Neuroprotective Effects of Ferrostatin and Necrostatin Against Entorhinal Amyloidopathy-Induced Electrophysiological Alterations Mediated by voltage-gated Ca2+ Channels in the Dentate Gyrus Granular Cells.

Alzheimer's disease (AD) is a progressive neurodegenerative disease that is the main form of dementia. Abnormal deposition of amyloid-beta (Aß) peptides in neurons and synapses cause neuronal loss and cognitive deficits. We have previously reported that ferroptosis and necroptosis were implicated in Aß25-35 neurotoxicity, and their specific inhibitors had attenuating effects on cognitive impairment induced by Aß25-35 neurotoxicity. Here, we aimed to examine the impact of ferroptosis and necroptosis inhibition following the Aß25-35 neurotoxicity on the neuronal excitability of dentate gyrus (DG) and the possible involvement of voltage-gated Ca2+ channels in their effects. After inducing Aß25-35 neurotoxicity, electrophysiological alterations in the intrinsic properties and excitability were recorded by the whole-cell patch-clamp under current-clamp condition. Voltage-clamp recordings were also performed to shed light on the involvement of calcium channel currents. Aß25-35 neurotoxicity induced a considerable reduction in input resistance (Rin), accompanied by a profoundly decreased excitability and a reduction in the amplitude of voltage-gated calcium channel currents in the DG granule cells. However, three days of administration of either ferrostatin-1 (Fer-1), a ferroptosis inhibitor, or Necrostatin-1 (Nec-1), a necroptosis inhibitor, in the entorhinal cortex could almost preserve the normal excitability and the Ca2+ currents. In conclusion, these findings suggest that ferroptosis and necroptosis involvement in EC amyloidopathy could be a potential candidate to prevent the suppressive effect of Aß on the Ca2+ channel current and neuronal function, which might take place in neurons during the development of AD.

Protective effect of melatonin against methamphetamine-induced attention deficits through miR-181/SIRT1 axis in the prefrontal cortex.

INTRODUCTION: Methamphetamine (METH) is an addictive psychostimulant with deleterious effects on the central nervous system. Chronic use of METH in high doses impairs cognition, attention and executive functions, but the underlying mechanisms are still unclear. Sirtuin 1 (SIRT1) is a post-translational regulator that is downregulated following METH neurotoxicity. Melatonin is a neuroprotective hormone that enhances mitochondrial metabolism. Here, we evaluated the effect of melatonin on METH-induced attention deficits disorder and the involvement of the miR-181/SIRT1 axis in melatonin neuroprotection. METHODS AND RESULTS: METH at a dose of 5 mg/kg was injected for 21 consecutive days. The animals were assigned to receive either melatonin or the vehicle after METH injections. Attention levels were evaluated with abject-based attention test. In the prefrontal cortex, the expression levels of miR-181a-5p, SIRT1, p53 and CCAR2, as well as the mtDNA copy numbers were evaluated using qRT-PCR and western blotting. The outcomes revealed that melatonin treatment following METH injections improved METH-induced attention deficits. METH toxicity can be associated with changes in the miR-181/SIRT1 axis, elevated levels of p53 and COXII, and decreased levels of mtDNA in the prefrontal cortex of adult rats. Interestingly, administration of melatonin can improve the expression of these molecules and reduces the toxic effects of METH. CONCLUSION: Melatonin ameliorated the neurotoxicity of METH in the prefrontal cortex and the miR-181/SIRT1 axis is involve in the protective effects of melatonin. However, melatonin can be potentially administrated to improve attention impairment in METH use disorders.

Reduction of ovarian reserves and activation of necroptosis to in vivo air pollution exposures.

We investigated the association between air pollution and changes in ovarian follicles, anti-mullerian hormone (AMH) levels, the occurrence of necroptosis cell death by activation of receptor-interacting protein kinase 3 (RIPK3) and, the activation of mixed lineage kinase domain-like (MLKL) proteins. Forty-two female Wistar rats were divided into three groups of 14 each, which were exposed to real-ambient air, filtered air and purified air (control) in two periods of 3 and 5 months. The results showed that the number of ovarian follicles decreased in the group exposed to real-ambient air versus the control group (P < 0.0001). The trend of age-related AMH changes with respect to exposure to air pollutants was affected and its levels decreased after 3 months of exposure. The MLKL increased in the group exposed to the real-ambient air compared to the control group (P = 0.033). Apparently long-term exposure to air pollution can reduce ovarian reserves.

Almond intake during pregnancy in rats improved the cognitive performance of adult male offspring.

Background: Based on evidence there are accepted links among early nutrition, epigenetic processes, and cognitive performance. Almond as a nutritious food could exert neuroprotective effects and improve anxiety, learning, and memory.Methods: In the current study, female rats were fed with a diet containing 5% (w/w) almonds during the mating period (two days) and gestation period (21 consecutive days). Then, the effect of the almond diet on short-term memory (Y maze), anxiety (elevated plus maze), and stress adaptation (forced swimming test) were investigated in the adult male offspring. The hippocampus (HIP), prefrontal cortex (PFC), and amygdala (AMY) of offspring were collected, and the level of cyclic AMP response element-binding proteins (CREB), brain-derived neurotrophic factor (BDNF) was assessed by western blotting. Also, Monoamine oxidases (MAO)-A and B activity were evaluated via enzymatic assays.Results: Our results indicated that prenatal almond consumption improved memory, made a modest reduction in anxiety-like behavior, and increased stress adaptation in adult male offspring. Also, molecular assessments showed an increased level of CREB phosphorylation and BDNF in the HIP and PFC of the almond group, while the activity of MAO-A and MAO-B was inhibited by almond consumption in mentioned areas.Discussion: These findings introduce almonds as a beneficial diet during pregnancy, for improving short-term memory, stress adaptation, and cognitive performance in adult offspring.

Does hazelnut consumption affect brain health and function against neurodegenerative diseases?

INTRODUCTION: A healthy daily diet and consuming certain nutrients, such as polyphenols, vitamins, and unsaturated fatty acids, may help neuronal health maintenance. Polyphenolic chemicals, which have antioxidant and anti-inflammatory properties, are involved in the neuroprotective pathway. Because of their nutritional value, nuts have been shown in recent research to be helpful in neuroprotection. OBJECTIVE: Hazelnut is often consumed worldwide in various items, including processed foods, particularly in bakery, chocolate, and confectionery products. This nut is an excellent source of vitamins, amino acids, tocopherols, phytosterols, polyphenols, minerals, and unsaturated fatty acids. Consuming hazelnut may attenuate the risk of neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and Huntington's disease due to its anti-inflammatory and anti-oxidant qualities. RESULTS: Many documents introduce hazelnut as an excellent choice to provide neuroprotection against neurodegenerative disorders and there is some direct proof of its neuroprotective effects. DISCUSSION: So hazelnut consumption in daily diet may reduce neurodegenerative disease risk and be advantageous in reducing the imposed costs of dealing with neurodegenerative diseases.

A role for flavonoids in the prevention and/or treatment of cognitive dysfunction, learning, and memory deficits: a review of preclinical and clinical studies.

OBJECTIVE: Natural food substances, due to high rates of antioxidants, antiviral and anti-inflammatory properties, have been proposed to have the potential for the prevention or treatment of cognitive deficits, learning and memory deficits and neuro inflammation. In particular, medicinal plants with rich amounts of beneficial components such as flavonoids are one of the most promising therapeutic candidates for the cognitive deficit and memory loss. Herein, we aimed to review the impact of medicinal plants with focus on flavonoids on cognitive dysfunction, learning and memory loss by considering their signaling pathways. METHODS: We extracted 93 preclinical and clinical studies related to the effects of flavonoids on learning and memory and cognition from published papers between 2000 and 2021 in the MEDLINE/PubMed, Cochrane Library, SCOPUS, and Airiti Library databases. RESULTS: In the preclinical studies, at least there seem to be two main neurological and biological processes in which flavonoids contribute to the improvement and/or prevention of learning, memory deficit and cognitive dysfunction: (1) Regulation of neurotransmission system and (2) Enhancement of neurogenesis, synaptic plasticity and neuronal survival. CONCLUSION: Although useful effects of flavonoids on learning and memory in preclinical investigations have been approved, more clinical trials are required to find out whether flavonoids and/or other ingredients of plants have the potent to prevent or treat neurodegenerative disorders.

Cytotoxic effects of crystalline silica in form of micro and nanoparticles on the human lung cell line A549.

Airborne crystalline silica (SiO2) particles are one of the most common pollutants in stone industries. Limited studies have investigated the health effects of crystalline SiO2 nanoparticles. Hence, the objective of this study was to study the cytotoxicity of SiO2 in nano and micron sizes. A mineral quartz sample in the range of 0.2-0.8 mm sizes was purchased. These particles were ground at about 5 and 0.1 microns. Human cell line A549 was exposed to micro and nanometer particles at concentrations of 10, 50, 100, and 250 µg/ml for 24 and 72 h. Subsequently, the cytotoxicity of exposed cells was investigated by measuring cell survival, ROS generation, mitochondrial permeability, and intracellular glutathione content. The results showed that crystalline SiO2 nano and microparticles decreased cell survival, increased ROS generation, damaged the mitochondrial membrane, and lowered the antioxidant content of these cells in a concentration- and time-dependent manner. The toxicity of crystalline SiO2 microparticles at concentrations ≤50 µg/mL was greater than for nanoparticles, which was the opposite at concentrations ≥100 µg/mL. Exposure time and concentration were crucial factors for the cytotoxicity of exposed A549 cells to crystalline SiO2 particles, which can affect the severity of the effect of particle size. Due to the limitation of exposure concentration and test durations in this study, further studies on the parameters of nanoparticle toxicity and underlying mechanisms could advance our knowledge.

Oxytocin Prevents the Development of 3-NP-Induced Anxiety and Depression in Male and Female Rats: Possible Interaction of OXTR and mGluR2.

Huntington disease (HD) is a progressive neurological disorder with dominant motor symptoms. It also has psychiatric manifestations, like anxiety and depression, that can emerge themselves before motor symptoms and impose a major burden on patients. Oxytocin (OXT) is a newly emerged treatment for disorders like autism and schizophrenia and recently is using to alleviate depression and anxiety. In the current study, we investigated the behavioral and molecular effects of OXT on the development of anxiety and depression in 3-nitropropionic acid (3-NP)-induced model of HD. Anxiety- and depression-like behaviors as well as the levels of oxytocin receptor (OXTR), metabotropic glutamate receptor (mGluR) 2, mGluR5, and glutathione (GSH) were measured in striatum, hippocampus, prefrontal cortex, and amygdala. Also, we questioned if sex had any modulatory effect. We found that 3-NP increased anxiety and depression compared to controls. It also reduced the levels of OXTR and mGluR2, increased mGluR5, and reduced GSH in studied brain regions. Pretreatment with OXT before the injection of 3-NP ameliorated anxiety and depression. Additionally, it protected the brain from developing low levels of OXTR, mGluR2, and GSH and high levels of mGluR5 in studied regions. The protective effects of OXT were similar between male and female animals. These data suggest that OXTR, mGluR2, mGluR5, and GSH may contribute to psychiatric manifestations of HD. In addition, pretreatment with OXT could prevent the mood changes in male and female rats.

Time-Dependent Changes in the Serum Levels of Neurobiochemical Factors After Acute Methadone Overdose in Adolescent Male Rat.

Acute methadone toxicity is a major public health concern which has adverse effects on brain tissue and results in recurrent or delayed respiratory arrest. Our study aimed to investigate the time-dependent changes in several serum biochemical markers of brain damage, spatial working memory, and the brain tissue following acute methadone overdose. Adolescent male rats underwent an intraperitoneal (i.p.) injection of 15 mg/kg methadone. In case of apnea occurrence, resuscitation was performed by a ventilatory pump and administrating naloxone (2 mg/kg; i.p.). The animals were classified into groups of treated rats; methadone and naloxone-Apnea (M/N-Apnea), M/N-Sedate, Methadone, Naloxone, and control (saline) groups. The serum levels of S100B, neuron-specific enolase (NSE), myelin basic protein factors, and (Lactate/Pyruvate) L/P ratio were evaluated at the time-points of 6, 24, and 48 h (h). We found that the alterations of S100B and L/P ratio were considerable in the M/N-Apnea and Methadone groups from the early hours post-methadone overdose, while NSE serum levels elevation was observed only in M/N-Apnea group with a delay at 48 h. Further, we assessed the spatial working memory (Y-maze test), morphological changes, and neuronal loss. The impaired spontaneous alternation behavior was detected in the M/N-Apnea groups on days 5 and 10 post-methadone overdose. The morphological changes of neurons and the neuronal loss were detectable in the CA1, striatum, and cerebellum regions, which were pronounced in both M/N-Apnea and Methadone groups. Together, our findings suggest that alterations in the serum levels of S100B and NSE factors as well as L/P ratio could be induced by methadone overdose with the presence or absence of apnea before the memory impairment and tissue injury in adolescent male rats.

Interval aerobic training improves bioenergetics state and mitochondrial dynamics of different brain regions in restraint stressed rats.

Evidence has validated the prophylactic effects of exercising on different aspects of health. On the opposite side, immobilization may lead to various destructive effects causing neurodegeneration. Here, we investigated the association between exercising and mitochondrial quality for preventing the destructive effects of restraint stress in different rat brain regions. Twenty-four male Wistar rats, were randomized into four groups (n = 6), exercise, stress, exercise + stress, and control. The exercise procedure consisted of running on a rodent treadmill for 8 weeks, and rats in the stress group were immobilized for 6 h. Rats were then euthanized by decapitation and tricarboxylic acid (TCA) cycle enzyme activity, antioxidant levels, and mitochondrial biogenesis factors were assessed in the frontal, hippocampus, parietal and temporal regions using spectrophotometer and western blot technique. Based on our results, increased activity of TCA cycle enzymes in the exercised and exercise-stressed groups was detected, except for malate dehydrogenase which was decreased in exercise-stressed group, and fumarase that did not change. Furthermore, the level of antioxidant agents (superoxide dismutase and reduced glutathione), mitochondrial biogenesis factors (peroxisome proliferator-activated receptor gamma coactivator 1-alpha and mitochondrial transcription factor A), and dynamics markers (Mitofusin 2, dynamic related protein 1, PTEN induced putative kinase-1, and parkin) increased in both mentioned groups. Interestingly our results also revealed that the majority of the mitochondrial factors increased in the frontal and parietal lobes, which may be in relation with the location of motor and sensory areas. Exercise can be used as a prophylactic approach against bioenergetics and mitochondrial dysfunction.

How cytosolic compartments play safeguard functions against neuroinflammation and cell death in cerebral ischemia.

Ischemic stroke is the second leading cause of mortality and disability globally. Neuronal damage following ischemic stroke is rapid and irreversible, and eventually results in neuronal death. In addition to activation of cell death signaling, neuroinflammation is also considered as another pathogenesis that can occur within hours after cerebral ischemia. Under physiological conditions, subcellular organelles play a substantial role in neuronal functionality and viability. However, their functions can be remarkably perturbed under neurological disorders, particularly cerebral ischemia. Therefore, their biochemical and structural response has a determining role in the sequel of neuronal cells and the progression of disease. However, their effects on cell death and neuroinflammation, as major underlying mechanisms of ischemic stroke, are still not understood. This review aims to provide a comprehensive overview of the contribution of each organelle on these pathological processes after ischemic stroke.

Altered D2 receptor and transcription factor EB expression in offspring of aggressive male rats, along with having depressive and anxiety-like behaviors.

MATERIALS AND METHODS: In this study we have evaluated the behavioral mood variations, and expression of DR-D2 and TFEB genes in the amygdala and PFC of aggressive male rats' offspring. RESULTS: Anxiety and depression-like behaviors were observed, but intra-ventricle injection of DR-D2 antagonist (Sulpiride) has shown to be efficient in reducing negative behavioral changes in offspring. Furthermore, DR-D2 gene expression was increased in the amygdala and PFC of aggressive male rats' offspring, which the injection of Sulpiride decreased it significantly. TFEB gene expression was also decreased in the amygdala and PFC of aggressive male rats' offspring, but the blockade of DR-D2 had no effect on it. CONCLUSIONS: The current data suggests the possible influence of dopaminergic receptors D2 and TFEB genes on the behavioral changes which is modified by having an aggressive father.

Interactive toxicity effect of combined exposure to hematite and amorphous silicon dioxide nanoparticles in human A549 cell line.

The study on the health effects of combined exposure to various contaminants has been recommended by many authors. The objective of the present study was to examine the effects of the co-exposure to hematite and amorphous silicon dioxide (A-SiO2) nanoparticles on the human lung A549 cell line. The A549 cell line was exposed to 10, 50, 100, and 250 µg/ml concentrations of hematite and A-SiO2 nanoparticles both independently and in combination. Their toxicity in both circumstances was investigated by MTT, intracellular reactive oxygen species, cell glutathione content, and mitochondrial membrane potential tests, and the type of interaction was investigated by statistical analysis using Statistical Package for Social Sciences (SPSS, v. 21). Results showed that the independent exposure to either hematite or A-SiO2 compared with the control group produced more toxic effects on the A549 cell line. The toxicity of combined exposure of the nanoparticles was lower compared with independent exposure, and antagonistic interactive effects were detected. The findings of this study could be useful in clarifying the present debate on the health effects of combined exposure of hematite and A-SiO2 nanoparticles. Because of the complexities of combined exposures, further studies of this kind are recommended.

Naloxone-precipitated withdrawal ameliorates impairment of cost-benefit decision making in morphine-treated rats: Involvement of BDNF, p-GSK3-ß, and p-CREB in the amygdala.

Several studies indicated that morphine administration impairs cognitive brain functions. Therefore, in the current study, we investigated the effect of subchronic exposure to morphine and its withdrawal on effort- and/or delay-based forms of cost-benefit decision making and alterations in p-CREB/CREB ratio, p-GSK3ß/GSK3ß ratio, and BDNF level during decision making in the amygdala. Our data displayed an impairment of both forms of cost-benefit decision making following subchronic exposure to morphine. However, preference of high reward/high effort and/or high delay reward increased after naloxone injection. In molecular section, levels of BDNF and p-CREB/CREB ratio increased during cost-benefit decision making while p-GSK3ß/GSK3ß ratio decreased in both forms of decision making. In morphine-treated rats, level of BDNF and p-CREB/CREB ratio reduced during both forms of decision making while p-GSK3ß/GSK3ß ratio increased during delay-based and did not have a significant difference with the control group during effort-based decision making. On the withdrawal day, BDNF level raised while p-GSK3ß/GSK3ß ratio attenuated compared to morphine-treated group in both form of decision making. In addition, p-CREB/CREB ratio increased only during delay-based decision making on the withdrawal day. In conclusion, our data revealed that subchronic exposure to morphine interferes with the cost-benefit decision making may be via changes in level of BDNF, p-CREB/CREB and p-GSK3ß/GSK3ß ratio in the amygdala.

Additive toxicity of Co-exposure to pristine multi-walled carbon nanotubes and benzo α pyrene in lung cells.

The Mixture exposure to pristine multi-walled carbon nanotubes (P-MWCNTs) and polycyclic aromatic hydrocarbons (PAHs) such as benzo α pyrene (BaP) in the environment is inevitable. Assessment toxicity of P-MWCNTs and BaP individually may not provide sufficient toxicological information. The objective of this work is to investigate the combined toxicity of P-MWCNTs and BaP in human epithelial lung cells (A549). The physico-chemical properties of P-MWCNTs were determined suing analytical instruments. The toxicity of P-MWCNTs and BaP on A549 lung cells individually or combined were assessed. For toxicity assessment, cell viability, ROS generation, oxidative DNA damage, and apoptosis experiments were conducted. The results of this study demonstrated that P-MWCNTs and BaP individually reduced cell viability in A549 lung cells, and oxidative stress was as the possible mechanism of cytotoxicity. The co-exposure to P-MWCNTs and BaP enhanced the cytotoxicity compared to exposure to P-MWCNTs and BaP individually, but not statistically significant. The two-factorial analysis demonstrated an additive toxicity interaction for co-exposure to P-MWCNTs and BaP. The complicated toxicity interaction among BaP with fibers and metal impurities of P-MWCNTS could be probable reasons for additive toxicity interaction. Results of this study could be helpful as the basis for future studies and risk assessment of co-exposure to MWCNTs and PAHs.

Effects of PM2.5 and gases exposure during prenatal and early-life on autism-like phenotypes in male rat offspring.

BACKGROUND: Epidemiological studies have reported associations between elevated air pollution and autism spectrum disorders (ASD). However, we hypothesized that exposure to air pollution that mimics real world scenarios, is a potential contributor to ASD. The exact etiology and molecular mechanisms underlying ASD are not well understood. Thus, we assessed whether changes in OXTR levels may be part of the mechanism linking PM2.5/gaseous pollutant exposure and ASD. The current in-vivo study investigated the effect of exposure to fine particulate matter (PM2.5) and gaseous pollutants on ASD using behavioral and molecular experiments. Four exposure groups of Wistar rats were included in this study: 1) particulate matter and gaseous pollutants exposed (PGE), 2) gaseous pollutants only exposed (GE), 3) autism-like model (ALM) with VPA induction, and 4) clean air exposed (CAE) as the control. Pregnant dams and male pups were exposed to air pollutants from embryonic day (E0) to postnatal day (PND21). RESULTS: The average ± SD concentrations of air pollutants were: PM2.5: 43.8 ± 21.1 µg/m3, CO: 13.5 ± 2.5 ppm, NO2: 0.341 ± 0.100 ppm, SO2: 0.275 ± 0.07 ppm, and O3: 0.135 ± 0.01 ppm. The OXTR protein level, catalase activity (CAT), and GSH concentrations in the ALM, PGE, and GE rats were lower than those in control group (CAE). However, the decrements in the GE rats were smaller than other groups. Also in behavioral assessments, the ALM, PGE, and GE rats demonstrated a repetitive /restricted behavior and poor social interaction, but the GE rats had weaker responses compared to other groups of rats. The PGE and GE rats showed similar trends in these tests compared to the VPA rats. CONCLUSIONS: This study suggested that exposure to ambient air pollution contributed to ASD and that OXTR protein may serve as part of the mechanism linking them.

Grafted human chorionic stem cells restore motor function and preclude cerebellar neurodegeneration in rat model of cerebellar ataxia.

Cerebellar ataxia (CA) is a form of ataxia that adversely affects the cerebellum. Cell replacement therapy (CRT) has been considered as a potential treatment for neurological disorders. In this report, we investigated the neuro-restorative effects of human chorionic stem cells (HCSCs) transplantation on rat model of CA induced by 3-acetylpyridine (3-AP). In this regard, HCSCs were isolated and phenotypically determined. Next, a single injection of 3-AP was administered for ataxia induction, and bilateral HCSCs implantation was conducted 3 days after 3-AP injection, followed by expression analysis of a number of apoptotic, autophagic and inflammatory genes as well as vascular endothelial growth factor (VEGF) level, along with assessment of cerebellar neurodegeneration, motor coordination and muscle activity. The findings revealed that grafting of HCSCs in 3-AP model of ataxia decreased the expression levels of several inflammatory, autophagic and apoptotic genes and provoked the up-regulation of VEGF in the cerebellar region, prevented the degeneration of Purkinje cells caused by 3-AP toxicity and ameliorated motor coordination and muscle function. In conclusion, these data indicate in vivo efficacy of HCSCs in the reestablishment of motor skills and reversal of CA.

Protective effects of ex-527 on cerebral ischemia-reperfusion injury through necroptosis signaling pathway attenuation.

Necroptosis, a novel type of programmed cell death, is involved in ischemia-reperfusion-induced brain injury. Sirtuin 1 (Sirt1), as a well-known member of histone deacetylase class III, plays pivotal roles in inflammation, metabolism, and neuron loss in cerebral ischemia. We explored the relationship between Sirt1 and the necroptosis signaling pathway and its downstream events by administration of ex-527, as a selective and potent inhibitor of Sirt1, and necrostatin-1 (nec-1), as a necroptosis inhibitor, in an animal model of focal cerebral ischemia. Our data showed different patterns of sirt1 and necroptosis critical regulators, including receptor-interacting protein kinase 3 and mixed lineage kinase domain-like protein gene expressions in the prefrontal cortex and the hippocampus after ischemia-reperfusion. We found that ex-527 microinjection reduces the infarction volume of ischemic brains and improves the survival rate, but not stroke-associated neurological deficits. Additionally, treatment with ex-527 effectively abolished the elevation of the critical regulators of necroptosis, whereas necroptosis inhibition through nec-1 microinjection did not influence Sirt1 expression levels. Our data also demonstrated that the ex-527 relieves ischemia-induced perturbation of necroptosis-associated metabolic enzymes activity in downstream. This study provides a new approach to the possible neuroprotective potential of ex-527 orchestrated by necroptosis pathway inhibition to alleviate ischemia-reperfusion brain injury.

Coenzyme Q10 supplementation improves acute outcomes of stroke in rats pretreated with atorvastatin.

OBJECTIVES: Coenzyme Q10 (CoQ10, ubiquinone) stands among the safest supplements in the elderly to protect against cardiovascular disorders. Noteworthy, CoQ10 deficiency is common in many surviving stroke patients as they are mostly prescribed statins for the secondary prevention of stroke incidence lifelong. Accordingly, the current study aims to experimentally examine whether CoQ10 supplementation in animals receiving atorvastatin may affect acute stroke-induced injury. METHODS: Adult rats underwent transient middle cerebral artery occlusion after atorvastatin pretreatment (5 or 10 mg/ kg/day; po; 30 days) with or without CoQ10 (200 mg/kg/day). After 24 hours ischemic/reperfusion injury, animals were subjected to functional assessments followed by cerebral molecular and histological to detect inflammation, apoptosis and oxidative stress. RESULTS: Animals dosed with 10 mg/kg presented the worst neurological function and brain damage in the acute phase of stroke injury. CoQ10 supplementation efficiently improved functional deficit and cerebral infarction in all stroke animals, particularly those exhibiting statin toxicity. Such benefits were associated with remarkable anti-inflammatory and anti-apoptotic effects, based on the analyzed tumor necrosis factor-α, interleukin-6, Bax/Bcl2 and cleaved caspase 3/9 immunoblots. Importantly, our fluoro-jade staining data indicated CoQ10 may revert the stroke-induced neurodegeneration. No parallel alteration was detected in stroke-induced oxidative stress as determined by malondialdehyde and 8-oxo-2'-deoxyguanosine levels. DISCUSSION: These data suggest that all stroke animals may benefit from CoQ10 administration through modulating inflammatory and degenerative pathways. This study provides empirical evidence for potential advantages of CoQ10 supplementation in atorvastatin-receiving patients which may not shadow its antioxidant properties.

Prevention of recognition memory loss and moderation of mitochondrial dynamic tendency toward fusion by flavone derivatives in Aß-injected rats: a comparison between two flavonoids with different polarity.

Growing evidence sheds light on the use of flavonoids as the promising alternatives for the treatment of chronic conditions, including cancer and neurodegenerative disorders. Accordingly, in the present study, we aimed at evaluating the effects of oral intake of two structurally different flavonoids 5-hydroxy-6,7,4'-trimethoxyflavone (flavone 1) and 5,7,4'-trihydroxyflavone (flavone 2) on recognition memory, hippocampal protein level of immediate early gene cFos and mitochondrial dynamic markers in Amyloid ß (Aß)-injected rats. Recognition aspect of memory and level of proteins were measured using novel object recognition test and Western blot, respectively. Our data indicated that even though flavone 1 was more effective than flavone 2 to prevent memory impairment, feeding with both flavones alleviated memory in Aß-injected rats. Furthermore, in flavones-administered rats, mitochondrial dynamic balancing returned to the control level by the decline in Dynamin-related protein-1 protein level, a known marker for mitochondrial fission, and elevation in protein level of mitochondrial fusion factors Mitofusins 1 and 2. In parallel with behavior results, flavone 1 was more effectual on mitochondrial dynamic moderating. The more neuroprotective effects of flavone 1 could be attributed to its methylated structure leading to crossing of the blood-brain barrier with ease and metabolic stability and bioactivity.