Protective effects of gallic acid against chronic cerebral hypoperfusion-induced cognitive deficit and brain oxidative damage in rats

Free radical induced neural damage is implicated in cerebral hypoperfusion disorders and antioxidants have protective effects. In the present study, we examined the effect of gallic acid (GA; 100 mg/kg, p.o. for 10 days) on cognitive deficit and cerebral oxidative stress induced by permanent bilateral common carotid artery occlusion (2VO) as an animal model of vascular dementia (VD). The results showed that 2VO significantly reduced the spatial memory performance in Morris water maze as well as non enzymatic (total thiol) and enzymatic glutathione peroxidase (GPx)] antioxidant contents and increased the level of malondialclehyde (MDA) in the hippocampus and frontal cortex of vehicle-treated group as compared to sham-operated rats. Furthermore, chronic administration of GA significantly restored the spatial memory, total thiol and GPx contents and also decreased MDA levels in these tissues. GA alone did not show any change neither in the status of various antioxidants nor behavioral tests over sham values. The results demonstrate that GA has beneficial activity against 2VO-induced cognitive deficits via enhancement of cerebral antioxidant defense. Taken together, the present study suggested that GA might be useful in the treatment of VD. (C) 2014 Elsevier B.V. All rights reserved

Post-stroke depression modulation and in vivo antioxidant activity of gallic acid and its synthetic derivatives in a murine model system

Gallic acid (3,4,5-trihydroxybenzoic acid, GA) is a plant secondary metabolite, which shows antioxidant activity and is commonly found in many plant-based foods and beverages. Recent evidence suggests that oxidative stress contributes to the development of many human chronic diseases, including cardiovascular and neurodegenerative pathologies, metabolic syndrome, type 2 diabetes and cancer. GA and its derivative, methyl-3-O-methyl gallate (M3OMG), possess physiological and pharmacological activities closely related to their antioxidant properties. This paper describes the antidepressive-like effects of intraperitoneal administration of GA and two synthetic analogues, M3OMG and P3OMG (propyl-3-O-methylgallate), in balb/c mice with post-stroke depression, a secondary form of depression that could be due to oxidative stress occurring during cerebral ischemia and the following reperfusion. Moreover, this study determined the in vivo antioxidant activity of these compounds through the evaluation of superoxide dismutase (SOD) and catalase (Cat) activity, thiobarbituric acid-reactive substances (TBARS) and reduced glutathione (GSH) levels in mouse brain. GA and its synthetic analogues were found to be active (at doses of 25 and 50 mg/kg) in the modulation of depressive symptoms and the reduction of oxidative stress, restoring normal behavior and, at least in part, antioxidant endogenous defenses, with M3OMG being the most active of these compounds. SOD, TBARS, and GSH all showed strong correlation with behavioral parameters, suggesting that oxidative stress is tightly linked to the pathological processes involved in stroke and PSD. As a whole, the obtained results show that the administration of GA, M3OMG and P3OMG induce a reduction in depressive symptoms and oxidative stress

Sesamin alleviates defects in seizure, behavioral symptoms, and hippocampus electroencephalogram in a pentylenetetrazol rat model

Objective(s): Seizure is a prevalent disorder reflected by powerful and sudden activity of neural networks in the brain that leads to tonic-clonic attacks. These signs may be due to an increase in excitatory/inhibitory neurotransmitters ratio. So, the current experiment aimed to examine the seizure and neurobehavioral parameters, as well as the hippocampus local electroencephalogram (EEG) after seizure with and without sesamin pretreatment.   Materials and Methods: Sesamin (15, 30, and 60 mg/kg/5 ml, intraperitoneal or IP, vehicle: dimethyl sulfoxide or DMSO, for 3 days) was administrated before pentylenetetrazol (PTZ) (60 mg/kg/10 ml, IP, vehicle: saline), which induces acute seizure in adult male Wistar rats (230 ± 20 g, six weeks old). Different phases of seizures (score, latency, duration, and frequency), behavioral parameters (passive avoidance memory, anxiety, and locomotor activity), and hippocampus local EEG were evaluated after the injections. At the end of the experiments, oxidative stress markers plus gene expression of phosphoinositide 3-kinase/protein kinase B or PI3K/Akt mRNA were measured in the hippocampus.  Results: Pretreatment with sesamin (30 mg/kg) could significantly decrease seizure scores and oxidative stress in the hippocampus. PTZ injection induced EEG deficits and neurobehavioral impairments which were significantly decreased by sesamin, especially in Beta, Theta, and delta EEG waves.  Also, the expression of PI3K/Akt significantly increased in the sesamin (30 mg/kg) group in comparison with the PTZ group. Conclusion: Sesamin could prevent seizure attacks and neurobehavioral and EEG deficits induced by pentylenetetrazol, probably through the PI3K/Akt signaling pathway

Time- and Dose-Dependent Neuroprotective Effects of Sex Steroid Hormones on Inflammatory Cytokines after a Traumatic Brain Injury

Following a traumatic brain injury (TBI), excessive release of proinflammatory cytokines is the major cause of cerebral edema and neuronal loss. This study was designed to examine changes in concentrations of some proinflammatory cytokines—including interleukin-1 beta (IL-1b), interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-a), and transforming growth factor-beta (TGF-b)—in a rat model of TBI in which the animals were treated with different doses of estrogen or progesterone 6 and 24 h after the TBI. Adult female rats were divided into 14 groups. Hormones or vehicle were given intraperitoneally 30 min after a moderate TBI was induced by the Marmarou method. The levels of proinflammatory cytokines in brain were measured at 6 and 24 h after the TBI. A high dose of estrogen (E2) or a low dose of progesterone (P1) increased brain levels of IL-1b 52.7% and 79.2% respectively at 6 h after the TBI. By 24h, IL-1b levels in the brain were 27.5% and 27% lower following administration of estrogen low dose (E1) or E2, respectively. High-dose administration of progesterone reduced brain levels of IL-6 to 45.9% at 6 h after the TBI, and P1 and E1 treatment significantly decreased IL-6 levels at 24 h. Brain levels of TNF-a were 72.5% lower at 6 h after the TBI following P2 treatment and 48.5% higher at 24 hrs following treatment with E2. The levels of TGF-b were also 3.37 times higher 24 h after the TBI following treatment with E1. Both doses of the hormones tested increases TGF-b levels 6 h after the TBI. Based on our findings, we conclude that progesterone and estrogen influence the levels of proinflammatory cytokines either at the primary or secondary stages after a TBI. Accordingly, this study suggests a mechanism by which hormones reduce cerebral edema

Gallic acid improves cognitive, hippocampal long-term potentiation deficits and brain damage induced by chronic cerebral hypoperfusion in rats

Cerebral Hypoperfusion Ischemia (CHI) has important role in neuronal damage and behavioral deficits, including memory and Long-term Potentiation (LTP) impairment. Protective effects of Gallic Acid (GA) on memory, hippocampus LTP and cell viability were examined in permanent bilateral common carotid artery occlusion in rats. Animals were divided into 9 groups: Control (Cont); sham operated (Sho); Cerebral Hypoperfusion Ischemia (CHI); CHI received normal saline (CHI +Veh); CHI treated with different doses gallic acid (50,100, 200 mg kg-1 for 5 days before and 5 days after CHI induction, orally); CHI treated with phenytoin (50 mg kg-1, ip) (CHI+Phe); and sham operated received 100 mg kg-1, orally (Sho+GAl 00). CHI was induced by bilateral common carotid artery occlusion (2VO). Behavioral, electrophysiological and histological evaluations were performed. Data were analyzed by one-way and repeated measures ANOVA followed by tukey's post-hoc test. GA improved passive avoidance memory, hippocampal LTP and cell viability in hippocampus and cortex of ischemic rats significantly (p<0.01). The results suggest that gallic acid via its antioxidative and free radicals scavenging properties attenuates CHI induced behavioral and electrophysiological deficits and has significant protective effect on brain cell viability. Dose of 100 mg kg-1 GA has affected the ischemic but not intact rats and its effect was more potent significantly than phenytoin, a routine drug for ischemic subjects. © 2014 Asian Network for Scientific Information

Effect of Estrogen and Progesterone on Cytokines Levels at Different Time Intervals after Traumatic Brain Injury

Introduction: Following a traumatic brain injury (TBI), the excessive release of proinflammatory cytokines is major cause of cerebral edema that can cause permanent neuronal loss. This study examined the changes in brain concentrations of proinflammatory cytokines IL-1, IL-6, TNF-α and TGF- after different doses of estrogen or progesterone treatment in brain-injured rats at 6 and 24 h post-injury. Methods: Adult female rats were divided into 14 groups, and underwent either bilateral ovariectomy (12 groups) or sham surgery (2 groups). The hormones or vehicle were given intraperitoneally 0.5 h after TBI. Moderate TBI was induced by Marmarou method in TBI or treatment groups and brain levels of proinflammatory cytokines were measured 6 and 24 h post-injury. Results: The results indicated that high dose of estrogen (E2) and low dose of progesterone (P1) increase brain levels of IL-1 6 h post-injury by 52.8% and 79.2%, respectively compared to the vehicle. By the 24th h post-injury brain IL-1 level was reduced 27.5% and 27%, respectively compared to vehicle, when estrogen low dose (E1) and E2 were administered. Progesterone high dose treatment reduced brain level of IL-6 by 45.9% at 6 h post-injury and P1 treatment reduced IL-6 level by 20.5% at 24 h post-injury when compared to the vehicle. The brain TNF-α level was reduced by 72.5% by P2 at 6 h and 48.5% by E2 at 24 h post-injury, when compared to the vehicle. In addition, TGF- level seem to be increased by E1 up to 3.37 times at 24 h post-injury compared to the vehicle. Both doses of hormones showed increased levels of TGF- at 6 h post-injury, when compared to the vehicle. Conclusion: We conclude that progesterone and estrogen may change the levels of proinflammatory cytokines in the acute or delayed phases after TBI and this may be one of the mechanisms by which hormones reduce cerebral edema

High-flavonoid intake induces cognitive improvement linked to changes in serum brain-derived neurotrophic factor: two randomised,controlled trials

BACKGROUND: Recent clinical studies have indicated the beneficial impact of dietary flavonoid intake on human cognitive performance. Although the mechanisms that mediate such improvements are currently unclear, animal and human trial data suggest that changes in neurotrophin expression, and related signalling apparatus, may be involved. OBJECTIVE: To investigate the link between changes in serum brain-derived neurotrophic factor (BDNF) and changes in human cognitive performance following flavonoid intake. METHODS: The relationship between serum levels of BDNF and age, gender, BMI, waist circumference, blood pressure and cognition at baseline, and following flavonoid intake, was investigated in two distinct randomised, controlled clinical trials. Trial 1 was conducted in men and women (aged 26–70 y; consuming an average of 3 portions of fruit and vegetables per day) and delivered high-flavonoid (>15 mg/100 g) or low-flavonoid (<5 mg/100 g) fruit and vegetables and increased intake by 2 portions every 6 weeks. The control arm was habitual diet over the same time frame. Trial 2 was conducted in an older males and female cohort (aged 62–75 y) intervening with a high-flavanol cocoa drink (494 mg total flavanols) and a low-flavanol cocoa drink (23 mg total flavanols) for 12 weeks. RESULTS: Serum BDNF levels increased linearly to the age of 65, after which BDNF levels were found to decrease markedly. All other physiological and anthropometric measurements proved to not be significantly associated with serum BDNF levels (p > 0.05), although higher levels in males compared to females almost achieved significance (p = 0.056). At baseline, higher serum BDNF levels were associated with significantly better global cognition scores, relative to individuals with lower serum levels. In addition, following intervention for 18 weeks, high-flavonoid, but not low-flavonoid, fruit and vegetable intake induced significant improvements in cognitive performance and increases in serum BDNF levels (p = <0.001). Flavanol intervention for 12 weeks also resulted in significant increases in serum BDNF (p = <0.001), and such increases were correlated with improvements in global cognitive performance. CONCLUSION: Increases in global cognition induced by high flavonoid fruit and vegetables, and cocoa flavanols were paralleled by concurrent changes in serum BDNF levels, suggesting a role for BDNF in flavonoid-induced cognitive improvements. Furthermore, we provide further data suggesting that serum BDNF levels may represent a biomarker of cognitive function

The Role of Proinflammatory Cytokines in Mediation of Brain Antiedema Effect of Female Sex Steroids Following Traumatic Brain Injury

Abstract: Background & Aims: Release of proinflammatory cytokines after traumatic brain injury (TBI) is a major cause of brain edema. Previous studies demonstrated that sex steroids decrease brain edema induced by TBI. In this study changes of brain cytokines after the administration of estrogen and progesterone 24 hours after TBI were evaluated. Materials and Methods: Female rats were divided into 7 groups. Groups 1 and 2 were considered as control and sham respectively and other 5 groups underwent bilateral ovariectomy and considered as vehicle, physiologic does of estrogen (E1), pharmacologic dose of estrogen (E2), physiologic dose of progesterone (P1) and pharmacologic dose of progesterone (P2). Vehicle and sexual steroid hormones were injected intraperitoneally 30 minutes after TBI. Moderate TBI was induced by Marmarou method. Neurologic scores (VCS) were evaluated immediately, 1 h, 4 h and 24 h after TBI. Brain level of IL-1β, IL-6, TNF-α, TGF- estrogen and progesterone were measured 24 hours after TBI by ELISA method. Results: E1 and E2 groups showed respectively 27.5% and 27% decrease in brain level of IL-1β compared to vehicle. Brain level of IL-1β increased in vehicle group compared to sham. E1 and P1 groups showed respectively 47% and 20.5% decrease of brain IL-6 level compared to vehicle. Brain Level of TNF-α increased 48.5% in E2 group compared to the vehicle group. Both estrogen and progesterone in physiologic and pharmacologic doses increased TGF-β, but the highest increase of TGF-β level was about 9.5 times and was observed in E1 group. Brain level of β-Estradiol increased 1.8 times in E2 group and progesterone increased 1.84 times in P2 group compared to the vehicle group. Veterinary coma scale (VCS) increased in E1, E2, P1 and P2 group at 1 hour after TBI, whereas, 4 h after TBI only in E1 and P1 and 24 h after TBI, in E1, E2 and P1 groups VCS, showed increase. Conclusion: Neuroprotective effect of sex hormones in reducing cerebral edema is probably performed by decrease of brain level of IL-1β and IL-6 and increase of brain level of TNF-α and TGF-β after TBI. Keywords: Brain injury, Estrogen, Progesterone, IL-1β, IL-6, TNF-α, TGF-

Impaired Learning Due to Noise Stress During Pregnancy in Rats Offspring

Background: Environmental noise is a known stressful factor,that induces alterations of various physiological responses in the exposed individuals. Extensive evidences from animal and human studies have indicated that stress influences cognitive functions. Studies have shown that chronic exposure to noise during pregnancy impairs neurobehavioral and reproductive functions and also reduces the body weight of the offspring. It seems that prenatal noise stress during last three months of fetal life damages the neurons in special areas of brain involved in cognition and impairs the activity of hypothalamuspituitary- adrenal (HPA) axis. It is known very little about the effect of prenatal noise stress on learning. The aim of present work was to determine the effect of prenatal chronic intermittent noise stress on learning in rats. Methods: Fifteen Wistar pregnant rats were exposed chronically to intermittent white noise (90-120dB, 350Hz) during the last two weeks of their pregnancy periods (dark cycle, 07:00Pm-07:00Am). Stressed and nonstressed puppies bred under normal condition up to 3 months of age. Both stressed and nonstressed adult male and female rats were trained in an equal 3 arms Y-maze with 20-25 Volts D.C. electrical footshock and a 12 Watts light stimuli as an active avoidance learning. Animals were trained one session daily and criterion condition response (CCR) was 90 percent of last session of training. Results: Data showed that chronic exposure to noise during pregnancy impairs learning of stressed male rats significantly at all sessions (P&lt;0.01). However, in the stressed female rats the response was decreased significantly only at the first two sessions (P&lt;0.05). Conclusion: The results indicate that prenatal noise stress may damage the neurons in special areas of brain such as hippocampus and alters cognition and behavioral functions. Keywords: noise stress, pregnancy, learning, rat

Effect of oral Aluminum intake on sex hormones of rat

History and Objectives: Aluminum absorbed through several means and its increased absorption is associated with some complications. Aluminum may alter and complicate the function of calcium and its biological effects leading to the sex hormone changes. Its absorption competes with Iron and may cause anemia. The present study is carried out to determine the effect of prescribed oral aluminum on the sex hormone changes of rat. Materials and Methods: An experimental study was performed on 52, 6 months old rat with average weight of 318 grams. Rats were divided into 4 groups of 13. One group was taken as control and 3 others were experimental groups. Experimental groups were given 0.625, 1.25 and 2.5 mg of aluminum in each meal for 60 days. The effect of aluminum intake was studied on the blood hemoglobin, hematocrit, LH, FSH and testosterone levels. T-test and analysis variance were performed. Results: Blood hemoglobin levels were 14.93±0.27, 13.24±0.27 and 11.84±0.35 for control and 1.25 and 2.5 mg experimental groups respectively (P<0.001). Hematocrit levels were 42±0.36% and 40±1 for control and 2.5mg experimental group respectively (P<0.001). FSH levels in 2.5mg experimental group and LH and testosterone levels in 2.5 and 1.5 mg experimental groups had less significant difference compared to the control group (P<0.05). No significant difference was observed with other groups. Conclusion: Increased aluminum intake in male rats induces anemia and decreases level of sex hormones