scholarly journals Combination of mild hypothermia with neuroprotectants has greater neuroprotective effects during oxygen-glucose deprivation and reoxygenation-mediated neuronal injury

2014 ◽  
Vol 4 (1) ◽  
Author(s):  
Xiao-Ya Gao ◽  
Jian-Ou Huang ◽  
Ya-Fang Hu ◽  
Yong Gu ◽  
Shu-Zhen Zhu ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Mild Hypothermia ◽  
Neuronal Damage ◽  
Combined Treatment ◽  
Neuronal Injury ◽  
Glucose Deprivation ◽  
Oxygen Glucose Deprivation ◽  
Single Treatment ◽  
Neuroprotective Effects ◽  
Apoptosis Pathway

Abstract Co-treatment of neuroprotective reagents may improve the therapeutic efficacy of hypothermia in protecting neurons during ischemic stroke. This study aimed to find promising drugs that enhance the neuroprotective effect of mild hypothermia (MH). 26 candidate drugs were selected based on different targets. Primary cultured cortical neurons were exposed to oxygen-glucose deprivation and reoxygenation (OGD/R) to induce neuronal damage, followed by either single treatment (a drug or MH) or a combination of a drug and MH. Results showed that, compared with single treatment, combination of MH with brain derived neurotrophic factor, glibenclamide, dizocilpine, human urinary kallidinogenase or neuroglobin displayed higher proportion of neuronal cell viability. The latter three drugs also caused less apoptosis rate in combined treatment. Furthermore, co-treatment of those three drugs and MH decreased the level of reactive oxygen species (ROS) and intracellular calcium accumulation, as well as stabilized mitochondrial membrane potential (MMP), indicating the combined neuroprotective effects are probably via inhibiting mitochondrial apoptosis pathway. Taken together, the study suggests that combined treatment with hypothermia and certain neuroprotective reagents provide a better protection against OGD/R-induced neuronal injury.

scholarly journals Neuroprotective effects of adenosine deaminase in the striatum

2016 ◽  
Vol 36 (4) ◽  
pp. 709-720 ◽  
Author(s):  
Risa Tamura ◽  
Hiroyuki Ohta ◽  
Yasushi Satoh ◽  
Shigeaki Nonoyama ◽  
Yasuhiro Nishida ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Adenosine Deaminase ◽  
Neuronal Damage ◽  
Brain Slices ◽  
Field Potential ◽  
Glucose Deprivation ◽  
Oxygen Glucose Deprivation ◽  
Protective Effects ◽  
Neuroprotective Effects ◽  
Negative Effect

Adenosine deaminase (ADA) is a ubiquitous enzyme that catabolizes adenosine and deoxyadenosine. During cerebral ischemia, extracellular adenosine levels increase acutely and adenosine deaminase catabolizes the increased levels of adenosine. Since adenosine is a known neuroprotective agent, adenosine deaminase was thought to have a negative effect during ischemia. In this study, however, we demonstrate that adenosine deaminase has substantial neuroprotective effects in the striatum, which is especially vulnerable during cerebral ischemia. We used temporary oxygen/glucose deprivation (OGD) to simulate ischemia in rat corticostriatal brain slices. We used field potentials as the primary measure of neuronal damage. For stable and efficient electrophysiological assessment, we used transgenic rats expressing channelrhodopsin-2, which depolarizes neurons in response to blue light. Time courses of electrically evoked striatal field potential (eFP) and optogenetically evoked striatal field potential (optFP) were recorded during and after oxygen/glucose deprivation. The levels of both eFP and optFP decreased after 10 min of oxygen/glucose deprivation. Bath-application of 10 µg/ml adenosine deaminase during oxygen/glucose deprivation significantly attenuated the oxygen/glucose deprivation-induced reduction in levels of eFP and optFP. The number of injured cells decreased significantly, and western blot analysis indicated a significant decrease of autophagic signaling in the adenosine deaminase-treated oxygen/glucose deprivation slices. These results indicate that adenosine deaminase has protective effects in the striatum.

scholarly journals Neuroprotective Effects of GV1001 in Animal Stroke Model and Neural Cells Subject to Oxygen-Glucose Deprivation/Reperfusion Injury

2021 ◽  
Vol 23 (3) ◽  
pp. 420-436
Author(s):  
Hyuk Sung Kwon ◽  
Ye Eun Kim ◽  
Hyun-Hee Park ◽  
Jeong-Woo Son ◽  
Hojin Choi ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Cortical Neurons ◽  
Ischemia Reperfusion ◽  
Glucose Deprivation ◽  
Oxygen Glucose Deprivation ◽  
Neural Cells ◽  
Lesion Volume ◽  
Stroke Model ◽  
Neuroprotective Effects ◽  
Neurobehavioral Function

Background and Purpose Previous studies have revealed the diverse neuroprotective effects of GV1001. In this study, we investigated the effects of GV1001 on focal cerebral ischemia-reperfusion injury (IRI) in rats and oxygen-glucose deprivation/reoxygenation (OGD/R)-induced injury in neural stem cells (NSCs) and cortical neurons. Methods Focal cerebral IRI was induced by transient middle cerebral artery occlusion (MCAO). Brain diffusion-weighted imaging (DWI) was performed 2 hours after occlusion, and a total of 37 rats were treated by reperfusion with GV1001 or saline 2 hours after occlusion. Fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging, immunohistochemistry, and neurobehavioral function analyses were performed. Additionally, OGD/R-injured NSCs and cortical neurons were treated with different GV1001 concentrations. Cell viability, proliferation, migration, and oxidative stress were determined by diverse molecular analyses. Results In the stroke model, GV1001 protected neural cells against IRI. The most effective dose of GV1001 was 60 μM/kg. The infarct volume on FLAIR 48 hours after MCAO compared to lesion volume on DWI showed a significantly smaller ratio in the GV1001-treated group. GV1001-treated rats exhibited better behavioral functions than the saline-treated rats. Treatment with GV1001 increased the viability, proliferation, and migration of the OGD/R-injured NSCs. Free radicals were significantly restored by treatment with GV1001. These neuroprotective effects of GV1001 have also been demonstrated in OGD/R-injured cortical neurons. Conclusions The results suggest that GV1001 has neuroprotective effects against IRI in NSCs, cortical neurons, and the rat brain. These effects are mediated through the induction of cellular proliferation, mitochondrial stabilization, and anti-apoptotic, anti-aging, and antioxidant effects.

scholarly journals The cell-permeable mitochondrial calcium uniporter inhibitor Ru265 preserves cortical neuron respiration after lethal oxygen glucose deprivation and reduces hypoxic/ischemic brain injury

2020 ◽  
Vol 40 (6) ◽  
pp. 1172-1181 ◽  
Author(s):  
Robyn J Novorolsky ◽  
Matthew Nichols ◽  
Jong S Kim ◽  
Evgeny V Pavlov ◽  
Joshua J Woods ◽  
...  
Keyword(s):  
Brain Injury ◽  
Cortical Neurons ◽  
Therapeutic Potential ◽  
High Capacity ◽  
Glucose Deprivation ◽  
Oxygen Glucose Deprivation ◽  
Mitochondrial Calcium ◽  
Neuroprotective Effects ◽  
Sensorimotor Deficits ◽  
Cultured Cortical Neurons

The mitochondrial calcium (Ca2+) uniporter (MCU) mediates high-capacity mitochondrial Ca2+ uptake implicated in ischemic/reperfusion cell death. We have recently shown that inducible MCU ablation in Thy1-expressing neurons renders mice resistant to sensorimotor deficits and forebrain neuron loss in a model of hypoxic/ischemic (HI) brain injury. These findings encouraged us to compare the neuroprotective effects of Ru360 and the recently identified cell permeable MCU inhibitor Ru265. Unlike Ru360, Ru265 (2–10 µM) reached intracellular concentrations in cultured cortical neurons that preserved cell viability, blocked the protease activity of Ca2+-dependent calpains and maintained mitochondrial respiration and glycolysis after a lethal period of oxygen–glucose deprivation (OGD). Intraperitoneal (i.p.) injection of adult male C57Bl/6 mice with Ru265 (3 mg/kg) also suppressed HI-induced sensorimotor deficits and brain injury. However, higher doses of Ru265 (10 and 30 mg/kg, i.p.) produced dose-dependent increases in the frequency and duration of seizure-like behaviours. Ru265 is proposed to promote convulsions by reducing Ca2+ buffering and energy production in highly energetic interneurons that suppress brain seizure activity. These findings support the therapeutic potential of MCU inhibition in the treatment of ischemic stroke but also indicate that such clinical translation will require drug delivery strategies which mitigate the pro-convulsant effects of Ru265.

scholarly journals Neuroprotective effects of orientin on oxygen-glucose deprivation/reperfusion-induced cell injury in primary culture of rat cortical neurons

2017 ◽  
Vol 243 (1) ◽  
pp. 78-86 ◽  
Author(s):  
Tian Tian ◽  
Junan Zeng ◽  
Guangyu Zhao ◽  
Wenjing Zhao ◽  
Songyi Gao ◽  
...  
Keyword(s):  
Primary Culture ◽  
Cortical Neurons ◽  
Caspase 3 ◽  
Cell Injury ◽  
Antioxidant Properties ◽  
Glucose Deprivation ◽  
Oxygen Glucose Deprivation ◽  
Ros Generation ◽  
Neuroprotective Effects ◽  
Rat Cortical Neurons

Orientin (luteolin-8-C-glucoside) is a phenolic compound found abundantly in millet, juice, and peel of passion fruit and has been shown to have antioxidant properties. In the present study, we explored the effects of orientin on oxygen-glucose deprivation/reperfusion (OGD/RP)-induced cell injury in primary culture of rat cortical neurons using an in vitro model of neonatal ischemic brain injury. The reduced cell viability and elevated lactate dehydrogenase leakage were observed after OGD/RP exposure, which were then reversed by orientin (10, 20, and 30 µM) pretreatment in a dose-dependent manner. Additionally, OGD/RP treatment resulted in significant oxidative stress, accompanied by enhanced intracellular reactive oxygen species (ROS) generation, and obvious depletion in the activities of intracellular Mn-superoxide dismutase, catalase, and glutathione peroxidase antioxidases. However, these effects were dose dependently restored by orientin pretreatment. We also found that orientin pretreatment dose dependently suppressed [Ca2+]i increase and mitochondrial membrane potential dissipation caused by OGD/RP in primary culture of rat cortical neurons. Western blot analysis showed that OGD/RP exposure induced a distinct decrease of Bcl-2 protein and a marked elevation of Bax, caspase-3, and cleaved caspase-3 proteins; whereas these effects were dose dependently reversed by orientin incubation. Both the caspase-3 activity and the apoptosis rate were increased under OGD/RP treatment, but was then dose dependently down-regulated by orientin (10, 20, and 30 µM) incubation. Moreover, orientin pretreatment dose dependently inhibited OGD/RP-induced phosphorylation of JNK and ERK1/2. Notably, JNK inhibitor SP600125 and ERK1/2 inhibitor PD98059 also dramatically attenuated OGD/RP-induced cell viability loss and ROS generation, and further, orientin failed to protect cortical neurons with the interference of JNK activator anisomycin or ERK1/2 activator FGF-2. Taken together, these results demonstrated that orientin has significant neuroprotective effects against OGD/RP-induced cell injury via JNK and ERK1/2 signaling pathways in primary culture of rat cortical neurons. Impact statement Orientin has been used in traditional eastern medicine and reported to possess antioxidant properties. However, the effects of orientin on neonatal ischemic brain injury and the underlying mechanisms involved have not been studied. Our results showed that orientin exerts significant neuroprotective effects on cell injury caused by oxygen-glucose deprivation/reperfusion via the JNK and ERK1/2 signaling pathways in primary culture of rat cortical neurons, implying the potential therapeutic application of orientin via the suppression of oxidative stress and cell apoptosis. This research suggested that orientin may be used as a therapeutic and preventive option for newborn cerebral ischemia/reperfusion injury.

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