Brain Tissue Malondialdehyde Research Articles

Angelica keiskei leaves extract attenuates psychosocial stress in overcrowding-subjected rats

Angelica keiskei is currently used as a popular functional food with various beneficial effects, including antioxidant, anti-obesity, anti-tumor, anti-diabetic, and anti-bacterial. A recent in vitro study reported that A. keiskei inhibits monoamine oxidases (MAOs), suggesting the antidepressant property of A. keiskei. However, in vivo studies on laboratory animals subjected to psychosocial stress have not been conducted. In this study, the effects of an A. keiskei leaf extract (AKE) on rats undergoing chronic social overcrowding stress were explored. Six-month-old male and female Wistar rats were housed in groups of three in 12 × 12 × 18 cm cages (overcrowding) for 28 days. Both male and female rats were divided into two groups (N = 10); the control group received oral distilled water, while the other group (treatment group) received 20 mg/kgBW/day of AKE supplementation. The results showed that AKE-treated rats exhibited lower anxiety- and depressive-related behaviors than that of control-stressed rats. AKE significantly decreased corticosterone and increased testosterone and estrogen levels in stressed rats. Additionally, brain tissue malondialdehyde and TNF-alpha levels were reduced, while brain neurotransmitter 5-hydroxytryptamine and antioxidant superoxide dismutase levels were elevated by the AKE. These findings suggest, for the first time, that AKE could alleviate overcrowding stress-induced behavioral, neuroendocrine, antioxidant, and inflammatory dysfunctions. AKE extract could potentially be used as an agonist to reduce stress and depression.

Protective Effect of Daidzein on Ifosfamide-Induced Neurotoxicity Via Improving Some Selected Oxidative Stress Parameters in Male Rats

In this study, the possible protective effects of daidzein on ifosfamide-induced neurotoxicity in male rats were examined by the determination of changes in selected oxidant–antioxidant markers of male rats’ brain tissue.
 Twenty-eight (28) apparently-healthy Wistar male rats weighing (120-150gm) allocated into 4 groups (n=7) were used in this study. Rats orally-administered 1% tween 20 dissolved in distilled water/Control (Group I); rats were orally-administered daidzein suspension (100mg/kg) for 7 days (Group II); rats intraperitoneally-injected with a single dose of ifosfamide (500 mg/kg) (Group III); rats orally-administered for 7 days with the daidzein (100mg/kg) before a single intraperitoneal dose of ifosfamide (500 mg/kg) at day 7 (Group IV). Twenty-four (24) hours after the end of treatment, determination of the malondialdehyde, reduced glutathione, and superoxide dismutase enzyme activity levels in the rats’ brain tissue homogenate were performed; in addition to the histopathological examination of the brain tissues sections. Results showed that the levels of malondialdehyde in brain tissue were significantly-increased (P<0.05) in (Group III/ifosfamide-only) rats compared to such level in the rats’ brain tissue of controls (Group I). Furthermore, the brain tissue level of the malondialdehyde was significantly-decreased (P<0.05) in rats of Group IV (orally-administered DZN prior to IFO) compared to such tissue level in rats of Group III. Moreover, the brain levels of each of the reduced glutathione and the superoxide dismutase enzyme activity were significantly-decreased (P<0.05) in (Group III) compared to each level in those of Group I. Additionally, the brain levels of each of the antioxidant parameters was significantly-increase (P<0.05) in Group IV rats compared to each of these tissue levels in rats of Group III.
 As a results, daidzein has a protective effect against ifosfamide-induced neurotoxicity in rats via improving some selected oxidative stress parameters in male rats.

Evaluation of prenatal administration of valproic acid on the cerebellum of albino rat offspring

Introduction: Autism is a severe neurodevelopmental disorder of poorly understood etiology; which may be genetic, epigenetic or environmental. Valproic acid (VPA), the most widely used antiepileptic drug, has been reported to increase the risk of autism among the offspring of human mothers who are medicated with it during early pregnancy. Aim: The current work aimed to study the biochemical and histological changes in the cerebellum of the offspring of prenatally VPA treated rats. Materials and Methods: Twelve pregnant female albino rats were divided into two groups; control and VPA treated (50 mg/kg/day orally). The cerebellar sections of male offspring rats were subjected to biochemical tests (brain tissue Malondialdehyde (MDA), Superoxide dismutase (SOD), Tumor necrosis factor-alpha (TNF-α) and glutamate), histological examination, immunohistochemical analyses for the expression of glial fibrillary acidic protein (GFAP) and Bcl-2 associated X protein (Bax), and electro microscopical studies. Results: VPA caused significant elevation in the brain levels of oxidative stress marker MDA, proinflammatory cytokine TNF-α and excitatory neurotransmitter glutamate, with significant reduction in the level of brain antioxidant marker SOD, compared to the control group.

The correlation between oxidative stress markers and increasing intracranial pressure: a study of Malondialdehyde (MDA), Superoxide Dismutase (MnSOD), Nicotinamide Adenine Dinucleotide Phosphate Hydrogen (NADPH), and catalase

Link of Video Abstract: https://youtu.be/nINFPi4uVow Background: Abnormalities in the neurosurgical field concerning cranial structure are almost always followed by increased intracranial pressure (ICP), which causes cerebral hypoxia and disrupts the whole cellular system. This study analyzes the correlation between ICP changes and oxidative stress markers, in subjects with various anatomical pathology abnormalities who underwent surgery. Methods: This was a cross sectional study of 24 subjects with ICP conducted in the Department of Neurosurgery, Cipto Mangunkusumo Hospital, Jakarta, from November to December 2009. In this study, ANOVA analysis has been done to measure the mean difference oxidative stress (MnSOD, NADPH, MDA, and catalase) in subjects with various changes in ICP who have undergone surgery and Spearman analysis to measure the correlation between each oxidative stress markers. Oxidative stress markers were measured from normal brain tissue taken intra-operatively, cerebrospinal fluid (CSF) taken while doing ventriculostomy, and peripheral blood taken from a central vein catheter (CVC). Results: The results showed that MDA concentrations in blood were significantly correlated with MDA in brain tissue (P = 0.029) in all of the ICP groups, CSF MnSOD concentration and CSF NADPH concentrations correlated with brain tissue NAPDH (p= 0.000) in congenital group and CSF catalase concentration correlated with brain tissue catalase (p = 0.00) in congenital group. Conclusion: Increased ICP caused by various pathological conditions causes changes in oxidative stress markers in brain cells, CSF and blood. Oxidative stress markers in blood and CSF are correlated strongly with the brain. It is suggested that it could be used to predict intracranial high pressure in all cases with intracranial abnormalities.

Chrysin alleviates cerebral ischemia-reperfusion injury by inhibiting ferroptosis in rats

The purpose of this study is to investigate whether chrysin reduces cerebral ischemia-reperfusion injury(CIRI) by inhi-biting ferroptosis in rats. Male SD rats were randomly divided into a sham group, a model group, high-, medium-, and low-dose chrysin groups(200, 100, and 50 mg·kg~(-1)), and a positive drug group(Ginaton, 21.6 mg·kg~(-1)). The CIRI model was induced in rats by transient middle cerebral artery occlusion(tMCAO). The indexes were evaluated and the samples were taken 24 h after the operation. The neurological deficit score was used to detect neurological function. The 2,3,5-triphenyl tetrazolium chloride(TTC) staining was used to detect the cerebral infarction area. Hematoxylin-eosin(HE) staining and Nissl staining were used to observe the morphological structure of brain tissues. Prussian blue staining was used to observe the iron accumulation in the brain. Total iron, lipid pero-xide, and malondialdehyde in serum and brain tissues were detected by biochemical reagents. Real-time quantitative polymerase chain reaction(RT-qPCR), immunohistochemistry, and Western blot were used to detect mRNA and protein expression of solute carrier fa-mily 7 member 11(SLC7A11), transferrin receptor 1(TFR1), glutathione peroxidase 4(GPX4), acyl-CoA synthetase long chain family member 4(ACSL4), and prostaglandin-endoperoxide synthase 2(PTGS2) in brain tissues. Compared with the model group, the groups with drug intervention showed restored neurological function, decreased cerebral infarction rate, and alleviated pathological changes. The low-dose chrysin group was selected as the optimal dosing group. Compared with the model group, the chrysin groups showed reduced content of total iron, lipid peroxide, and malondialdehyde in brain tissues and serum, increased mRNA and protein expression levels of SLC7A11 and GPX4, and decreased mRNA and protein expression levels of TFR1, PTGS2, and ACSL4. Chrysin may regulate iron metabolism via regulating the related targets of ferroptosis and inhibit neuronal ferroptosis induced by CIRI.

UHPLC-ESI-QE-Orbitrap-MS based metabolomics reveals the antioxidant mechanism of icaritin on mice with cerebral ischemic reperfusion.

Icaritin (ICT) has been previously demonstrated to display protective effects against cerebral ischemic reperfusion (I/R) by inhibiting oxidative stress, but the mechanism remains unclear. This study aimed to explore the mechanism from the perspective of metabolomics. A mice cerebral artery occlusion/reperfusion (MCAO/R) model was explored to mimic cerebral ischemic reperfusion and protective effect of ICT was assessed by neurologic deficit scoring, infarct volume and brain water content. Ultra-high-performance liquid chromatography electrospray ionization orbitrap tandem mass spectrometry (UHPLC-ESI-QE-Orbitrap-MS) based metabolomic was performed to explore potential biomarkers. Brain tissue metabolic profiles were analyzed and metabolic biomarkers were identified through multivariate data analysis. The protein levels of Nrf2, HO-1 and HQO1 were assayed by western blot. The release of malondialdehyde (MDA) and the activity of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT) were detected using corresponding assay kits. The results showed that after ICT treatment, the neurological deficit, cerebral infarction area, brain edema and the level of MDA in brain tissue of MCAO/R mice were significantly reduced. Meanwhile, ICT enhanced the activity of SOD, CAT and GSH-Px. Western blot results confirmed that ICT up-regulated the protein levels of antioxidant-related protein including Nrf2, HO-1 and NQO1. According to the metabolomic profiling of brain tissues, clear separations were observed among the Sham, Model and ICT groups. A total of 44 biomarkers were identified, and the identified biomarkers were mainly related to linoleic acid metabolism, arachidonic acid metabolism, alanine, aspartate and glutamate metabolism, arginine biosynthesis, arginine and proline metabolism, D-glutamine and D-glutamate metabolism, taurine and hypotaurine metabolism and purine metabolism, respectively. At the same time, the inhibitory effect of ICT on arachidonic acid and linoleic acid in brain tissue, as well as the promoting effect on taurine, GABA, NAAG, may be the key factors for the anti-neurooxidative function of mice after MCAO/R injury. Our results demonstrate that ICT has benefits for MCAO/R injury, which are partially related to the suppression of oxidative stress via stimulating the Nrf2 signaling and regulating the production of arachidonic acid, linoleic acid, taurine, GABA, NAAG in brain tissue.

Neuroprotective effects of Vaccinium myrtillus on damage-related brain injury

Traumatic brain injury may trigger the secondary brain injury, which has the potential to be reversible and thus preventable. Anthocyanins are phylotherapeutic plants, which are reported to exhibit anti-inflammatory properties. This study aimed to evaluate the therapeutic efficiency of an anthocyanin, namely Vaccinium myrtillus, to alleviate secondary brain injury and identify possible mechanism of actions.It is hypothesized that lipid peroxidation and Na+ -K+ -ATPase activity may be involved in neuronal ischemia. Thus, brain tissue Malondialdehyde content, Na+ -K+ -ATPase content, and cleaved caspase-3 content was investigated following moderate head trauma in a rat model. Twenty-four Sprague-Dawley male rats were allocated into four groups: Control, Trauma, Solvent-Control, and Treatment.Trauma and Solvent-Control groups showed more prominent brain edema, neuronal ischemia, vascular congestion, increase in brain tissue Malondialdehyde and cleaved caspase-3 levels, and decreased Na+-K+-ATPase activity compared to the Control group. Although the Treatment group had comparable histological signs to the Trauma and Solvent-Control groups, Malondialdehyde level and Na+-K+-ATPase activity was similar to Control group, and cleaved caspase-3 levels were lower compared to Trauma and Solvent-Control groups. We conclude that anthocyanin extracts may alleviate secondary brain injury via anti-oxidative and anti-apoptotic mechanisms.

Inhaled Carbon Dioxide Improves Neurological Outcomes by Downregulating Hippocampal Autophagy and Apoptosis in an Asphyxia-Induced Cardiac Arrest and Resuscitation Rat Model.

Background Protracted cerebral hypoperfusion following cardiac arrest (CA) may cause poor neurological recovery. We hypothesized that inhaled carbon dioxide (CO2) could augment cerebral blood flow (CBF) and improve post-CA neurological outcomes. Methods and Results After 6-minute asphyxia-induced CA and resuscitation, Wistar rats were randomly allocated to 4 groups (n=25/group) and administered with different inhaled CO2 concentrations, including control (0% CO2), 4% CO2, 8% CO2, and 12% CO2. Invasive monitoring was maintained for 120 minutes, and neurological outcomes were evaluated with neurological function score at 24 hours post-CA. After the 120-minute experiment, CBF was 242.3% (median; interquartile range, 221.1%-267.4%) of baseline in the 12% CO2 group while CBF fell to 45.8% (interquartile range, 41.2%-58.1%) of baseline in the control group (P<0.001). CBF increased along with increasing inhaled CO2 concentrations with significant linear trends (P<0.001). At 24 hours post-CA, compared with the control group (neurological function score, 9 [interquartile range, 8-9]), neurological recovery was significantly better in the 12% CO2 group (neurological function score, 10 [interquartile range, 9.8-10]) (P<0.001) while no survival difference was observed. Brain tissue malondialdehyde (P=0.02) and serum neuron-specific enolase (P=0.002) and S100β levels (P=0.002) were significantly lower in the 12% CO2 group. TUNEL (terminal deoxynucleotidyl transferase-mediated biotin-deoxyuridine triphosphate nick-end labeling)-positive cell densities in hippocampal CA1 (P<0.001) and CA3 (P<0.001) regions were also significantly reduced in the 12% CO2 group. Western blotting showed that beclin-1 (P=0.02), p62 (P=0.02), and LAMP2 (lysosome-associated membrane protein 2) (P=0.01) expression levels, and the LC3B-II:LC3B-I ratio (P=0.02) were significantly lower in the 12% CO2 group. Conclusions Administering inhaled CO2 augmented post-CA CBF, mitigated oxidative brain injuries, ameliorated neuronal injury, and downregulated apoptosis and autophagy, thereby improving neurological outcomes.

Edaravone Dexborneol Alleviates Cerebral Ischemic Injury via MKP-1-Mediated Inhibition of MAPKs and Activation of Nrf2.

The edaravone and dexborneol concentrated solution for injection (edaravone-dexborneol) is a medication used clinically to treat neurological impairment induced by ischemic stroke. This study was aimed at investigating the preventive effects and the underlying mechanisms of edaravone-dexborneol on cerebral ischemic injury. A rat four-vessel occlusion (4-VO) model was established, and the neuronal injury and consequent neurological impairment of rats was investigated. Brain tissue malondialdehyde (MDA), myeloperoxidase (MPO), and nitric oxide (NO) levels were determined. The levels of proteins in mitogen-activated protein kinases (MAPKs), nuclear factor erythroid 2-related factor 2 (Nrf2), and nuclear factor-κB (NF-κB) signaling pathways were determined by western immunoblotting. The function of mitogen-activated protein kinase phosphatase 1 (MKP-1) was investigated using both western blot and immunofluorescence methods, and the effect of the MKP-1 inhibitor, (2E)-2-benzylidene-3-(cyclohexylamino)-3H-inden-1-one (BCI), was investigated. The results indicated that edaravone-dexborneol alleviated neurological deficiency symptoms and decreased apoptosis and neuron damage in the hippocampal CA1 area of the ischemic rats. Edaravone-dexborneol increased the MKP-1 level; decreased the phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (p38 MAPK); inhibited NF-κB p65 activation; and boosted Nrf2 activation, all of which were partially reversed by the MKP-1 inhibitor, BCI. The above results indicated that the upregulation of MKP-1 contributed to the protective effects of edaravone-dexborneol against ischemic brain injury. Our findings support the hypothesis that edaravone-dexborneol can alleviate cerebral ischemic injury via the upregulation of MKP-1, which inhibits MAPKs and activates Nrf2.

Ginkgolide B‑mediated therapeutic effects on perioperative neurocognitive dysfunction are associated with the inhibition of iNOS‑mediated production of NO.

Perioperative neurocognitive dysfunction (PND) is a prevalent neurological complication after anesthesia and surgery. Ginkgolide B (GB) has been suggested to improve lipopolysaccharide-induced learning and memory impairment. The present study aimed to investigate whether GB serves a protective role against PND by inhibiting inducible nitric oxide synthase (iNOS) and nitric oxide (NO). Abdominal surgery was performed on 10- to 12-week-old male C57BL/6 mice under isoflurane anesthesia. Prior to surgery, 1400W (a specific iNOS inhibitor) and GB were administered via intraperitoneal injection. Open field and fear conditioning tests were conducted to assess cognitive function on postoperative days 1 and 3. Biochemical assays were performed to evaluate alterations in NO, malondialdehyde (MDA) and superoxide dismutase (SOD) levels. Western blotting was performed to measure iNOS expression in the hippocampus on postoperative day 1. In addition, hematoxylin and eosin staining was performed to detect the neuronal morphology in the hippocampus. Following treatment with 1400W or GB, surgery-induced cognitive dysfunction was improved. Compared with the control group, the surgery group exhibited significant overproduction of iNOS and MDA in the hippocampus on postoperative day 1. Higher levels of NO were also detected in the hippocampus and prefrontal cortex of the surgery group on postoperative day 1. Furthermore, pretreatment with 1400W or GB significantly inhibited the surgery-induced elevation of NO and MDA in brain tissues. Moreover, GB pretreatment significantly inhibited surgery-induced downregulation of SOD and upregulation of iNOS. Surgery-induced increases in neuronal loss and the Bax/Bcl-2 ratio in the hippocampus were significantly inhibited by pretreatment with GB. Collectively, the results of the present study demonstrated that the therapeutic effects of GB on PND were associated with inhibition of iNOS-induced NO production, increased SOD, and the alleviation of neuronal loss and apoptosis.

High-fat diet-induced memory impairment and anxiety-like behavior in rats attenuated by peel extract of Ananas comosus fruit via atheroprotective, antioxidant and anti-inflammatory actions

BackgroundPineapple peel is a waste component of pineapple with valuable source of metabolites as phytoactive compounds in ameliorating metabolic-related disorders. This study investigated the atheroprotective and neuroprotective effects of peel extract of Ananas comosus fruit (PEAC) in normal diet (ND) and high-fat diet (HFD) fed rats. MethodsMale Wistar rats were fed ND or HFD for 9 weeks, and beginning from the 6th week animals were also orally treated with PEAC (200 mg/kg). Memory performance was assessed using Y-maze test (YMT) and novel object recognition test (NORT) while anxiolytic-like effect was assessed on the elevated plus maze (EPM). Serum cholesterol, triglycerides and HDL-C were determined, while LDL-C and atherogenic risk calculated. Serum and brain tissue malondialdehyde, reduced glutathione, catalase were determined. Brain acetylcholinesterase activity and interleukin-6 level were also determined. ResultsPEAC significantly attenuated HFD-induced reduction in correct alternation in YMT, and discrimination index in NORT. Also, PEAC demonstrated anxiolytic-like activity in EPM test. PEAC significantly improved lipid profile and decreased risk of atherogenicity in ND and HFD-fed rats. In addition, PEAC improves serum and brain antioxidant status by decreasing malondialdehyde and increasing GSH and catalase. PEAC significantly impaired HFD-induced brain acetylcholinesterase activity and IL-6 levels. ConclusionThese findings suggest that peel extract of Ananas comosus fruit may protect against diet-induced behavioral disturbances via atheroprotective, antioxidants and anti-inflammatory activities.

Hypolipidemic and Antioxidant Efficacy of Apigenin in Hydrogen Peroxide induced Oxidative Stress in Adult Male Rats

This study was conducted to assess the role of apigenin extracted from parsley seeds either in glycosidic(aqueous extract) or aglycone forms (organic solvent extract), comparing to butylated hydroxyl tolouene(BHT)in serum lipid profile and brain tissue peroxidation in H2O2 induced oxidative stress adult male rats.The yield of crude flavonoids from parsley seeds was found to be approximately 2.65% and thin layerchromatography techniques confirmed that apigenin is the main flavonoid with RF similar to that of thestandard apigenin.Experimentally induction of oxidative stress in male rats by 0.75% H2O2 in drinking water for eight weeksshowed a significant alterations in normal serum lipid profile manifested by significant elevation (p&lt;0.05)in total cholesterol, Triacyle glycerol (TAG), Low density lipoprotein-Cholestrol (LDL-C) and Very lowdensity lipoprotein-Cholestrol (VLDL-C) and a significant decrease in High density lipoprotein-Cholestrol(HDL-C) as compared to the control and BHT treated groups. On the other hand, daily oral administrationof apigenin in a dose of 150 mg/Kg B.W. to H2O2 treated groups were caused a significant correction of thelipid profile parameters.Examination of brain tissues of H2O2 and apigenin concurrent H2O2 treated rats showed a significant decrease(p&lt;0.05) in brain tissue malondialdehyde (MDA) and significant elevation in catalase and cholinesteraseactivities in apigenin and BHT treated groups comparing with H2O2 treated and control groups.

Stigmasterol alleviates cerebral ischemia/reperfusion injury by attenuating inflammation and improving antioxidant defenses in rats.

Background/aims: The paper aimed to investigate the effects of Stigmasterol on inflammatory factors, antioxidant capacity, and apoptotic signaling pathways in brain tissue of rats with cerebral ischemia/reperfusion (I/R) injury. Methods: The neurological deficits of the rats were analyzed and HE staining was performed. The cerebral infarct volume was calculated by means of TTC staining, and neuronal apoptosis was detected by TUNEL staining. At the same time, the contents of glutathione peroxidase, glutathione, superoxide dismutase (SOD), nitric oxide, and malondialdehyde in brain tissue were measured. The expression of the relevant protein was detected by means of Western blotting. Results: The results showed that the neurological deficit score and infarct area of the I/R rats in the soy sterol treatment group were significantly lower than those in the I/R group. Moreover, the levels of carbon monoxide and malondialdehyde in the soysterol group were significantly lower than those in the I/R group, and the expressions of cyclooxygenase-2 (Cox-2) and NF-κB (p65) in the soysterol group were also significantly lower than those in the I/R group. The expression of Nrf2 (nucleus) and heme oxygenase-1 (HO-1) increased significantly, and the activities of antioxidant enzymes and SOD were increased. In addition, the stigmasterol treatment can inhibit apoptosis, down-regulate Bax and cleaved caspase-3 expression, and up-regulate Bcl-Xl expression. Conclusion: Stigmasterol protects the brain from brain I/R damage by reducing oxidative stress and inflammation.

Redox Signaling in Human Brain Vascular Smooth Muscle Cells

BackgroundStroke is a leading cause of death in the U.S. and worldwide. Ischemic stroke is the major type of stroke, in which blood vessels in the brain become blocked. Thickening of the vascular wall narrows the lumen of the brain vessel and increases the incidence of ischemic stroke. Smooth muscle cell (SMC) growth contributes to the thickening of the vascular wall. Therapeutic strategies to inhibit and/or reverse brain vascular SMC growth, therefore, should reduce the incidence of ischemic stroke. However, the mechanism of brain vascular SMC growth is not well understood. Redox processes through the generation of reactive oxygen species (ROS) regulate cell signaling in various biological processes. The present study examined redox signaling, in particular, iron‐dependent protein carbonylation signaling in brain vascular SMCs.Methods &amp; ResultsTreatment of cultured human brain vascular SMCs with deferoxamine (an iron chelator) resulted in a dose‐dependent reduction of cell growth induced by serum or by platelet‐derived growth factor (PDGF) as monitored by CCK8 colorimetric cell viability assay. As our laboratory previously discovered that iron‐catalyzed protein carbonylation mediates cell signaling in other cell types, we tested the effects of PDGF on protein carbonylation in human brain vascular SMCs. Treatment with PDGF promoted transient carbonylation of various proteins with a peak at 10 min. U0126, an inhibitor of the MEK/ERK pathway suppressed PDGF‐induced growth of human brain vascular SMCs and deferoxamine reduced ERK phosphorylation and activation in response to PDGF, suggesting that redox signaling occurs upstream from the ERK activation. The immunohistochemistry detection of malondialdehyde in brain tissues from human patients who died of stroke indicated the production of ROS in the vascular smooth muscle layer.ConclusionsWe demonstrate that redox signaling mediates the growth of brain vascular SMCs, opening up the possibility for targeting redox processes to improve therapeutic strategies to reduce the incidence of ischemic stroke.Support or Funding InformationSupported by NIH

The Neuroprotective Effect of Ginkgo Biloba Extract on Valproic Acid Induced Autistic Features in Mice

Introduction: Autism Spectrum Disorders (ASD) are among the severe developmental disorders, but have no specific treatments available. Ginkgo biloba (GK) has been reported to affect the neurotransmitter system and have anti-oxidant and anti-inflammatory properties that could impact the pathogenesis of valproic acid-induced autistic features. Aim: To identify the neuromodulatory effects of Ginkgo biloba extract on ASD induced by valproic acid in mice. Materials and Methods: A total of 24 male Wistar albino mice, 14-day-old, were used and divided into four groups (6 mice/group): Control, Ginkgo biloba extract-treated group {received GK at a dose 100 mg/kg via intraperitoneal injection once daily from Postnatal Day (PND) 13 to PND 40}, Valproic acid-treated group (VPA) (received Sodium Valproate at a dose 400 mg/kg via subcutaneous injection once on PND14), and Valproic acid + Ginkgo biloba extract-treated group (received VPA on PND14 and GK from PND 13 to PND 40). Neuro-behaviour tests (Open field, Social approach (three-chamber) test and T-maze spontaneous alternation) of mice were assessed. Biochemical tests (brain tissue malondialdehyde (MDA), Glutathione (GSH), Interleukin-6 (IL-6), Transforming Growth Factor-Beta (TGF-β1) and serum interleukin-17 (IL-17) were done. Also, histopathological, immunohistochemical and morphometric studies for the cerebellum were done. Analysis of Variances (ANOVA) was used for statistical analysis of the different groups followed by a post-hoc Tukey test. Results: VPA showed significant neuro-behavioural changes with a significant increase of (MDA, IL-6 and IL-17) and a significant decrease in (GSH and TGF-β1). Histopathological results revealed widespread neuronal affection, specifically of the Purkinje Cells (PCs) layer with a significant decrease in the expression of Myelin Basic Protein (MBP) and Serotonin. Ginkgo biloba ameliorated significantly VPA-induced autistic changes. Conclusion: Ginkgo biloba extract can ameliorate the autistic changes in mice through its anti-inflammatory and anti-oxidant activities in addition to its ability to modulate serotonin and MBP expression. It can be concluded that GK can be used as a potential disease-modifying treatment for Autism.

Amelioration of postoperative cognitive dysfunction in mice by mesenchymal stem cell-conditioned medium treatments is associated with reduced inflammation, oxidative stress and increased BDNF expression in brain tissues

ObjectiveMesenchymal stem cells (MSCs) are widely used in regeneration and repair of various tissues and organs, and whether MSC-conditioned medium (MSC-CM) has protective effects in postoperative cognitive dysfunction (POCD) remains largely unknown. We aimed to assess the therapeutic effect and explore the mechanisms of MSC-CM therapy in a POCD mouse model. MethodsSixty C57BL/6 mice were randomly assigned to 3 groups: control, POCD and POCD + MSC-CM. The POCD mouse model was established by left liver lobectomy. While mice in the control group were sham-operated, mice in the POCD + MSC-CM group were immediately administrated with MSC-CM after operation. The Morris water maze was used to determine cognitive function of mice at 1, 3, and 7 days after operation. The levels of IL-1β, IL-6, TNF-α and malondialdehyde in brain tissues at 3 days after operation were assessed by ELISA, while the protein level of brain derived neurotrophic factor (BDNF) was determined by western blot. ResultsLeft liver lobectomy induced POCD in mice resulted in decrease of cognitive function, increase of brain IL-1β, IL-6, TNF-α and malondialdehyde levels, and decreased BDNF expression, while administration of MSC-CM significantly reversed these changes. ConclusionMSC-CM ameliorates POCD in mice, and its protective roles are associated with reduced levels of inflammatory factors, attenuated oxidative stress, and increased BDNF expression.

Melatonin receptor activation provides cerebral protection after traumatic brain injury by mitigating oxidative stress and inflammation via the Nrf2 signaling pathway

Traumatic brain injury (TBI) is a principal cause of death and disability worldwide. Melatonin, a hormone made by the pineal gland, is known to have anti-inflammatory and antioxidant properties. In this study, using a weight-drop model of TBI, we investigated the protective effects of ramelteon, a melatonin MT1/MT2 receptor agonist, and its underlying mechanisms of action. Administration of ramelteon (10 mg/kg) daily at 10:00 a.m. alleviated TBI-induced early brain damage on day 3 and long-term neurobehavioral deficits on day 28 in C57BL/6 mice. Ramelteon also increased the protein levels of interleukin (IL)-10, IL-4, superoxide dismutase (SOD), glutathione, and glutathione peroxidase and reduced the protein levels of IL-1β, tumor necrosis factor, and malondialdehyde in brain tissue and serum on days 1, 3, and 7 post-TBI. Similarly, ramelteon attenuated microglial and astrocyte activation in the perilesional cortex on day 3. Furthermore, ramelteon decreased Keap 1 expression, promoted nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear accumulation, and increased levels of downstream proteins, including SOD-1, heme oxygenase-1, and NQO1 on day 3 post-TBI. However, in Nrf2 knockout mice with TBI, ramelteon did not decrease the lesion volume, neuronal degeneration, or myelin loss on day 3; nor did it mitigate depression-like behavior or most motor behavior deficits on day 28. Thus, timed ramelteon treatment appears to prevent inflammation and oxidative stress via the Nrf2-antioxidant response element pathway and might represent a potential chronotherapeutic strategy for treating TBI.

Ginsenoside Compound K Regulates Amyloid β via the Nrf2/Keap1 Signaling Pathway in Mice with Scopolamine Hydrobromide-Induced Memory Impairments.

The objective of this study was to investigate the neuroprotective and antioxidant effects of ginsenoside compound K (CK) in a model of scopolamine hydrobromide-induced, memory-impaired mice. The role of CK in the regulation of amyloid β (Aβ) and its capacity to activate the Nrf2/Keap1 signaling pathway were also studied due to their translational relevance to Alzheimer's disease. The Morris water maze was used to assess spatial memory functions. Levels of superoxide dismutase, glutathione peroxidase, and malondialdehyde in brain tissues were tested. Cell morphology was detected by hematoxylin and eosin staining and terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling assay. Immunohistochemistry and western blotting were used to determine expression levels of Nrf2/Keap1 signaling pathway-related factors and Aβ. Ginsenoside CK was found to enhance memory function, normalize neuronal morphology, decrease neuronal apoptosis, increase superoxide dismutase and glutathione peroxidase levels, reduce malondialdehyde levels, inhibit Aβ expression, and activate the Nrf2/Keap1 signaling pathway in scopolamine-exposed animals. Based on these results, we conclude that CK may improve memory function in scopolamine-injured mice by regulating Aβ aggregation and promoting the transduction of the Nrf2/Keap1 signaling pathway, thereby reducing oxidative damage to neurons and inhibiting neuronal apoptosis. This study suggests that CK may serve as a future preventative agent or treatment for Alzheimer's disease.

Role of autophagy in cerebral ischemia-reperfusion injury in diabetic mice: the relationship with HDAC3/Bmal1 signaling pathway

Objective To evaluate the role of autophagy in cerebral ischemia-reperfusion (I/R) injury in diabetic mice and the relationship with histone deacetylase 3 (HDAC3)/Bmal1 signaling pathway. Methods Healthy clean-grade male C57BL/6 mice were used in the study.Diabetes mellitus was induced by intraperitoneal injection of streptozotocin.Thirty-six mice with diabetes mellitus after being fed for 8 weeks were divided into 3 groups (n=12 each) using a random number table method: sham operation group (group S), I/R group and I/R plus HDAC3 inhibitor group (group I/R-H). Cerebral I/R was induced by middle cerebral artery occlusion for 1 h, followed by 24-h reperfusion in anesthetized mice.Specific HDAC3 inhibitor RGFP966 10 mg/kg was subcutaneously injected at 30 min before establishing the model in group I/R-H.Brain tissues were obtained at 24 h of reperfusion for microscopic examination and for determination of cerebral infarct size (by TTC), cell apoptosis (by TUNEL), activities of superoxide dismutase (SOD) and reactive oxygen species (ROS) and malondialdehyde (MDA) content (by colorimetric assay), expression of autophagy-related protein Beclin-1 and LC3B (by immunofluorescence), and expression of HDAC3, Bmal1, GSK-3β and p62 (by Western blot). Apoptosis index (AI) was calculated. Results Compared with group S, the cerebral infarct size was significantly increased, the activities of SOD and ROS and content of MDA in brain tissues were decreased, the expression of Bmal1, p-GSK-3β and HDAC3 was down-regulated, and AI was increased in group I/R (P<0.05). Compared with group I/R, the cerebral infarct size was significantly increased, the activities of SOD and ROS and content of MDA in brain tissues were increased, the expression of Bmal1, p-GSK-3β, Beclin-1 and LC3B was up-regulated, AI was decreased, and the expression of HDAC3 and p62 was down-regulated in group I/R-H (P<0.05). Conclusion HDAC3/Bmal1 signaling pathway exerts endogenous protective effect through activating autophagy and increasing the antioxidant capacity following cerebral I/R in diabetic mice. Key words: HDAC3; Bmal1; Autophagy; Diabetic; Cerebral ischemia reperfusion injury

An effort toward molecular biology of food deprivation induced food hoarding in gonadectomized NMRI mouse model: focus on neural oxidative status

BackgroundEnvironmental uncertainty, such as food deprivation, may alter internal milieu of nervous system through various mechanisms. In combination with circumstances of stress or aging, high consumption of unsaturated fatty acids and oxygen can make neural tissues sensitive to oxidative stress (OS). For adult rats, diminished level of gonadal steroid hormones accelerates OS and may result in special behavioral manifestations. This study was aimed to partially answer the question whether OS mediates trade-off between food hoarding and food intake (fat hoarding) in environmental uncertainty (e.g., fluctuations in food resource) within gonadectomized mouse model in the presence of food deprivation-induced food hoarding behavior.ResultsHoarding behavior was not uniformly expressed in all male mice that exposed to food deprivation. Extended phenotypes including hoarder and non-hoarder mice stored higher and lower amounts of food respectively as compared to that of low-hoarder mice (normal phenotype) after food deprivation. Results showed that neural oxidative status was not changed in the presence of hoarding behavior in gonadectomized mice regardless of tissue type, however, glutathione levels of brain tissues were increased in the presence of hoarding behavior. Decreased superoxide dismutase activity in brain and spinal cord tissues and increased malondialdehyde in brain tissues of gonadectomized mice were also seen.ConclusionsAlthough, food deprivation-induced hoarding behavior is a strategic response to food shortage in mice, it did not induce the same amount of hoarding across all colony mates. Hoarding behavior, in this case, is a response to the environmental uncertainty of food shortage, therefore is not an abnormal behavior. Hoarding behavior induced neural OS with regard to an increase in brain glutathione levels but failed to show other markers of neural OS. Decreased superoxide dismutase activity in brain and spinal cord tissues and increased malondialdehyde levels in brain tissues of gonadectomized mice could be a hallmark of debilitated antioxidative defense and more lipid peroxidation due to reduced amount of gonadal steroid hormones during aging.