Neuronal Damage Induced by Perinatal Asphyxia Is Attenuated by Postinjury Glutaredoxin-2 Administration

The general disruption of redox signaling following an ischemia-reperfusion episode has been proposed as a crucial component in neuronal death and consequently brain damage. Thioredoxin (Trx) family proteins control redox reactions and ensure protein regulation via specific, oxidative posttranslational modifications as part of cellular signaling processes. Trx proteins function in the manifestation, progression, and recovery following hypoxic/ischemic damage. Here, we analyzed the neuroprotective effects of postinjury, exogenous administration of Grx2 and Trx1 in a neonatal hypoxia/ischemia model. P7 Sprague-Dawley rats were subjected to right common carotid ligation or sham surgery, followed by an exposure to nitrogen. 1 h later, animals were injected i.p. with saline solution, 10 mg/kg recombinant Grx2 or Trx1, and euthanized 72 h postinjury. Results showed that Grx2 administration, and to some extent Trx1, attenuated part of the neuronal damage associated with a perinatal hypoxic/ischemic damage, such as glutamate excitotoxicity, axonal integrity, and astrogliosis. Moreover, these treatments also prevented some of the consequences of the induced neural injury, such as the delay of neurobehavioral development. To our knowledge, this is the first study demonstrating neuroprotective effects of recombinant Trx proteins on the outcome of neonatal hypoxia/ischemia, implying clinical potential as neuroprotective agents that might counteract neonatal hypoxia/ischemia injury.

Download Full-text

Gynura procumbens Root Extract Ameliorates Ischemia-Induced Neuronal Damage in the Hippocampal CA1 Region by Reducing Neuroinflammation

Nutrients ◽

10.3390/nu13010181 ◽

2021 ◽

Vol 13 (1) ◽

pp. 181

Author(s):

Woosuk Kim ◽

Hyo Young Jung ◽

Dae Young Yoo ◽

Hyun Jung Kwon ◽

Kyu Ri Hahn ◽

...

Keyword(s):

Inflammatory Responses ◽

Neuronal Damage ◽

Ischemia Reperfusion ◽

Treated Group ◽

Biological Properties ◽

Root Extract ◽

Ischemic Damage ◽

Neuroprotective Effects ◽

Hippocampal Ca1 ◽

Vehicle Treated Group

Gynura procumbens has been used in Southeast Asia for the treatment of hypertension, hyperglycemia, and skin problems induced by ultraviolet irradiation. Although considerable studies have reported the biological properties of Gynura procumbens root extract (GPE-R), there are no studies on the effects of GPE-R in brain damages, for example following brain ischemia. In the present study, we screened the neuroprotective effects of GPE-R against ischemic damage and neuroinflammation in the hippocampus based on behavioral, morphological, and biological approaches. Gerbils received oral administration of GPE-R (30 and 300 mg/kg) every day for three weeks and 2 h after the last administration, ischemic surgery was done by occlusion of both common carotid arteries for 5 min. Administration of 300 mg/kg GPE-R significantly reduced ischemia-induced locomotor hyperactivity 1 day after ischemia. Significantly more NeuN-positive neurons were observed in the hippocampal CA1 regions of 300 mg/kg GPE-R-treated animals compared to those in the vehicle-treated group 4 days after ischemia. Administration of GPE-R significantly reduced levels of pro-inflammatory cytokines such as interleukin-1β, -6, and tumor necrosis factor-α 6 h after ischemia/reperfusion. In addition, activated microglia were significantly decreased in the 300 mg/kg GPE-R-treated group four days after ischemia/reperfusion compared to the vehicle-treated group. These results suggest that GPE-R may be one of the possible agents to protect neurons from ischemic damage by reducing inflammatory responses.

Download Full-text

Neuroprotective effects of thymoquinone against MDMA-induced neurotoxicity

Research Journal of Pharmacy and Technology ◽

10.52711/0974-360x.2021.01033 ◽

2021 ◽

pp. 5945-5952

Author(s):

Mustafa NS. ◽

Mohamad N. ◽

Abu Bakar NH. ◽

Mohd Adnan LH. ◽

Jeharsae R. ◽

...

Keyword(s):

Memory Impairment ◽

Natural Compound ◽

Neuronal Damage ◽

Memory Performance ◽

Novel Object Recognition ◽

Psychoactive Substance ◽

Sprague Dawley ◽

Hippocampal Dentate Gyrus ◽

Object Recognition Test ◽

Neuroprotective Effects

MDMA (3, 4-methylenedioxymethamphetamine) is a psychoactive substance that is associated with neurotoxicity. MDMA exposure to human results in the degeneration of neuronal cells in the hippocampus. Hence, the purpose of this study was to examine the potential of a natural compound known as thymoquinone (TQ) to protect against neuronal damage and memory impairment in rats stimulated by MDMA. The administration of TQ into MDMA-induced neuronal damage rats was carried out in male Sprague Dawley via a 1-week treatment dividing into four groups (n=36, 7-9 per group). The studied groups involved with the treatments comprise i) Control (1 mL/kg saline), ii) MDMA (10 mg/kg MDMA), iii) MDMA+TQ (10 mg/kg MDMA + 40 mg/kg TQ) and iv) TQ control (40 mg/kg TQ). A novel object recognition test (NORT) was carried out to evaluate the memory performance of the rats, followed by a histopathological assessment of the hippocampal dentate gyrus. The histopathology analysis revealed a significant increase in numbers of positive cells by Fluoro-Jade C following the effect of MDMA on neuronal damage (MDMA induced group) compared to control (P<0.05). Next, the TQ treatments observed in MDMA+TQ exhibited a decline in positive cells from Fluoro-Jade C. The index of recognition memory was found to be increased in MDMA+TQ compared to the MDMA alone (P<0.05). This study suggests that the neuronal damage inflicted by MDMA in a rat model has the potential to be treated by TQ.

Download Full-text

Tat-Cannabinoid Receptor Interacting Protein Reduces Ischemia-Induced Neuronal Damage and Its Possible Relationship with 14-3-3η

Cells ◽

10.3390/cells9081827 ◽

2020 ◽

Vol 9 (8) ◽

pp. 1827 ◽

Cited By ~ 1

Author(s):

Hyun Jung Kwon ◽

Duk-Soo Kim ◽

Woosuk Kim ◽

Hyo Young Jung ◽

Yeon Hee Yu ◽

...

Keyword(s):

Cannabinoid Receptor ◽

Neuronal Damage ◽

Cell Damage ◽

Ischemia Reperfusion ◽

Ischemic Damage ◽

Dependent Manner ◽

Ht22 Cells ◽

Concentration Dependent Manner ◽

H2o2 Treatment ◽

Interacting Protein

Cannabinoid receptor-interacting protein 1a (CRIP1a) binds to the C-terminal domain of cannabinoid 1 receptor (CB1R) and regulates CB1R activities. In this study, we made Tat-CRIP1a fusion proteins to enhance CRIP1a penetration into neurons and brain and to evaluate the function of CRIP1a in neuroprotection following oxidative stress in HT22 hippocampal cells and transient forebrain ischemia in gerbils. Purified exogenous Tat-CRIP1a was penetrated into HT22 cells in a time and concentration-dependent manner and prevented H2O2-induced reactive oxygen species formation, DNA fragmentation, and cell damage. Tat-CRIP1a fusion protein also ameliorated the reduction of 14-3-3η expression by H2O2 treatment in HT22 cells. Ischemia–reperfusion damage caused motor hyperactivity in the open field test of gerbils; however, the treatment of Tat-CRIP1a significantly reduced hyperactivity 1 day after ischemia. Four days after ischemia, the administration of Tat-CRIP1a restored the loss of pyramidal neurons and decreased reactive astrocytosis and microgliosis induced by ischemic damage in the hippocampal cornu Ammonis (CA)1 region. Ischemic damage decreased 14-3-3η expression in all hippocampal sub-regions 4 days after ischemia; however, the treatment of Tat-CRIP1 ameliorated the reduction of 14-3-3η expression. These results suggest that Tat-CRIP1a attenuates neuronal damage and hyperactivity induced by ischemic damage, and it restores normal expression levels of 14-3-3η protein in the hippocampus.

Download Full-text

Neuroprotective effects of hydrogen saline in neonatal hypoxia–ischemia rat model

Brain Research ◽

10.1016/j.brainres.2008.11.048 ◽

2009 ◽

Vol 1256 ◽

pp. 129-137 ◽

Cited By ~ 151

Author(s):

Jianmei Cai ◽

Zhimin Kang ◽

Kan Liu ◽

WenWu Liu ◽

RunPing Li ◽

...

Keyword(s):

Rat Model ◽

Neuroprotective Effects ◽

Neonatal Hypoxia ◽

Hypoxia Ischemia

Download Full-text

Neuroprotective Effects of Mitochondria-Targeted Plastoquinone in a Rat Model of Neonatal Hypoxic–Ischemic Brain Injury

Molecules ◽

10.3390/molecules23081871 ◽

2018 ◽

Vol 23 (8) ◽

pp. 1871 ◽

Cited By ~ 14

Author(s):

Denis Silachev ◽

Egor Plotnikov ◽

Irina Pevzner ◽

Ljubava Zorova ◽

Anastasia Balakireva ◽

...

Keyword(s):

Oxidative Stress ◽

Targeted Delivery ◽

Cell Damage ◽

Brain Cell ◽

Neuroprotective Effects ◽

Neonatal Hypoxia ◽

Hypoxia Ischemia ◽

Causes Of Mortality ◽

High Production ◽

The Brain

Neonatal hypoxia–ischemia is one of the main causes of mortality and disability of newborns. To study the mechanisms of neonatal brain cell damage, we used a model of neonatal hypoxia–ischemia in seven-day-old rats, by annealing of the common carotid artery with subsequent hypoxia of 8% oxygen. We demonstrate that neonatal hypoxia–ischemia causes mitochondrial dysfunction associated with high production of reactive oxygen species, which leads to oxidative stress. Targeted delivery of antioxidants to the mitochondria can be an effective therapeutic approach to treat the deleterious effects of brain hypoxia–ischemia. We explored the neuroprotective properties of the mitochondria-targeted antioxidant SkQR1, which is the conjugate of a plant plastoquinone and a penetrating cation, rhodamine 19. Being introduced before or immediately after hypoxia–ischemia, SkQR1 affords neuroprotection as judged by the diminished brain damage and recovery of long-term neurological functions. Using vital sections of the brain, SkQR1 has been shown to reduce the development of oxidative stress. Thus, the mitochondrial-targeted antioxidant derived from plant plastoquinone can effectively protect the brain of newborns both in pre-ischemic and post-stroke conditions, making it a promising candidate for further clinical studies.

Download Full-text

Neuroprotective Effects of Bone Marrow Mononuclear Cells Therapy in a Rat Model of Ischemia Stroke

Journal of Biomaterials and Tissue Engineering ◽

10.1166/jbt.2020.2256 ◽

2020 ◽

Vol 10 (3) ◽

pp. 346-351

Author(s):

Jianfeng Liu ◽

Yamei Hu ◽

Gang Li ◽

Qianlin Zhang ◽

Jiewen Zhang

Keyword(s):

Bone Marrow ◽

Caspase 3 ◽

Mononuclear Cells ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Neurological Deficits ◽

Bone Marrow Mononuclear Cells ◽

Sprague Dawley ◽

Neuroprotective Effects ◽

Rat Models

Objective: Bone marrow mononuclear cells (BMMCs) are considered a potential approach to promote the recovery of stroke-induced neurological deficit. However, the exact mechanism of BMMCs in nerve function recovery is still unclear. Methods: Adult Sprague-Dawley (SD) rat models of cerebral ischemia-reperfusion injury was established by using thread method. BMMCs were transplanted into rat models. Neurological deficits were evaluated by Longa score scale. Immunohistochemistry assay were employed to examine the expression of GFAP and Nogo-A around the ischemic foci in the right frontal lobe. Caspase-3 activity was examined by Western Blot. Results: Rats in BMMCs group had lessened neurological deficits and cleaved Caspase-3 expression on day 21 after reper-fusion, as well as higher expression of GFAP [(37.62±2.45) vs. (27.62±1.69) and (38.00±1.85) vs. (27.25±1.83), P < 0.05] and lower expression of Nogo-A [(28.88±2.64) vs. (32.50±1.60) and (23.87±2.36) vs. (32.00±1.85), P < 0.05] on day 14 and 21 after reperfusion. Meanwhile, the expression of Nogo-A on day 21 was lower than that on day 14 after reperfusion [(23.87±2.36) vs. (28.88±2.64), P < 0.05] in BMMCs group. Conclusion: These findings suggested that BMMCs treatment could improve the functional recovery of neurological deficits in rats with MCAO, which was probably related to enhanced expression of GFAP and reduced Nogo-A expression and Caspase-3 activity in the ischemic brain tissues.

Download Full-text

Ginkgo biloba and Its Constituent 6-hydroxykynurenic-acid as well as Its Proanthocyanidins Exert Neurorestorative Effects against Cerebral Ischemia

Planta Medica ◽

10.1055/a-1146-2861 ◽

2020 ◽

Vol 86 (10) ◽

pp. 696-707

Author(s):

Jianbiao Yao ◽

Hongxiang Qiao ◽

Zhuming Jin ◽

Ruwei Wang ◽

Haibo Huang ◽

...

Keyword(s):

Cerebral Ischemia ◽

Ginkgo Biloba ◽

Ischemia Reperfusion ◽

Grape Seed ◽

Negative Control ◽

Major Contributor ◽

Sprague Dawley ◽

Neuroprotective Effects ◽

Phenolic Constituents

AbstractNeuroprotective effects against cerebral ischemia/reperfusion (I/R) injury by Ginkgo biloba leaves are commonly attributed to the antioxidant activity of its proanthocyanidins. Furthermore, preliminary experiments identified 6-hydroxykynurenic acid (6-HKA) as a major contributor to this effect of extract of G. biloba leaves (EGb) prepared according to the Chinese Pharmacopoeia (ChP). In order to elucidate the specific contribution of both proanthocyanidins and 6-HKA to the overall neurorestorative effects of this extract according to ChP, EGb ChP was separated into pure 6-HKA and a newly developed Ginkgo proanthocyanidin extract (GPE), enriched in proanthocyanidins but not containing 6-HKA. Male Sprague-Dawley rats were divided into the groups: sham: 8; model (placebo): 25; GPE 80 mg/kg: 13; GPE 40 mg/kg: 13; GPE 20 mg/kg: 16; grape seed extract (negative control) 40 mg/kg: 18; nimodipine (positive control) 2 mg/kg: 8. All non-sham animals were subjected to cerebral I/R injury by occluding the middle cerebral artery with a nylon suture that was removed after 2 h of ischemia to establish reperfusion. For comparison, a parallel series of experiments were performed with 6-HKA. In these in vivo experiments, neurological dysfunctions were reduced by both GPE and 6-HKA, and both average infarct size and concentrations of malondialdehyde (MDA) and super oxide dismutase (SOD) were significantly ameliorated as compared to the model group. This data, therefore, demonstrates that the neuroprotective effects of EGb cannot be explained by a purely chemical antioxidative effect alone as has been previously proposed, especially with regards to the proanthocyanidins. A pharmacological neurorestorative effect of EGb on neurons and brain tissue itself seems to be a much more straightforward explanation for the presented observations. This effect is most likely explained by the synergistic action of both its numerous phenolic constituents (GPE) and 6-hydroxykynurenic acid (6-HKA), which could be identified as one major contributor to the observed activity.

Download Full-text

Abstract 217: Increased Oxidation of Amplex Red in Post-Cardiac Arrest Human and Rat Plasma Can Be Utilized as a Potential Marker of Injury Severity

Circulation ◽

10.1161/circ.140.suppl_2.217 ◽

2019 ◽

Vol 140 (Suppl_2) ◽

Author(s):

Muhammad Shoaib ◽

Ann Iverson ◽

Tai Yin ◽

Lance B Becker ◽

Junhwan KIM

Keyword(s):

Hydrogen Peroxide ◽

Cardiac Arrest ◽

Injury Severity ◽

Ischemia Reperfusion ◽

University Hospital ◽

Ros Generation ◽

Ischemic Damage ◽

Sprague Dawley ◽

Amplex Red ◽

Potential Marker

Introduction: Cardiac arrest (CA), an unexpected loss of appropriate electrical signaling in the heart, leads to a loss of blood circulation and decreased oxygen perfusion. Ischemia results in the generation of hydrogen peroxide and other reactive oxygen species (ROS), thereby causing damage to tissues. Currently, there are no available biomarkers to elucidate the severity of ischemic damage. Therefore, oxidation of the Amplex Red (AR) assay by ROS into its fluorescent product, resorufin, may be used as a marker to determine injury severity. Methods: Plasma isolated from human CA patients from North Shore University Hospital was obtained to determine ROS generation. A commercially available Amplex Red assay kit was used to measure the amount of resorufin produced after oxidation due to hydrogen peroxide, peroxynitrite, and other ROS. To verify our human findings, we arbitrarily assigned adult male Sprague-Dawley rats into three groups (control, 10 min cardiac arrest, and 20 min cardiac arrest) using our reliable asphyxia-induced cardiac arrest model. Results: Despite human variations, our data on human CA patients showed an increased amount of AR oxidation as a result of ischemia. Our 10 min CA rat experimental model verified that Amplex Red is capable of detecting hydrogen peroxide and peroxynitrite formation after ischemia. Rats with 20 mins of ischemia time also produced resorufin, confirming that ischemia induces AR oxidation. Removing horseradish peroxidase and adding catalase controls for hydrogen peroxide and peroxynitrite, which should decrease AR oxidation; however, we observed an increase in AR oxidation. Therefore, we added phenylmethyl sulfonyl acid (PMSF), an inhibitor of carboxylesterase, an enzyme also capable of oxidizing Amplex Red, which resulted in decreased AR oxidation. Conclusion: By accounting for peroxide and peroxynitrite species, the increase in Amplex Red oxidation in the plasma of cardiac arrest human patients and rats can be attributed to carboxylesterase activity. Our data corroborates the various mechanisms of AR oxidation in the setting of ischemia-reperfusion allowing the Amplex Red assay to be utilized as a potential tool for assessing the degree of ischemic damage resulting from cardiac arrest.

Download Full-text