The regulation of matrix metalloproteinases (MMPs), especially MMP-9, has a critical role in both physiological and pathological events in the central nervous system (CNS). MMP-9 is an indicator of inflammation that triggers several CNS disorders, including neurodegeneration. Tumor necrosis factor-α (TNF-α) has the ability to stimulate the production of different inflammatory factors, including MMP-9, in several conditions. Numerous phytochemicals are hypothesized to mitigate inflammation, including the CNS. Among them, a flavonoid compound, sophoraflavanone G (SG), found in Sophora flavescens has been found to possess several medicinal properties, including anti-bacterial and anti-inflammatory effects. In this study, mouse brain microvascular endothelial cells (bMECs) were used to explore TNF-α-induced MMP-9 signaling. The effects of SG on TNF-α-induced MMP-9 expression and its mechanisms were further evaluated. Our study revealed that the expression of MMP-9 in bMECs was stimulated by TNF-α through the activation of ERK1/2, p38 MAPK, and JNK1/2 via the TNF receptor (TNFR) with a connection to the NF-κB signaling pathway. Moreover, we found that SG can interact with the TNFR. The upregulation of MMP-9 by TNF-α may lead to the disruption of zonula occludens-1 (ZO-1), which can be mitigated by SG administration. These findings provide evidence that SG may possess neuroprotective properties by inhibiting the signaling pathways associated with TNFR-mediated MMP-9 expression and the subsequent disruption of tight junctions in brain microvascular endothelial cells.

Research progress on the role of hormones in ischemic stroke.

Ischemic stroke is a major cause of death and disability around the world. However, ischemic stroke treatment is currently limited, with a narrow therapeutic window and unsatisfactory post-treatment outcomes. Therefore, it is critical to investigate the pathophysiological mechanisms following ischemic stroke brain injury. Changes in the immunometabolism and endocrine system after ischemic stroke are important in understanding the pathophysiological mechanisms of cerebral ischemic injury. Hormones are biologically active substances produced by endocrine glands or endocrine cells that play an important role in the organism's growth, development, metabolism, reproduction, and aging. Hormone research in ischemic stroke has made very promising progress. Hormone levels fluctuate during an ischemic stroke. Hormones regulate neuronal plasticity, promote neurotrophic factor formation, reduce cell death, apoptosis, inflammation, excitotoxicity, oxidative and nitrative stress, and brain edema in ischemic stroke. In recent years, many studies have been done on the role of thyroid hormone, growth hormone, testosterone, prolactin, oxytocin, glucocorticoid, parathyroid hormone, and dopamine in ischemic stroke, but comprehensive reviews are scarce. This review focuses on the role of hormones in the pathophysiology of ischemic stroke and discusses the mechanisms involved, intending to provide a reference value for ischemic stroke treatment and prevention.

Investigation of Naoluoxintong on the neural stem cells by facilitating proliferation and differentiation in vitro and on protecting neurons by up-regulating the expression of nestin in MCAO rats.

ETHNOPHARMACOLOGICAL RELEVANCE: The classic traditional Chinese compound Naoluoxintong (NLXT) has been proven an effective remedy for ischemic stroke (IS). The protective effect of NLXT on neural stem cells (NSCs), however, remains unclear. AIM OF THE STUDY: To investigate the protective effect of NLXT on NSCs in rats with middle cerebral artery occlusion (MCAO) and the effect of Nestin expression in vivo. MATERIALS AND METHODS: Sprague-Dawley (SD) rats were randomly divided into three groups: the sham-operated group, the MCAO model group and the NLXT group. The MCAO model in rats was established by modified Longa wire embolization method. The sham-operated group, the model group and the NLXT groups were divided into three subgroups according to the sampling time points of 1 d, 3 d and 7 d after successful model-making. Immunofluorescence staining, including bromodeoxyuridine (BrdU)/glial fibrillary acidic protein (GFAP), ß-tubulinIII/GFAP, BrdU/doublecortin (DCX) and BrdU/neuronal nuclei (NeuN), was used to detect the proliferation and survival of NSCs in the hippocampal after drug administration. Protein expression of Nestin, DCX, GFAP and NeuN in the hippocampal was detected by Western blot (WB). RESULTS: Immunofluorescence experiment of Nestin labeled: on the first day, a few Nestin-positive cells were found in the hippocampal DG area. Afterwards, the number of Nestin-labeled positive cells in the model group increased, while the number of cells in the sham group did not fluctuate significantly. The number of positive cells in each administration group increased more than that in the model and normal group. ß-tubulin III/GFAP double-labeled: a small amount of double labeled cells was expressed in the normal group, and the number subsequently fluctuated little. In the model group, ß-tubulin III/GFAP positive cells increased initially after acute ischemia, and gradually decreased afterwards. In the NLXT-treated group, ß-Tubulin III positive cells were significantly increased on day 1, 3 and 7, while GFAP positive cells had little change. BrdU/DCX double-labeled: initially, a small number of BrdU/DCX-labeled positive cells were observed in the normal group and the model group, but there was no increasing trend over time. The positive cells in the NLXT group increased over time, and those in the seven-day group were significantly higher than those in the one-day and three-day groups. BrdU/NEUN double-labeled: in the normal group, BrdU/NEUN positive cells were enriched and distributed regularly. The number of positive cells in the model group was small and decreased gradually with time, and the decrease was most obvious on the third day. The number of positive cells in the NLXT group was significantly higher than that in the model group, and the number of positive cells in the seven-day group was significantly higher than that in the one-day and three-day groups. WB results reflected those three proteins, Nestin, NeuN and DCX, showed an increase in expression, except GFAP, which showed a decreasing trend. CONCLUSIONS: Preliminarily, NLXT can promote the migration and differentiation of NSCs. It may have a protective effect on the brain by promoting repair of brain tissue damage through upregulation of Nestin after IS.

Woodpeckers minimize cranial absorption of shocks.

The skull of a woodpecker is hypothesized to serve as a shock absorber that minimizes the harmful deceleration of its brain upon impact into trees1-11 and has inspired the engineering of shock-absorbing materials12-15 and tools, such as helmets.16 However, this hypothesis remains paradoxical since any absorption or dissipation of the head's kinetic energy by the skull would likely impair the bird's hammering performance4 and is therefore unlikely to have evolved by natural selection. In vivo quantification of impact decelerations during pecking in three woodpecker species and biomechanical models now show that their cranial skeleton is used as a stiff hammer to enhance pecking performance, and not as a shock-absorbing system to protect the brain. Numerical simulations of the effect of braincase size and shape on intracranial pressure indicate that the woodpeckers' brains are still safe below the threshold of concussions known for primate brains. These results contradict the currently prevailing conception of the adaptive evolution of cranial function in one of nature's most spectacular behaviors. VIDEO ABSTRACT.

Reactive Oxygen Species Scavenging Functional Hydrogel Delivers Procyanidins for the Treatment of Traumatic Brain Injury in Mice.

Traumatic brain injury (TBI) is accompanied by the overload of reactive oxygen species (ROS), which can result in secondary brain injury. Although procyanidins (PCs) have a powerful free radical scavenging capability and have been widely studied in the treatment of TBI, conventional systemic drug therapy cannot make the drug reach the targeted area in the early stage of TBI and will cause systemic side effects because of the presence of the blood-brain barrier (BBB). To address this tissue, we designed and fabricated a ROS-scavenging functional hydrogel loaded PC (GelMA-PPS/PC) to deliver the drug by responding to the traumatic microenvironment. In situ injection of the GelMA-PPS/PC hydrogel effectively avoided the BBB and was directly applied to the surface of brain tissue to target the traumatic area. Hydrophobic poly(propylene sulfide)60 (PPS60), an ROS quencher and H2O2-responsive substance, was covalently bound to GelMA and exposed in response to the trauma microenvironment. At the same time, the H2O2 response of PPS60 further caused the structure of the hydrogel to degrade and release the encapsulated PC. Then PC could regulate the oxidative stress response in the cells and synergistically deplete ROS to play a neurotrophic protective role. This work suggests a novel method for the treatment of secondary brain injury by inhibiting the oxidative stress response after TBI.

Brain Protective Effect of Resveratrol via Ameliorating Interleukin-1ß-Induced MMP-9-Mediated Disruption of ZO-1 Arranged Integrity.

In the central nervous system (CNS), the matrix metalloproteinase-9 (MMP-9) is induced by several factors and contributes to CNS disorders, including inflammation and neurodegeneration. Thus, the upregulation of MMP-9 has been considered to be an indicator of inflammation. Interleukin-1ß (IL-1ß) is an important proinflammatory cytokine which can induce various inflammatory factors, such as MMP-9, in many inflammatory disorders. Several phytochemicals are believed to reduce the risk of several inflammatory disorders, including the CNS diseases. Among them, the resveratrol, a principal phenolic compound of the grape, blueberry, and mulberry peels and Cassia plants, has been shown to possess several medicinal properties, including antioxidative, anti-inflammatory, and antitumor function. Herein, we used mouse-brain microvascular endothelial cells (bMECs) to demonstrate the signaling mechanisms of IL-1ß-induced MMP-9 expression via zymographic, RT-PCR, Western blot, reactive oxygen species (ROS) detection, immunofluorescence stain, and promoter reporter analyses. Then we evaluated the effects of resveratrol on IL-1ß-induced MMP-9 expression in bMECs and its mechanism of action. We first demonstrated that IL-1ß induced MMP-9 expression in bMECs. Subsequently, IL-1ß induced MMP-9 expression via ROS-mediated c-Src-dependent transactivation of EGFR, and then activation of the ERK1/2, p38 MAPK, JNK1/2, and NF-κB signaling pathway. Finally, we determined that IL-1ß-induced upregulation of MMP-9 may cause the disruption of the arranged integrity of zonula occludens-1 (ZO-1), but this could be inhibited by resveratrol. These data indicated that resveratrol may have antioxidative and brain-protective activities by reducing these related pathways of ROS-mediated MMP-9 expression and tight junction disruption in brain microvascular endothelial cells.