Hippocampal Oxidative Status Research Articles

The Protective Effects of High-Intensity Interval Training Combined with Q10 Supplementation on Learning and Memory Impairments in Male Rats with Amyloid-β-Induced Alzheimer's Disease.

Oxidative stress plays a major role in the progression of Alzheimer's disease (AD)-related cognitive deficits. This study was done to determine the protective effects of coenzyme Q10 (CoQ10) and high-intensity interval training (HIIT) alone and in combination for eight continuous weeks, on oxidative status, cognitive functions, and histological changes in the hippocampus in amyloid-β (Aβ)-induced AD rats. Ninety male Wistar rats were randomly assigned to the sham, control, Q10 (50 mg/kg of CoQ10; P.O.), HIIT (high intensity: 4 min running at 85-90% VO2max, low intensity: 3 min running at 50-60% VO2max), Q10 + HIIT, AD, AD+Q10, AD+HIIT, and AD+Q10 + HIIT groups. The results showed that Aβ injection reduced cognitive functions in the Morris water maze (MWM) test and recognition memory in the novel object recognition test (NORT), which was accompanied by a decrease in total thiol groups, catalase, and glutathione peroxidase activities, an increase in malondialdehyde levels, and neuronal loss in the hippocampus. Interestingly, pretreatment with CoQ10, HIIT, or both, could markedly improve the oxidative status and cognitive decline in the MWM and NOR tests, and hinder neuronal loss in the hippocampus of Aβ-induced AD rats. Therefore, a combination of CoQ10 and HIIT can improve Aβ-related cognitive deficits, probably through an amelioration in hippocampal oxidative status and prevention of neuronal loss.

Effects of ghrelin on sulfite induced changes in lipid peroxidation, spatial memory, and locomotor activity in rats

ABSTRACT Background Humans are constantly exposed to sulfites and their derivatives, both endogenously and exogenously. Recent studies have shown that sulfite and its derivatives can cause oxidative stress. . Ghrelin has been reported to possess antioxidant properties and stimulates neurogenesis in hippocampal progenitor cells. This study aimed to investigate the effects of ghrelin on sulfite-induced changes in hippocampal oxidative status, spatial learning and locomotor activity in rats. Methods Forty male albino Wistar rats were randomized into four groups as follows; Group 1: Control (C); Group 2: Sodium metabisulfite (Na2S2O5) treated (S); Group 3: Ghrelin treated (G); Group 4: Na2S2O5 + Ghrelin treated (SG). Sodium metabisulfite (100 mg/kg/day) was given by gastric gavage, and ghrelin (20 µg/kg/day) was administered intraperitoneally for 5 weeks. Thiobarbituric acid reactive substances (TBARS) were measured through fluorometric method. The spatial memory and locomotor activity of the rats were evaluated by Y-maze test. Results Y-maze results revealed an enhancement of short-term spatial learning and memory in S and SG groups compared to C group. TBARS levels were increased significantly in S group with respect to C group. The increase in TBARS levels induced by sulfite was completely prevented by ghrelin in SG group. Conclusion We suggest that systemic ghrelin administration might ameliorate ingested sodium metabisulfite-induced hippocampal oxidative damage without providing any changes in spatial learning, memory and locomotion. Further investigation concerning the mechanism of ghrelin action in hippocampus might provide valuable information for developing new therapeutic approaches to attenuate oxidative stress in hippocampal tissue.

Therapeutic Effects of High-Intensity Interval Training Exercise Alone and Its Combination with Ecdysterone Against Amyloid Beta-Induced Rat Model of Alzheimer's Disease: A Behavioral, Biochemical, and Histological Study.

Hippocampal oxidative stress has a vital role in the pathophysiology of Alzheimer's disease (AD)-associated behavioral deficits. Ecdysterone (Ecdy), a natural product and primary steroid hormone, exhibits anti-oxidative and neuroprotective effects. High-intensity interval training (HIIT) has emerged as an effective method for improving physiological brain functions. The present study was designed to investigate the comparative effects of separate and combined HIIT and Ecdy treatment on behavioral functions, hippocampal oxidative status, histological changes in an amyloid-beta (Aβ)-induced rat model of AD. Adult male rats were treated simultaneously with HIIT exercise and Ecdy (10mg/kg/day; P.O.), starting ten days after Aβ-injection, and they continued for eight consecutive weeks. At the end of the treatment course, the behavioral functions of the rats were assessed by commonly-used behavioral paradigms. Subsequently, brain samples were collected for histological analysis and hippocampus samples were collected for biochemical analysis. Results illustrated that Aβ injection impaired learning and memory performances in both novel object recognition and Barnes maze tests, reduced exploratory/locomotor activities in open field test, enhanced anxiety-like behavior in elevated plus-maze (P < 0.05). These behavioral deficits accompanied hippocampal oxidative stress (decreased total antioxidant capacity content and glutathione peroxidase enzyme activity, increased total oxidant status and malondialdehyde level) and neuronal loss in the cerebral cortex and hippocampus in H&E staining (P < 0.05). HIIT and Ecdy improved anxiety-like behavior, attenuated total oxidant status and malondialdehyde, and prevented the neuronal loss (P < 0.05). However, their combination resulted in a more complete and powerful improvement in all the above-mentioned Aβ-related deficits (P < 0.05). Overall, these data provide evidence that a combination of HIIT and Ecdy treatment improves Aβ-induced behavioral deficits, possibly through ameliorating hippocampal oxidative status and preventing neuronal loss.

Noise-induced hippocampal oxidative imbalance and aminoacidergic neurotransmitters alterations in developing male rats: Influence of enriched environment during adolescence.

Living in big cities might involuntarily expose people to high levels of noise causing auditory and/or extra-auditory impairments, including adverse effects on central nervous system (CNS) areas such as the hippocampus. In particular, CNS development is a very complex process that can be altered by environmental stimuli. We have previously shown that noise exposure of developing rats can induce hippocampal-related behavioral alterations. However, noise-induced biochemical alterations had not been studied yet. Thus, the aim of this work was to assess whether early noise exposure can affect rat hippocampal oxidative state and aminoacidergic neurotransmission tone. Additionally, the effectiveness of an enriched environment (EE) as a neuroprotective strategy was evaluated. Male Wistar rats were exposed to different noise schemes at 7 or 15days after birth. Upon weaning, some animals were transferred to an EE whereas others were kept in standard cages. Short- and long-term measurements were performed to evaluate reactive oxygen species, thioredoxins levels and catalase activity as indicators of hippocampal oxidative status as well as glutamic acid decarboxylase and a subtype of glutamate transporter to evaluate aminoacidergic neurotransmission tone. Results showed noise-induced changes in hippocampal oxidative state and aminoacidergic neurotransmission markers that lasted until adolescence and differed according to the scheme and the age of exposure. Finally, EE housing was effective in preventing some of these changes. These findings suggest that CNS development seems to be sensitive to the effects of stressors such as noise, as well as those of an environmental stimulation, favoring prompt and lasting molecular changes.

Effect of vitamin E on cisplatin-induced memory impairment in male rats.

Neurotoxicity is an adverse effect caused by cisplatin due to inflammation and oxidative stress in the central nervous system. The present study aimed to assess the effects of vitamin E injection on the learning and memory of rats with cisplatin-induced cognitive impairment. Male rats were administered with cisplatin (2 mg/kg/7 day; intraperitoneally [i i.p.]) and/or vitamin E (200 mg/kg/7 day; i.p.) for 1 week, and the control group received saline solution. Spatial memory was evaluated using Morris water maze (MWM). In addition, the hippocampal concentrations of malondialdehyde (MDA), thiol, and superoxide dismutase (SOD) were measured using biochemical methods. According to the findings, cisplatin significantly increased the escape latency, while decreasing the time spent and travelled pathway in the target quadrant on the final trial day compared to the control group. Furthermore, pre-treatment with vitamin E significantly reversed all the results in the spatial memory test. The biochemical data indicated that vitamin E could decrease MDA activity and increase thiol and SOD activity compared to the control group. According to the results, vitamin E could improve cisplatin-induced memory impairment possibly through affecting the hippocampal oxidative status.

Investigation of the effect of REM sleep deprivation on epileptic seizures caused by pentylenetetrazole in mice

Aim: To investigate whether different periods of rapid eye movement sleep deprivation (REM SD) contribute to seizure susceptibility, hippocampal oxidative status and balance of inhibition-excitation in the acute epilepsy model. Methods: REM SD was performed using the modified multiple platforms method on adult male BALB/c mice. Pentylentetrazol (PTZ) was injected to induce seizures and hippocampal total antioxidant status (TAS), total oxidant status (TOS), gamma aminobutyric acid (GABA), and glutamate levels were measured using the ELISA method. Results: PTZ-induced seizures following 8 h and 72 h REM SD significantly reduced the hippocampal TAS levels, but did not affect the TOS levels. In REM SD groups, especially after 8 hours of REM sleep loss, there was a significant increase in glutamate in PTZ induction. The hippocampal GABA levels were increased by PTZ-induced seizures after 72 h REM SD. PTZ- induction after 8 hours of RAM SD leads to a significant increase in the seizure duration. Conclusion: It can be speculated that the REM SD can contribute to seizure susceptibility by changing the oxidant-antioxidant balance and excitatory and inhibitory tone in the hippocampus.

Strength training and running elicit different neuroprotective outcomes in a β-amyloid peptide-mediated Alzheimer's disease model

Aerobic exercise induces neuroprotection, but few studies investigated whether strength training has similar potential. Here we examine whether effects of strength training differ from those of running training concerning cognitive symptomatology, oxidative stress and cholinergic status in a model of AD-like cognitive impairment induced by intrahippocampal infusion of a mix of β-amyloid peptides (Aβ) in rats. Male Wistar rats were submitted to 8 weeks of running exercise (RunEx; 40 min sessions at 70% of indirect VO2 max, 3 times/week) or strength exercise (StrEx; 3 sessions/week, 12 repetitions in 8 sets, 2 sets with repetitions at 50%, 2 at 75%, 2 at 90% and 2 at 100% of the maximum load), followed by Aβ infusion in the dorsal hippocampus. Short-term (STM) and long-term (LTM) object recognition (OR) and social recognition (SR) memories were evaluated. Hippocampal oxidative status was determined by quantification of reactive oxygen species, lipid peroxidation by thiobarbituric acid reactive substance test, total antioxidant capacity by ferric reducing/antioxidant power, and acetylcholinesterase enzyme activity (AChE). Aβ infusion impaired STM and LTM and resulted in higher hippocampal oxidative damage and impaired AChE activity. StrEx results in better neuroprotection than RunEx by preventing deficits in OR and SR memories, prevents increases in lipid peroxidation, and decreases in AChE activity. RunEx elicits neuroprotection only for SR memory deficits, prevents increase in ROS and lipid peroxidation, and preserves the total antioxidant capacity. While RunEx effects are related to oxidative status, only StrEx shows potential to also influence the cholinergic system.

Environmental enrichment and exercise are better than social enrichment to reduce memory deficits in amyloid beta neurotoxicity

Recently, nongenetic animal models to study the onset and development of Alzheimer's disease (AD) have appeared, such as the intrahippocampal infusion of peptides present in Alzheimer amyloid plaques [i.e., amyloid-β (Aβ)]. Nonpharmacological approaches to AD treatment also have been advanced recently, which involve combinations of behavioral interventions whose specific effects are often difficult to determine. Here we isolate the neuroprotective effects of three of these interventions-environmental enrichment (EE), anaerobic physical exercise (AnPE), and social enrichment (SE)-on Aβ-induced oxidative stress and on impairments in learning and memory induced by Aβ. Wistar rats were submitted to 8 wk of EE, AnPE, or SE, followed by Aβ infusion in the dorsal hippocampus. Short-term memory (STM) and long-term memory (LTM) of object recognition (OR) and social recognition (SR) were evaluated. Biochemical assays determined hippocampal oxidative status: reactive oxygen species, lipid peroxidation by thiobarbituric acid reactive substance (TBARS) test, and total antioxidant capacity by ferric reducing/antioxidant power (FRAP), as well as acetylcholinesterase activity. Aβ infusion resulted in memory deficits and hippocampal oxidative damage. EE and AnPE prevented all memory deficits (STM and LTM of OR and SR) and lipid peroxidation (i.e., TBARS). SE prevented only the SR memory deficits and the decrease of total antioxidant capacity decrease (i.e., FRAP). Traditionally, findings obtained with EE protocols do not allow discrimination of the roles of the three individual factors involved. Here we demonstrate that EE and physical exercise have better neuroprotective effects than SE in memory deficits related to Aβ neurotoxicity in the AD model tested.

Green tea protects against memory deficits related to maternal deprivation

Maternal deprivation (MD) in early life affects the development of the brain, causing cognitive losses in adulthood. Oxidative imbalance may be one of the factors that trigger these deficits. Therapies with antioxidant components, like green tea from Camellia sinensis (GT) has been used to treat or prevent memory deficits in a variety of conditions related to oxidative stress. Here we demonstrate that memory deficits caused by MD can be prevented by GT antioxidant activity in hippocampus. Pregnant female rats were used. Her puppies were submitted to MD and intake of GT. Recognition and aversive memory were evaluated, as well as hippocampal oxidative status. Data showed that MD prejudice short and long-term recognition and aversive memory and that GT protected memory. Hippocampal reactive oxygen species levels were increased in MD rats; this increase was avoided by GT supplementation. GSH was decreased on hippocampus MD rats. GT did not avoid GSH decrease, but promote the increase of total antioxidant capacity in MD rats' hippocampus. In conclusion, GT protects against memory deficits related to MD, and one of the implicated mechanism seems to be the antioxidant effects of GT.

Supplementation with different teas from Camellia sinensis prevents memory deficits and hippocampus oxidative stress in ischemia-reperfusion

Memory and cognition impairments resultant of ischemic stroke could be minimized or avoided by antioxidant supplementation. In this regard, the neuroprotective potential of Green tea from Camellia sinensis has been investigated. However, there is a lack of information regarding the neuroprotective potential of others teas processed from the Camellia sinensis. Here we investigate the neuroprotective role of green, red, white and black tea on memory deficits and brain oxidative stress in a model of ischemic stroke in rats. Our findings show that green and red teas prevent deficits in object and social recognition memories, but only green tea protects against deficits in spatial memory and avoids hippocampal oxidative status and intense necrosis and others alterations in the brain tissue. In summary, green tea shows better neuroprotection in ischemic stroke than the others teas from Camellia sinensis.

An evaluation of aversive memory and hippocampal oxidative status in streptozotocin-induced diabetic rats treated with resveratrol

The present study evaluated the effects of streptozotocin (STZ)-induced diabetes on aversive memory, free radical content and enzymatic antioxidant activity in the hippocampus of adult Wistar rats submitted to oral treatment with resveratrol. Animals were divided into eight groups: non-diabetic rats treated with saline (ND SAL), non-diabetic rats treated with resveratrol at a dose 5mg/kg (ND RSV 5), non-diabetic rats treated with resveratrol at a dose 10mg/kg (ND RSV 10), non-diabetic rats treated with resveratrol at a dose 20mg/kg (ND RSV 20), diabetic rats treated with saline (D SAL), diabetic rats treated with resveratrol at a dose 5mg/kg (D RSV 5), diabetic rats treated with resveratrol at a dose 10mg/kg (D RSV 10) and diabetic rats treated with resveratrol at a dose 20mg/kg (D RSV 20). The animals received oral gavage for 35days. The contextual fear conditioning task was performed to evaluate aversive-based learning and memory. The oxidative status was evaluated in the hippocampus, by measuring the free radical content – using a 2′,7′-dichlorofluorescein diacetate probe – and enzymatic antioxidant activities, such as superoxide dismutase and glutathione peroxidase. Our main behavioral results demonstrated that rats from the D RSV 10 and D RSV 20 groups showed an increase in freezing behavior when compared, respectively, to the ND RSV 10 (p<0.01) and ND RSV 20 (p<0.05). Oxidative stress parameters remained unchanged in the hippocampus of all the experimental groups. In contrast to previous experimental findings, our study was unable to detect either cognitive impairments or oxidative stress in the hippocampus of the diabetic rats. We suggest additional long-term investigations be conducted into the temporal pattern of STZ-induced diabetic disruption in memory and hippocampal oxidative status, as well as the effects of resveratrol on these parameters, in a time and dose-dependent manner.

Involvement of nitric oxide in improving stress-induced behavioural alteration by glatiramer acetate treatment in female BALB/c mice

Oxidative stress and neurotrophins are among the most important factors involved in several pathophysiological brain processes. In addition, long-term exposure to stressful situations has deleterious effects on behaviour. We have previously shown that stressed female BALB/c mice show poor learning performance and that this behaviour is reversed by glatiramer acetate (GA) treatment. We investigated the involvement of the hippocampal oxidative status and neurotrophin levels in cognitive deficit and the improvement of this deficit by GA treatment in chronic stressed BALB/c mice. Female BALB/c mice were exposed to a chronic mild stress (CMS) model for 9 weeks. During the last 3 weeks of the stress exposure, one group of mice was subcutaneously injected four times with 100 μg GA/mouse. Following this period, behavioural studies were performed. The mice were then sacrificed, and biochemical studies were performed on the hippocampus. The stressed mice exhibited a significant decline in their performance in the open-field and in object-in-place tasks. This decline was accompanied by an increase in reactive oxygen species (ROS) and a decrease in nitric oxide (NO) production by neuronal nitric oxide synthase (nNOS). Neither antioxidant defences nor neurotrophin protein levels were involved in this process. Interestingly, the administration of GA re-established the normal levels of ROS, restored nNOS activity and improved learning performance. The GA treatment improved learning and memory in female BALB/c mice under chronic stress through a mechanism that involves the regulation of NO production, which in turn modulates the ROS levels.

Acute restraint stress induces rapid and prolonged changes in erythrocyte and hippocampal redox status

The onset and consequential changes in reduction-oxidation (redox) status that take place in response to short-term stress have not been well defined. This study utilized erythrocytes and neural tissue from male Wistar rats to demonstrate the rapid redox alterations that occur following an acute restraining stress. Serial blood samples collected from catheterized animals were used to measure prolactin, corticosterone, glucose, general oxidative status, and glutathione/glutathione disulfide ratios. Restraint increased prolactin concentration by approximately 300% at 30 min and rapidly returned to baseline values by 120 min of stress. Baseline blood glucose and corticosterone increased during stress exposure by approximately 25% and 150% respectively. Over the experimental period, the erythrocytic oxidative status of restrained animals increased by approximately 10% per hour which persisted after stress exposure, while changes in the glutathione redox couple were not observed until 120 min following the onset of stress. Application of restraint stress increased hippocampal oxidative status by approximately 17% while no change was observed in the amygdala. It was concluded that while endocrine and metabolic markers of stress rapidly increase and habituate to stress exposure, redox status continues to change following stress in both peripheral and neural tissue. Studies with longer post-restraint times and the inclusion of several brain regions should further elucidate the consequential redox changes induced by acute restraint stress.

Greater resistance to inflammation at adulthood could contribute to extended life span of p66 Shc−/− mice

Evidence is mounting that reactive oxygen species (ROS) produced because of stressful challenges could interfere with the proper functioning of the hypothalamic-pituitary-adrenal (HPA) axis, resulting in greater vulnerability to aging and neurodegeneration. Here we tested the hypothesis that p66 Shc−/− mice, which have been described to have an extended life span and a high resistance to oxidative stress, might be less susceptible to the effects of inflammatory insults at adulthood. Although adrenocortical reactivity in response to bacterial endotoxin (lipopolysaccharide, LPS) did not differ as a function of the genotype, a hyperdrive of the HPA axis was revealed following treatment with a synthetic glucocorticoid agonist. When measuring changes in hippocampal oxidative status following LPS, only wild-type (WT) subjects showed increased levels of F 2-isoprostanes, an index of lipid peroxidation and free radical formation. At the same time, the neurotrophin brain-derived neurotrophic factor was selectively increased in WT subjects, while levels of prostaglandin E 2 were decreased in the mutants. Overall, the greater resilience to inflammation-induced changes in the p66 Shc−/− mutants might underlie the better health status and the longevity characterizing these mice.

Green tea improves hippocampal oxidative status during aging

Aging is associated with disruption of the redox balance leading to oxidative stress. Studies have suggested that dietary antioxidants may modify cellular redox status. As green tea (GT) contains large amounts of catechins, we intended to examine the effects of its intake on hippocampal formation redox status, a brain region especially prone to oxidative events during aging. Five 12‐month old male Wistar rats were fed with GT as the only liquid source for 7 months and results were compared to those from 12 (C12) and 19 months old (C19) controls. Oxidative markers (protein carbonyls, malondialdehyde, GSH and GSSG) and antioxidant enzyme activities [glutathione reductase (GR), glutathione S‐transferase (GST), Se‐dependent glutathione peroxidase (Se‐GPX) and superoxide dismutase (SOD)] were measured in hippocampal homogenates. GT protected hippocampal proteins and lipids against oxidation and increased GSH and decreased GSSG levels when compared to C19 rats. GR and GST were decreased by GT relatively to C19 group. There was an age‐dependent decrease in Se‐GPX that could not be altered by GT intake, whereas SOD was similar in C12 and C19 rats, being significantly increased after GT treatment. The global results confirm the neuroprotective ability of GT, showing its hippocampal specific action probably due to attenuation of age‐related redox changes. Granted by Unit 121/94 and SFRH/BD/19497/2004 from FCT.

Effect of a neuroprotective exercise protocol on oxidative state and BDNF levels in the rat hippocampus

Daily moderate intensity exercise (2 weeks of 20 min/day of treadmill training), which reduces damage to hippocampal slices from rats submitted to in vitro ischemia, did not modify oxidative stress parameters in the hippocampus nor the brain-derived neurotrophic factor (BDNF) levels in different brain regions. The aim was to investigate whether the modulation of hippocampal oxidative status and/or brain BDNF content is involved in exercise-induced neuroprotection. Wistar rats were submitted to daily exercise in the treadmill and were sacrificed approximately 16 h after the last treadmill running. Some several oxidative stress parameters were determined, specifically the free radical levels, the macromolecule damage, the total reactive antioxidant potential and reactivity levels, which represent the total antioxidant capacity, in the hippocampus. In addition, BDNF levels in different rat cerebral regions (hippocampus, cortex, striatum, and the cerebellum) were measured by ELISA. The used exercise protocol did not affect any oxidative stress parameters studied in the hippocampus, suggesting that it does not cause a significant oxidative stress nor induce adaptations of the cellular antioxidant system. Treadmill training also did not change the BDNF content in brain areas studied. Considering the fact that this exercise protocol have been shown to be neuroprotective, we might speculate that BDNF levels and oxidative status may not be directly involved with the mechanisms of exercise-induced neuroprotection after ischemia.