miR-137 boosts the neuroprotective effect of endothelial progenitor cell-derived exosomes in oxyhemoglobin-treated SH-SY5Y cells partially via COX2/PGE2 pathway

Abstract Background We have previously verified the beneficial effects of exosomes from endothelial progenitor cells (EPC-EXs) in ischemic stroke. However, the effects of EPC-EXs in hemorrhagic stroke have not been investigated. Additionally, miR-137 is reported to regulate ferroptosis and to be involved in the neuroprotection against ischemic stroke. Hence, the present work explored the effects of miR-137-overexpressing EPC-EXs on apoptosis, mitochondrial dysfunction, and ferroptosis in oxyhemoglobin (oxyHb)-injured SH-SY5Y cells. Methods The lentiviral miR-137 was transfected into EPCs and then the EPC-EXs were collected. RT-PCR was used to detect the miR-137 level in EPCs, EXs, and neurons. The uptake mechanisms of EPC-EXs in SH-SY5Y cells were explored by the co-incubation of Dynasore, Pitstop 2, Ly294002, and Genistein. After the transfection of different types of EPC-EXs, flow cytometry and expression of cytochrome c and cleaved caspase-3 were used to detect the apoptosis of oxyHb-injured neurons. Neuronal mitochondrial function was assessed by reactive oxygen species (ROS) level, mitochondrial membrane potential (MMP) depolarization, and cellular ATP content. Cell ferroptosis was measured by lipid peroxidation, iron overload, degradation of glutathione, and glutathione peroxidase 4. Additionally, recombinational PGE2 was used to detect if activation of COX2/PGE2 pathway could reverse the protection of miR-137 overexpression. Results The present work showed (1) EPC-EXs could be taken in by SH-SY5Y cells via caveolin-/clathrin-mediated pathways and macropinocytosis; (2) miR-137 was decreased in neurons after oxyHb treatment, and EXsmiR-137 could restore the miR-137 levels; (3) EXsmiR-137 worked better than EXs in reducing the number of apoptotic neurons and pro-apoptotic protein expression after oxyHb treatment; (4) EXsmiR-137 are more effective in improving the cellular MMP, ROS, and ATP level; (5) EXsmiR-137, but not EXs, protected oxyHb-treated SH-SY5Y cells against lipid peroxidation, iron overload, degradation of glutathione, and glutathione peroxidase 4; and (6) EXsmiR-137 suppressed the expression of the COX2/PGE2 pathway, and activation of the pathway could partially reverse the neuroprotective effects of EXsmiR-137. Conclusion miR-137 overexpression boosts the neuroprotective effects of EPC-EXs against apoptosis and mitochondrial dysfunction in oxyHb-treated SH-SY5Y cells. Furthermore, EXsmiR-137 rather than EXs can restore the decrease in miR-137 levels and inhibit ferroptosis, and the protection mechanism might involve the miR-137-COX2/PGE2 signaling pathway.

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MiR-137 Boosts the Neuroprotective Effect of Endothelial Progenitor Cell Derived-Exosomes in Oxyhemoglobin Treated SH-SY5Y Cells Partially via COX2/PGE2 Pathway

10.21203/rs.3.rs-20037/v2 ◽

2020 ◽

Author(s):

Yuchen Li ◽

Jinju Wang ◽

Shuzhen Chen ◽

Pei Wu ◽

Shancai Xu ◽

...

Keyword(s):

Lipid Peroxidation ◽

Ischemic Stroke ◽

Glutathione Peroxidase ◽

Iron Overload ◽

Mitochondrial Dysfunction ◽

Neuroprotective Effect ◽

Endothelial Progenitor ◽

Neuroprotective Effects ◽

Protection Mechanism ◽

Beneficial Effects

Abstract Background: We have previously verified the beneficial effects of exosomes from endothelial progenitor cells (EPC-EXs) in ischemic stroke. However, the effects of EPC-EXs in hemorrhagic stroke have not been investigated. Additionally, miR-137 is reported to regulate ferroptosis and to be involved in the neuroprotection against ischemic stroke. Hence, the present work explored the effects of miR-137-overexpressing EPC-EXs on apoptosis, mitochondrial dysfunction, and ferroptosis in oxyhemoglobin (oxyHb)-injured SH-SY5Y cells. Methods: The lentiviral miR-137 was transfected into EPCs and then the EPC-EXs were collected. RT-PCR was used to detect the miR-137 level in EPCs, EXs and neurons. The uptake mechanisms of EPC-EXs in SH-SY5Y cells were explored by the co-incubation of Dynasore, Pitstop 2, Ly294002 and Genistein. After the transfection of different types of EPC-EXs, flow cytometry and expression of cytochrome c and cleaved caspase-3 were used to detect the apoptosis of oxyHb-injured neurons. Neuronal mitochondrial function was assessed by reactive oxygen species (ROS) level, mitochondrial membrane potential (MMP) depolarization, and cellular ATP content. Cell ferroptosis was measured by lipid peroxidation, iron overload, degradation of glutathione and glutathione peroxidase 4. Additionally, recombinational PGE2 was used to detect if activation of COX2/PGE2 pathway could reverse the protection of miR-137 overexpression.Results: The present work showed 1) EPC-EXs could be taken in by SH-SY5Y cells via caveolin-/clathrin-mediated pathways and macropinocytosis; 2) miR-137 was decreased in neurons after oxyHb treatment, and EXsmiR-137 could restore the miR-137 levels; 3) EXsmiR-137 worked better than EXs in reducing the number of apoptotic neurons and pro-apoptotic protein expression after oxyHb treatment; 4) EXsmiR-137 are more effective in improving the cellular MMP, ROS and ATP level; 5) EXsmiR-137, but not EXs, protected oxyHb-treated SH-SY5Y cells against lipid peroxidation, iron overload, degradation of glutathione and glutathione peroxidase 4; 6) EXsmiR-137 suppressed the expression of the COX2/PGE2 pathway, and activation of the pathway could partially reverse the neuroprotective effects of EXsmiR-137. Conclusion: MiR-137 overexpression boosts the neuroprotective effects of EPC-EXs against apoptosis and mitochondrial dysfunction in oxyHb-treated SH-SY5Y cells. Furthermore, EXsmiR-137 rather than EXs can restore the decrease in miR-137 levels and inhibit ferroptosis, and the protection mechanism might involve the miR-137-COX2/PGE2 signaling pathway.

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MiR-137 Boosts the Neuroprotective Effect of Endothelial Progenitor Cell Derived-Exosomes in Oxyhemoglobin Treated SH-SY5Y Cells Partially via COX2/PGE2 Pathway

10.21203/rs.3.rs-20037/v1 ◽

2020 ◽

Author(s):

Yuchen Li ◽

Jinju Wang ◽

Shuzhen Chen ◽

Pei Wu ◽

Shancai Xu ◽

...

Keyword(s):

Lipid Peroxidation ◽

Ischemic Stroke ◽

Glutathione Peroxidase ◽

Iron Overload ◽

Mitochondrial Dysfunction ◽

Neuroprotective Effect ◽

Endothelial Progenitor ◽

Neuroprotective Effects ◽

Protection Mechanism ◽

Beneficial Effects

Abstract Background: We have previously verified the beneficial effects of exosomes from endothelial progenitor cells (EPC-EXs) in ischemic stroke. However, the effects of EPC-EXs in hemorrhagic stroke have not been investigated. Additionally, miR-137 is reported to regulate ferroptosis and to be involved in the neuroprotection against ischemic stroke. Hence, the present work explored the effects of miR-137-overexpressing EPC-EXs on apoptosis, mitochondrial dysfunction, and ferroptosis in oxyhemoglobin (oxyHb)-injured neurons.Methods: The lentiviral miR-137 was transfected into EPCs and then the EPC-EXs were collected. RT-PCR was used to detect the miR-137 level in EPCs, EXs and neurons. The uptake mechanisms of EPC-EXs in neurons were explored by the co-incubation of Dynasore, Pitstop 2, Ly294002 and Genistein. After the transfection of different types of EPC-EXs, flow cytometry and expression of cytochrome c and cleaved caspase-3 were used to detect the apoptosis of oxyHb-injured neurons. Neuronal mitochondrial function was assessed by reactive oxygen species (ROS) level, mitochondrial membrane potential (MMP) depolarization, and cellular ATP content. Cell ferroptosis was measured by lipid peroxidation, iron overload, degradation of glutathione and glutathione peroxidase 4. Additionally, recombinational PGE2 was used to detect if activation of COX2/PGE2 pathway could reverse the protection of miR-137 overexpression.Results: The present work showed 1) EPC-EXs could be taken in by SH-SY5Y cells via caveolin-/clathrin-mediated pathways and macropinocytosis; 2) miR-137 was decreased in neurons after oxyHb treatment, and EXs miR-137 could restore the miR-137 levels; 3) EXs miR-137 worked better than EXs in reducing the number of apoptotic neurons and pro-apoptotic protein expression after oxyHb treatment; 4) EXs miR-137 are more effective in improving the cellular MMP, ROS and ATP level; 5) EXs miR-137 , but not EXs, protected oxyHb-treated neurons against lipid peroxidation, iron overload, degradation of glutathione and glutathione peroxidase 4; 6) EXs miR-137 suppressed the expression of the COX2/PGE2 pathway, and activation of the pathway could partially reverse the neuroprotective effects of EXs miR-137 .Conclusion: MiR-137 overexpression boosts the neuroprotective effects of EPC-EXs against apoptosis and mitochondrial dysfunction in oxyHb-treated neurons. Furthermore, EXs miR-137 rather than EXs can restore the decrease in miR-137 levels and inhibit ferroptosis, and the protection mechanism might involve the miR-137-COX2/PGE2 signaling pathway.

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Long-Term Caloric Restriction Attenuates β-Amyloid Neuropathology and Is Accompanied by Autophagy in APPswe/PS1delta9 Mice

Nutrients ◽

10.3390/nu13030985 ◽

2021 ◽

Vol 13 (3) ◽

pp. 985

Author(s):

Luisa Müller ◽

Nicole Power Guerra ◽

Jan Stenzel ◽

Claire Rühlmann ◽

Tobias Lindner ◽

...

Keyword(s):

Caloric Restriction ◽

Neuroprotective Effect ◽

Resonance Spectroscopy ◽

Neuroprotective Effects ◽

Beneficial Effects ◽

Positron Emission ◽

Pet Ct ◽

Amyloid Aβ ◽

Β Amyloid

Caloric restriction (CR) slows the aging process, extends lifespan, and exerts neuroprotective effects. It is widely accepted that CR attenuates β-amyloid (Aβ) neuropathology in models of Alzheimer’s disease (AD) by so-far unknown mechanisms. One promising process induced by CR is autophagy, which is known to degrade aggregated proteins such as amyloids. In addition, autophagy positively regulates glucose uptake and may improve cerebral hypometabolism—a hallmark of AD—and, consequently, neural activity. To evaluate this hypothesis, APPswe/PS1delta9 (tg) mice and their littermates (wild-type, wt) underwent CR for either 16 or 68 weeks. Whereas short-term CR for 16 weeks revealed no noteworthy changes of AD phenotype in tg mice, long-term CR for 68 weeks showed beneficial effects. Thus, cerebral glucose metabolism and neuronal integrity were markedly increased upon 68 weeks CR in tg mice, indicated by an elevated hippocampal fluorodeoxyglucose [18F] ([18F]FDG) uptake and increased N-acetylaspartate-to-creatine ratio using positron emission tomography/computer tomography (PET/CT) imaging and magnet resonance spectroscopy (MRS). Improved neuronal activity and integrity resulted in a better cognitive performance within the Morris Water Maze. Moreover, CR for 68 weeks caused a significant increase of LC3BII and p62 protein expression, showing enhanced autophagy. Additionally, a significant decrease of Aβ plaques in tg mice in the hippocampus was observed, accompanied by reduced microgliosis as indicated by significantly decreased numbers of iba1-positive cells. In summary, long-term CR revealed an overall neuroprotective effect in tg mice. Further, this study shows, for the first time, that CR-induced autophagy in tg mice accompanies the observed attenuation of Aβ pathology.

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Neurotherapeutic Effect of Inula britannica var. Chinensis against H2O2-Induced Oxidative Stress and Mitochondrial Dysfunction in Cortical Neurons

Antioxidants ◽

10.3390/antiox10030375 ◽

2021 ◽

Vol 10 (3) ◽

pp. 375

Author(s):

Jin Young Hong ◽

Hyunseong Kim ◽

Junseon Lee ◽

Wan-Jin Jeon ◽

Seung Ho Baek ◽

...

Keyword(s):

Oxidative Stress ◽

Mitochondrial Dysfunction ◽

Cortical Neurons ◽

Inflammatory Diseases ◽

Neuroprotective Effect ◽

Neuroprotective Effects ◽

Neuronal Viability ◽

Inula Britannica ◽

Oxidative Effects

Inula britannica var. chinensis (IBC) has been used as a traditional medicinal herb to treat inflammatory diseases. Although its anti-inflammatory and anti-oxidative effects have been reported, whether IBC exerts neuroprotective effects and the related mechanisms in cortical neurons remain unknown. In this study, we investigated the effects of different concentrations of IBC extract (5, 10, and 20 µg/mL) on cortical neurons using a hydrogen peroxide (H2O2)-induced injury model. Our results demonstrate that IBC can effectively enhance neuronal viability under in vitro-modeled reaction oxygen species (ROS)-generating conditions by inhibiting mitochondrial ROS production and increasing adenosine triphosphate level in H2O2-treated neurons. Additionally, we confirmed that neuronal death was attenuated by improving the mitochondrial membrane potential status and regulating the expression of cytochrome c, a protein related to cell death. Furthermore, IBC increased the expression of brain-derived neurotrophic factor and nerve growth factor. Furthermore, IBC inhibited the loss and induced the production of synaptophysin, a major synaptic vesicle protein. This study is the first to demonstrate that IBC exerts its neuroprotective effect by reducing mitochondria-associated oxidative stress and improving mitochondrial dysfunction.

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Sirtuin 3 Mediates Neuroprotection of Ketones against Ischemic Stroke

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2015.123 ◽

2015 ◽

Vol 35 (11) ◽

pp. 1783-1789 ◽

Cited By ~ 54

Author(s):

Junxiang Yin ◽

Pengcheng Han ◽

Zhiwei Tang ◽

Qingwei Liu ◽

Jiong Shi

Keyword(s):

Ischemic Stroke ◽

Ketone Bodies ◽

Infarct Volume ◽

Field Tests ◽

Underlying Mechanism ◽

Sirtuin 3 ◽

Neuroprotective Effects ◽

Beneficial Effects ◽

Beta Hydroxybutyrate

Stroke is one of the leading causes of death. Growing evidence indicates that ketone bodies have beneficial effects in treating stroke, but their underlying mechanism remains unclear. Our previous study showed ketone bodies reduced reactive oxygen species by using NADH as an electron donor, thus increasing the NAD+/NADH ratio. In this study, we investigated whether mitochondrial NAD+-dependent Sirtuin 3 (SIRT3) could mediate the neuroprotective effects of ketone bodies after ischemic stroke. We injected mice with either normal saline or ketones (beta-hydroxybutyrate and acetoacetate) at 30 minutes after ischemia induced by transient middle cerebral artery (MCA) occlusion. We found that ketone treatment enhanced mitochondria function, reduced oxidative stress, and therefore reduced infarct volume. This led to improved neurologic function after ischemia, including the neurologic score and the performance in Rotarod and open field tests. We further showed that ketones' effects were achieved by upregulating NAD+-dependent SIRT3 and its downstream substrates forkhead box O3a (FoxO3a) and superoxide dismutase 2 (SOD2) in the penumbra region since knocking down SIRT3 in vitro diminished ketones' beneficial effects. These results provide us a foundation to develop novel therapeutics targeting this SIRT3-FoxO3a-SOD2 pathway.

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American Ginseng (Panax quinquefolium L.) as a Source of Bioactive Phytochemicals with Pro-Health Properties

Nutrients ◽

10.3390/nu11051041 ◽

2019 ◽

Vol 11 (5) ◽

pp. 1041 ◽

Cited By ~ 8

Author(s):

Daria Szczuka ◽

Adriana Nowak ◽

Małgorzata Zakłos-Szyda ◽

Ewa Kochan ◽

Grażyna Szymańska ◽

...

Keyword(s):

Ischemic Stroke ◽

Contractile Function ◽

Neuronal Damage ◽

American Ginseng ◽

Anxiolytic Activity ◽

Panax Quinquefolium ◽

Cardiac Contractile Function ◽

Neuroprotective Effects ◽

Beneficial Effects ◽

Model Of Alzheimer’S Disease

Panax quinquefolium L. (American Ginseng, AG) is an herb characteristic for regions of North America and Asia. Due to its beneficial properties it has been extensively investigated for decades. Nowadays, it is one of the most commonly applied medical herbs worldwide. Active compounds of AG are ginsenosides, saponins of the glycosides group that are abundant in roots, leaves, stem, and fruits of the plant. Ginsenosides are suggested to be primarily responsible for health-beneficial effects of AG. AG acts on the nervous system; it was reported to improve the cognitive function in a mouse model of Alzheimer’s disease, display anxiolytic activity, and neuroprotective effects against neuronal damage resulting from ischemic stroke in animals, demonstrate anxiolytic activity, and induce neuroprotective effects against neuronal damage in ischemic stroke in animals. Administration of AG leads to inhibition of hypertrophy in heart failure by regulation of reactive oxygen species (ROS) in mice as well as depletion of cardiac contractile function in rats. It also has an anti-diabetic and anti-obesity potential as it increases insulin sensitivity and inhibits formation of adipose tissue. AG displays anti-cancer effect by induction of apoptosis of cancer cells and reducing local inflammation. It exerts antimicrobial effects against several pathogenic strains of bacteria. Therefore, AG presents a high potential to induce beneficial health effects in humans and should be further explored to formulate precise nutritional recommendations, as well as to assess its value in prevention and therapy of some disorders, including cancer.

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Neuroprotective Effects of Tempol, a Catalytic Scavenger of Peroxynitrite-Derived Free Radicals, in a Mouse Traumatic Brain Injury Model

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2008.10 ◽

2008 ◽

Vol 28 (6) ◽

pp. 1114-1126 ◽

Cited By ~ 94

Author(s):

Ying Deng-Bryant ◽

Indrapal N Singh ◽

Kimberly M Carrico ◽

Edward D Hall

Keyword(s):

Traumatic Brain Injury ◽

Free Radicals ◽

Brain Injury ◽

Oxidative Damage ◽

Mitochondrial Dysfunction ◽

Neuroprotective Effect ◽

Complete Suppression ◽

Post Injury ◽

Multiple Dosing ◽

Neuroprotective Effects

We examined the ability of tempol, a catalytic scavenger of peroxynitrite (PN)-derived free radicals, to reduce cortical oxidative damage, mitochondrial dysfunction, calpain-mediated cytoskeletal (α-spectrin) degradation, and neurodegeneration, and to improve behavioral recovery after a severe (depth 1.0 mm), unilateral controlled cortical impact traumatic brain injury (CCI-TBI) in male CF-1 mice. Administration of a single 300 mg/kg intraperitoneal dose of tempol 15 mins after TBI produced a complete suppression of PN-mediated oxidative damage (3-nitrotyrosine, 3NT) in injured cortical tissue at 1 h after injury. Identical tempol dosing maintained respiratory function and attenuated 3NT in isolated cortical mitochondria at 12 h after injury, the peak of mitochondrial dysfunction. Multiple dosing with tempol (300 mg/kg intraperitoneally at 15 mins, 3, 6, 9, and 12 h) also suppressed α-spectrin degradation by 45% at its 24 h post-injury peak. The same dosing regimen improved 48 h motor function and produced a significant, but limited (17.4%, P<0.05), decrease in hemispheric neurodegeneration at 7 days. These results are consistent with a mechanistic link between PN-mediated oxidative damage to brain mitochondria, calpain-mediated proteolytic damage, and neurodegeneration. However, the modest neuroprotective effect of tempol suggests that multitarget combination strategies may be needed to interfere with posttraumatic secondary injury to a degree worthy of clinical translation.

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Post-stroke treatment with argon preserved neurons and attenuated microglia/macrophage activation long-termly in a rat model of transient middle cerebral artery occlusion (tMCAO)

Scientific Reports ◽

10.1038/s41598-021-04666-x ◽

2022 ◽

Vol 12 (1) ◽

Author(s):

Jingjin Liu ◽

Michael Veldeman ◽

Anke Höllig ◽

Kay Nolte ◽

Lisa Liebenstund ◽

...

Keyword(s):

Ischemic Stroke ◽

Macrophage Activation ◽

Neuroprotective Effect ◽

Macrophage Polarization ◽

Artery Occlusion ◽

Brain Inflammation ◽

Long Term Effects ◽

Neuroprotective Effects ◽

Stroke Treatment

AbstractIn a previous study from our group, argon has shown to significantly attenuate brain injury, reduce brain inflammation and enhance M2 microglia/macrophage polarization until 7 days after ischemic stroke. However, the long-term effects of argon have not been reported thus far. In the present study, we analyzed the underlying neuroprotective effects and potential mechanisms of argon, up to 30 days after ischemic stroke. Argon administration with a 3 h delay after stroke onset and 1 h after reperfusion demonstrated long-term neuroprotective effect by preserving the neurons at the ischemic boundary zone 30 days after stroke. Furthermore, the excessive microglia/macrophage activation in rat brain was reduced by argon treatment 30 days after ischemic insult. However, long-lasting neurological improvement was not detectable. More sensorimotor functional measures, age- and disease-related models, as well as further histological and molecular biological analyses will be needed to extend the understanding of argon’s neuroprotective effects and mechanism of action after ischemic stroke.

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Neuroprotective Effects of Purple Sweet Potato Balinese Cultivar in Wistar Rats With Ischemic Stroke

Open Access Macedonian Journal of Medical Sciences ◽

10.3889/oamjms.2018.435 ◽

2018 ◽

Vol 6 (11) ◽

pp. 1959-1964 ◽

Cited By ~ 2

Author(s):

I Made Oka Adnyana ◽

AA Raka Sudewi ◽

DPG Purwa Samatra ◽

DN Suprapta

Keyword(s):

Ischemic Stroke ◽

Cytochrome C ◽

Sweet Potato ◽

Ipomoea Batatas ◽

Caspase 3 ◽

Neuroprotective Effect ◽

Control Group ◽

Neuroprotective Effects ◽

Apoptosis Rate ◽

Purple Sweet Potato

BACKGROUND: Purple sweet potato (Ipomoea Batatas L.) is one of the sources for anthocyanin, which promotes the health through antioxidant, anti-inflammatory, anti-cancer, neuroprotection, and anti-apoptosis activities. Oxidative stress has been shown to be the cause of apoptosis in ischemic stroke. AIM: The objective of this research was to delineate the pleiotropic effects of anthocyanin for neuroprotection during an acute stroke event. METHODS: Anthocyanin was extracted from Balinese cultivar of purple sweet potato and subsequently administered to rat models of induced ischemic stroke (labelled as treatment group), as well as a placebo (labelled as a control group). Several parameters were in turn evaluated, i.e. the activities of anti-apoptotic (Bcl-2) as well as pro-apoptotic (cytochrome c, caspase-3) molecules, and apoptosis rate. Bcl-2 levels were determined using the histochemical method, cytochrome c and caspase-3 via ELISA method, while apoptosis rate was measured by TdT-medicated Dutp-Nick End Labeling (TUNEL) assay. RESULTS: Bcl-2 expression demonstrated significantly higher Bcl-2 expression in the treatment compared with control group (median 31.2 vs. 1.1; p = 0.001). Accordingly, pro-apoptotic cytochrome c and caspase-3 levels were also found significantly lower in the treatment as opposed to control group (mean 4.17 vs. 8.06; p = 0.001; mean 3.81 vs. 8.02; p = 0.001). Ultimately, apoptosis rate was found markedly lower among treatment than control groups (mean 3.81 vs. control 21.97; p = 0.003). CONCLUSION: The results of this study indicated a significant neuroprotective effect of anthocyanin derived from Balinese cultivar of PSP. Anthocyanin was able to increase and reduce anti-apoptotic and pro-apoptotic protein levels, respectively, resulting in lesser cellular apoptotic rate when compared with placebo. The potential mechanism was thought mainly due to its anti-oxidant properties.

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Chronic Alcohol Intoxication and Cortical Ischemia: Study of Their Comorbidity and the Protective Effects of Minocycline

Oxidative Medicine and Cellular Longevity ◽

10.1155/2016/1341453 ◽

2016 ◽

Vol 2016 ◽

pp. 1-10 ◽

Cited By ~ 15

Author(s):

Enéas Andrade Fontes-Júnior ◽

Cristiane Socorro Ferraz Maia ◽

Luanna Melo Pereira Fernandes ◽

Walace Gomes-Leal ◽

Allan Costa-Malaquias ◽

...

Keyword(s):

Lipid Peroxidation ◽

Ischemic Stroke ◽

Alcohol Intoxication ◽

Neuroprotective Effect ◽

Neuronal Loss ◽

Protective Effects ◽

Chronic Alcohol ◽

Cellular Density ◽

Chronic Alcohol Intoxication ◽

Cortical Ischemia

Chronic alcohol intoxication (CAI) increases both morbidity and mortality of stroke patients. Despite the high prevalence of CAI and ischemic stroke, studies addressing their comorbidity and/or protective alternatives remain scarce. Thus, the influence of CAI on both stroke outcome and minocycline treatment (recognized for its neuroprotective effect) was investigated. Female Wistar rats (35 days old) were treated with water or ethanol (6.5 g/kg/day, 22.5% w/v) for 55 days. Then, focal ischemia was induced by endothelin-1 in the motor cortex. Two hours later, four doses of 50 mg/kg of minocycline every 12 hours followed by five doses of 25 mg/kg every 24 hours were administered. Behavioral performance (open field and rotarod tests) and immunohistochemical (cellular density, neuronal death, and astrocytic activation) and biochemical (lipid peroxidation and nitrite levels) analyses were performed. CAI increased motor disruption, nitrite and lipid peroxidation levels, and neuronal loss caused by ischemia, whereas it reduced the astrogliosis. Minocycline was effective in preventing the motor and tissue damage caused by stroke. However, these effects were attenuated when CAI preceded stroke. Our data suggest that CAI beginning in adolescence contributes to a worse outcome in ischemic stroke survivors and reduces the benefits of minocycline, possibly requiring adjustments in therapy.

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