Unveiling the Effects of Left Hemispheric Intracerebral Hemorrhage on Long-term Potentiation and Inflammation in the Bilateral Hippocampus: A Preclinical Study.

OBJECTIVE: Changes in cognition and memory are common complications of intracerebral hemorrhage (ICH), although the exact cause of this phenomenon is still unknown. The objectives of our project were to assess the changes in long-term potentiation, inflammation, and cell damage in the bilateral hippocampus following striatal intracerebral hemorrhage at different time points. MATERIALS AND METHODS: Unilateral ICH was induced in the striatum of 96 Wistar rats (6 control groups and 6 ICH groups). We measured changes in synaptic inputs in the bilateral hippocampus using the field potential recording method on days 3, 7, and 14 after ICH. After staining the section with hematoxylin, the volume and number of hippocampal cells were measured. The number of NF-κB positive cells was evaluated using the immunohistochemistry method. RESULTS: There was a significant change in the amplitude and slope of the hippocampal excitatory potential in the ICH group compared to the sham group, but only on the 7th day after surgery. Specifically, the ipsilateral hippocampus in the ICH-7 group showed an increase in stimulation recording in 90 minutes compared to the sham-7 group (p<0.0001), while the contralateral hippocampus in the ICH-7 group exhibited a decrease in potential recording compared to the sham-7 group (p<0.0001). By day 14, the ICH group had a lower cell density in both the ipsilateral (p<0.05) and contralateral hippocampus (p<0.05) compared to the sham group, but there was no significant change in the hippocampal volume between the groups at any time interval. Furthermore, our immunohistochemical analysis revealed that the number of NF-kB-positive cells in both hemispheres of the ICH groups was significantly greater than that of the sham groups across all time intervals. CONCLUSIONS: These findings suggest that striatal injury may lead to inflammation and cell death in the bilateral hippocampus, which can impair cognitive function after ICH.

The effects of curcumin in learning and memory impairment associated with hypothyroidism in juvenile rats: the role of nitric oxide, oxidative stress, and brain-derived neurotrophic factor.

The effect of curcumin (Cur) on cognitive impairment and the possible role of brain tissue oxidative stress, nitric oxide (NO) levels, and brain-derived neurotrophic factor (BDNF) were investigated in juvenile hypothyroid rats. The juvenile rats (21 days old) were allocated into the following groups: (1) control; (2) hypothyroid (0.05% propylthiouracil (PTU) in drinking water); (3-5) hypothyroid-Cur 50, 100, and 150, which in these groups 50, 100, or 150 mg/kg, Cur was orally administered by gavage during 6 weeks. In the hypothyroid rats, the time elapsed and the traveled distance to locate the hidden platform in the learning trials of Morris water maze (MWM) increased, and on the probe day, the amount of time spent in the target quadrant and the distance traveled in there was decreased. Hypothyroidism also decreased the latency and increased the time spent in the darkroom of the passive avoidance (PA) test. Compared with the hypothyroid group, Cur enhanced the performance of the rats in both MWM and PA tests. In addition, Cur reduced malondialdehyde concentration and NO metabolites; however, it increased thiol content as well as the activity of catalase (CAT) and superoxide dismutase enzymes in both the cortex and hippocampus. Cur also increased hippocampal synthesis of BDNF in hypothyroid rats. The beneficial effects of Cur cognitive function in juvenile hypothyroid rats might be attributed to its protective effect against oxidative stress and potentiation of BDNF production.

Losartan modulates brain inflammation and improves mood disorders and memory impairment induced by innate immune activation: The role of PPAR-γ activation.

In recent years, the role of angiotensin II (Ang II) and Ang II type 1 receptor (AT1) in the crosstalk between the immune system and the central nervous system has received more attention. The present study aimed to investigate the role of losartan, an AT1 receptor blocker, in the modulation of long-lasting adverse effects of repeated systemic lipopolysaccharide (LPS) injection in the brain function. For this purpose, 110 male BALB/c mice were administrated LPS (250 µg/kg) intraperitoneally (i.p.) for seven consecutive days. Mice were i.p. injected with losartan (1 and 3 mg/kg) three days before and during the LPS injection. To determine the role of PPAR-γ activation in the protective actions of losartan, GW9662, a PPAR-γ antagonist, was also co-administrated with losartan. Then, behavioral tests, including Morris water maze (MWM), novel object recognition test, passive avoidance, forced swim test (FST), elevated plus maze, and marble burying task, were conducted. The results demonstrated that losartan improved learning and memory impairment, attenuated anxiety-like behaviors, modulated brain inflammation and oxidative stress, and decreased amyloid-ß accumulation. Losartan was unable to improve hippocampal BDNF and IL-10 levels as well as the retention trial in the MWM task and depressive-like behaviors. In addition, the PPAR-γ antagonist did not significantly influence the beneficial effects of losartan. Our findings suggest that AT1R blockade can protect the brain against most long-lasting hallmark effects of systemic inflammation. Also, based on the results, the beneficial actions of losartan were not mediated through PPAR-γ activation.

Effects of PPAR-γ agonist, pioglitazone on brain tissues oxidative damage and learning and memory impairment in juvenile hypothyroid rats.

Aim: The effect of peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist pioglitazone on the brain tissues oxidative damage and learning and memory impairment in the juvenile hypothyroid rats was evaluated. Main methods: Rats were classified as: ( 1 ) Control; (2) Propylthiouracil (PTU); (3) PTU-Pio 10 and (4) PTU-Pio 20. PTU was given in drinking water (0.05%) during 6 weeks. Pioglitazone (10 or 20 mg/kg) was daily injected intraperitoneally. Passive avoidance (PA) and Morris water maze (MMW) were conducted. Later, the animals were sacrificed and the brain tissues were removed for biochemical measurements. Key funding: The results indicated that in the MWM escape latency as well as traveled path increased in the PTU group as compared to the control group. Also, the time spent in the target quadrant in the probe test of MWM and step-through latency in the PA test were decreased in the PTU group as compared to the control group. Pioglitazone reversed all the negative behavioral effects of hypothyroidism. Administration of PTU attenuated thiol and superoxide dismutase (SOD), and catalase (CAT) activities in the brain tissues, whereas increased malondialdehyde (MDA) and nitric oxide (NO) metabolites. PPARγ agonist improved thiol, SOD and CAT, while diminished MDA concentration. Significance: Our finding in the present study indicated that PPARγ agonist pioglitazone prevented the brain tissues from oxidative damage and learning and memory impairments in juvenile hypothyroid rats.

The effects of vitamin E on brain derived neurotrophic factor, tissues oxidative damage and learning and memory of juvenile hypothyroid rats.

The effects of vitamin E (Vit E) on brain derived neurotrophic factor (BDNF) and brain tissues oxidative damage as well as on learning and memory impairments in juvenile hypothyroid rats were examined. The rats were grouped as: (1) Control; (2) Propylthiouracil (PTU); (3) PTU-Vit E and (4) Vit E. PTU was added to their drinking water (0.05%) during 6 weeks. Vit E (20 mg/kg) was daily injected (IP). Morris water maze (MWM) and passive avoidance (PA) were carried out. The animals were deeply anesthetized and the brain tissues were removed for biochemical measurements. PTU increased the escape latency and traveled path in MWM (P < 0.001). It also shortened the latency to enter the dark compartment of PA as well as the time spent in the target quadrant in probe trial of MWM (P < 0.01-P < 0.001). All the effects of PTU were reversed by Vit E (P < 0.01-P < 0.001). PTU administration attenuated thiol and BDNF content as well as the activities of superoxide dismutase (SOD) and catalase (CAT) in the brain tissues while increased molondialdehyde (MDA). Moreover, Vit E improved BDNF, thiol, SOD and CAT while diminished MDA. The results of the present study showed that Vit E improved BDNF and prevented from brain tissues oxidative damage as well as learning and memory impairments in juvenile hypothyroid rats.

In vitro assessment of soybean lecithin and egg yolk based diluents for cryopreservation of goat semen.

Soybean lecithin is a suitable plant-based cryoprotectant for freezing ruminant sperm. Optimum level of lecithin was not clear for goat semen cryopreservation. The objective of this study was to investigate the effects of different levels of soybean lecithin in semen extender on post-thaw sperm quality including CASA-motion parameters, viability, plasma membrane integrity and lipid peroxidation. Semen samples were collected from 4 Mahabadi bucks using an artificial vagina. Different concentrations of soy lecithin (SL, 0.5%, 1%, 1.5%, 2% and 2.5% w/v) were compared to 15% (v/v) egg yolk-based extender (TR-EY). No significant difference was observed for sperm progressive motility, viability or plasma membrane integrity in 1.5% SL media (33.8%, 66%, and 62.7%, respectively) and TR-EY medium (35.4%, 67.2%, and 64.9%, respectively). Sperm motion characteristics (VAP, VSL, VCL, ALH and LIN) and rapid spermatozoa were improved with extender containing 1% and 1.5% SL, compared to TR-EY extender. Furthermore, egg yolk produced significantly higher malondialdehyde (4.02±0.21) than other groups. Results suggest that the optimal lecithin concentration in the semen extender was 1.5% and also soy lecithin can substitute for egg yolk during cryopreservation for caprine sperm.

The Antidiabetic Drug Metformin Attenuated Depressive and Anxiety-like Behaviors and Oxidative Stress in the Brain in a Rodent Model of Inflammation Induced by Lipopolysaccharide in Male Rats.

BACKGROUND: Inflammation is considered to be a link between diabetes and central nervous system (CNS) disorders, including depression and anxiety. Metformin is suggested to have antioxidant, anti-inflammatory, and mood-improving effects. The aim of the current research was to investigate the effects of the antidiabetic drug metformin on depressive- and anxiety- like behaviors and oxidative stress in the brain in a rodent model of inflammation induced by lipopolysaccharide (LPS) in male rats. MATERIALS AND METHODS: The rats were treated as follows: (1) Vehicle instead of metformin and lipopolysaccharide, (2) Lipopolysaccharide (1 mg/ kg) + vehicle instead of metformin, (3-5) Lipopolysaccharide + 50, 100, or 150 mg/ kg of metformin. After the behavioral tests, including open field (OF), elevated pulse maze (EPM), and force swimming (FS) tests, the brains were removed, and malondialdehyde (MDA), nitric oxide (NO) metabolites, total thiol, catalase (CAT) activity, interleukin-6 (IL-6) and superoxide dismutase (SOD) activity were determined. RESULTS: In the EPM, metformin increased the open arm time and entry and decreased closed arm time and entry. In the FS test, metformin lowered the immobility and increased active time compared to lipopolysaccharide. In the OF test, metformin increased total crossing and total distance, time spent, traveled distance, and crossing number in the central zone. As a result of metformin administration, IL-6, MDA, and NO metabolites were decreased while thiol content, SOD, and CAT activity were increased. CONCLUSION: The results indicated that the well-known antidiabetic drug metformin attenuated depressive- and anxiety-like behaviors induced by inflammation in rats. These beneficial effects are suggested to be due to their attenuating effects on neuroinflammation, oxidative stress, and NO in the brain.

Minocycline mitigated enduring neurological consequences in the mice model of sepsis.

AIM: Sepsis-associated encephalopathy is a frequently observed consequence of sepsis, often resulting in chronic brain inflammation and injury, ultimately leading to a range of behavioral abnormalities. This study explores the potential preventive effects of minocycline on the long-lasting outcome of sepsis in a mice model of sepsis. METHODS: Adult male C57 mice were subjected to experimental sepsis through a single intraperitoneal injection of 5 mg/kg lipopolysaccharide (LPS). Minocycline administration via oral gavage (12.5, 25, and 50 mg/kg) commenced three days before sepsis induction and continued on the day of induction. Mice underwent behavioral assessments one month post-sepsis, with subsequent brain tissue analysis to investigate oxidative stress markers and cholinergic function. KEY FINDINGS: One month following sepsis induction, mice exhibited significant anxiety- and depressive-like behaviors as determined by assessments in the elevated plus maze (EPM), open field, and tail suspension test (TST). Additionally, they displayed impaired recognition memory in the novel object recognition (NOR) test. Brain tissue analysis revealed a notable increase in oxidative stress markers and acetylcholinesterase (AChE) activity in septic mice. Notably, minocycline treatment effectively mitigated the long-term behavioral abnormalities resulting from sepsis, attenuated oxidative stress markers, and reduced AChE activity. SIGNIFICANCE: These findings underscore the potential of minocycline as a therapeutic intervention during sepsis induction to prevent the enduring behavioral and neurological consequences of experimental sepsis.

The effect of olibanum on the rats with memory deficit induced by scopolamine.

BACKGROUND: Oxidative stress is an important contributor to Alzheimer's disease. Olibanum has therapeutic effects on various diseases. The effect of Olibanum on memory deficit induced by scopolamine (Sco) was challenged. METHODS: Four groups were considered as (1) control (2) Sco, (3-4) Sco - Olib 100 and 200 mg/kg. Treatment by Olib or vehicle was done for two weeks. The third week was accompanied by the Morris water maze (MWM) and passive avoidance (PA) with Sco injection. On the last day, the brain and hippocampus were used for evaluation of the malondialdehyde (MDA), catalase (CAT), superoxide dismutase (SOD), and a total thiol group. RESULTS: Sco increased the traveled time and distance to reach the hidden platform during five days of learning (p<0.01 - p<0.001) whereas it decreased the traveled time and distance (p<0.05- p<0.01) in the target area during the probe test of MWM. Sco also decreased delay time in the PA test (P<0.05 - P<0.001). Sco also decreased CAT, SOD, and thiol, whereas it, increased MDA in both the cortex and hippocampus (p<0.01 - p<0.001). Olib attenuated the impaired performance of the rats induced by Sco in MWM and PA tests. Olib reversed the increasing effects of Sco on MDA in both cortex and hippocampus and also reversed the attenuating effects of Sco on CAT, SOD, and thiol. CONCLUSION: Olib had an inhibitory effect on memory deficit induced by Sco probably through its anti-oxidant property.

Protective effects of hydro-alcoholic extract of Zataria multiflora on lipopolysaccharide-induced inflammation and oxidative stress in rat liver.

Objective: Liver is an important player in regulation of body homeostasis. Study investigated the effects of hydro-alcohol extract of Zataria multiflora (ZM) on oxidative damage, level of IL-6 and enzymes of liver in lipopolysaccharide (LPS)-treated rats. Materials and Methods: The rats were distributed into 5 groups: 1) Control; 2) LPS; and 3-5) ZM-Extract (Ext) 50, ZM-Ext 100, and ZM-Ext 200. ZM-Ext groups received 50, 100 and 200 mg/kg of extract 30 min before LPS. Drugs were injected intraperitoneally. The entire period of this project was 17 days. In first three days, only extract was injected and then, ZM was injected along with LPS. Results: LPS increased the level of ALT (Alanine aminotransferase), AST (Aspartate aminotransferase ), ALK-P (Alkaline Phosphatase), IL-6, malondialdehyde (MDA), and nitric oxide (NO) metabolites and lowered thiol, superoxide dismutase (SOD) and catalase (CAT) concentration. ZM extract not only reduced ALT, AST, ALK-P, IL-6, MDA, and NO metabolites concentrations but also increased thiol content, and SOD and CAT levels. Conclusion: Extract of ZM prevented LPS-induced hepatotoxicity. This protective effect was associated with reduction in inflammation and oxidative stress.

Rosiglitazone attenuates amyloid beta and glial fibrillary acidic protein in the hippocampus and neuroinflammation associated learning and memory impairments in rats.

OBJECTIVE: The aim of the current study was to investigate the beneficial effects of rosiglitazone (Rosi) on amyloid beta(Aß) and glial fibrillary acidic protein (GFAP) in the hippocampus and neuroinflammation-associated learning and memory impairments in rats. MATERIALS AND METHODS: The rats were grouped and treated as follows: (1) Control in which saline and vehicle were administered instead of LPS and Rosi respectively. (2) Lipopolysaccharide (LPS) group in which LPS was dissolved in saline and injected (1 mg/kg) intraperitoneally. Vehicle was administered instead of Rosi in this group. (3-5) LPS+ Rosi 1, LPS+ Rosi 3, and LPS+ Rosi 5 groups in them 1, 3, or 5 mg/kg of Rosi respectively was administered 30 min before LPS. The treatments were done for two weeks. In the first week, Rosi or its vehicle was injected 30 min before LPS. In the second week, the treatments were the same as the first week and behavioral tests were also carried out in the second week. The hippocampal tissues were finally detached for biochemical assessment. RESULTS: The results showed that Rosi reversed increased levels of Aß, GFAP, interleukin (IL)- 6, tumor necrosis factor-α (TNF-α), nitric oxide (NO) metabolites, and malondialdehyde (MDA) due to LPS injection. Rosi also reversed attenuating effects of LPS on IL-10 and thiol concentration and activities of catalase (CAT) and superoxide dismutase (SOD). In the Morris water maze test, the LPS group had a longer latency to find the platform while spent a shorter time spent in the target quadrant in the probe trial than the control group. In the passive avoidance test, the animals of the LPS group had a shorter delay to enter the dark chamber than the animals of the control group. Treatment with Rosi reversed these parameters. CONCLUSION: The findings showed Rosi attenuated Aß, GFAP, and oxidative stress in the hippocampus and neuroinflammation-associated learning and memory impairments in rats.

Memantine, an NMDA receptor antagonist, protected the brain against the long-term consequences of sepsis in mice.

AIMS: Long-term neuroinflammation and brain dysfunction have frequently been reported in sepsis survivors. In this study, the protective effect of memantine (an NMDA receptor antagonist) on the long-term consequences of sepsis on the brain was investigated in mice. MATERIALS AND METHODS: Eighty-five male C57 mice were included. Memantine was administrated through gavage at 5, 10, and 20 mg/kg three days before sepsis and continued for three days after sepsis induction. Sepsis was induced by intraperitoneal injection of 5 mg/kg LPS. A cohort of mice was sacrificed on the 4th day post sepsis to measure NF-κB, TNF-α, and IL-1ß mRNA expression and oxidative stress markers in the brain. The second cohort was used for behavioral tests one month after sepsis induction and then sacrificed for oxidative stress markers and acetylcholinesterase (AChE) activity measurement. KEY FINDINGS: MDA levels and mRNA expression of NF-κB, TNF-α, and IL-1ß ameliorated by memantine at the early days of sepsis induction, and total thiol content and SOD activity were increased. Post-septic mice showed significant disruption of recognition memory in novel object recognition (NOR) and depressive and anxiety-like behaviors in tail suspension test, elevated plus maze (EPM), and open field tests one month after sepsis. Memantine at 10 and 20 mg/kg dose-dependently ameliorated behavioral abnormalities, reduced AChE activity and MDA levels, and enhanced SOD activity and thiol content one month after sepsis. SIGNIFICANCE: These findings suggest that early treatment of septic mice with memantine could ameliorate brain inflammation and oxidative damage and prevent long-term behavioral consequences of sepsis.

Vitamin E Prevented Hepatic and Renal Tissue Damage in Hypothyroid Rats.

Background: Considering antioxidant effects of vitamin E (Vit E), in the present study, the effect of Vit E on liver and kidney functions and oxidative stress parameters in tissues of these organs of hypothyroid (Hypo) rats were reported. Materials and Methods: The animals were included in three groups:(1) control, (2) hypo, and (3) hypo-hypo-Vit E. Hypothyroidism was induced in rats by giving 0.05% propylthiouracil (PTU) in drinking water. Besides PTU, the rats in group 3 were daily injected with Vit E (20 mg/kg) for 42 days. The animals were deeply anesthetized and sacrificed, and the serum of the rats was immediately removed to measure thyroxin level and subsequent analysis. The liver and kidney tissues were also immediately removed for biochemical oxidative stress criteria. Results: PTU administration reduced serum thyroxin level and also thiol content, superoxide dismutase (SOD), and catalase (CAT) activities in the liver and kidney tissues while increasing malondialdehyde (MDA). Hypothyroidism also increased alanine aminotransferase (ALT), blood urea nitrogen (BUN), and creatinine while decreasing albumin. Vit E increased thiol, SOD, and CAT in the liver and kidney tissues while diminished MDA. Vit E also decreased ALT, BUN, and creatinine while increased albumin. Conclusion: The results of this study showed that Vit E prevented liver and renal tissue damage in hypothyroid rats.

The effects of vitamin D on cardiovascular damage induced by lipopolysaccharides in rats.

Introduction: Inflammation and oxidative stress are contributed to cardiovascular diseases. Vitamin D (Vit D) has antioxidant and anti-inflammatory properties. In the current research, the effect of Vit D on cardiac fibrosis and inflammation, and oxidative stress indicators in cardiovascular tissues was studied in lipopolysaccharides(LPS) injected rats. Methods: Rats were distributed into 5 groups and were treated for 2 weeks. Control: received vehicle(saline supplemented with tween-80) instead of Vit D and saline instead of LPS, LPS: treated by 1 mg/kg of LPS and was given vehicle instead of Vit D, LPS-Vit D groups: received 3 doses of Vit D (100, 1000, and 10000 IU/kg) of Vit D in addition to LPS. Vit D was dissolved in saline supplemented with tween-80 (final concentration 0.1%) and LPS was dissolved in saline. The white blood cell (WBC) was counted. Oxidative stress markers were determined in serum, aorta, and heart. Cardiac tissue fibrosis was also estimated using Masson's trichrome staining method. Results: WBC and malondialdehyde (MDA) were higher in the LPS group than the control group, whereas the thiol content, superoxide dismutase (SOD), and catalase (CAT) were lower in the LPS group than the control group (P<0.01 and P<0.001). Administration of Vit D decreased WBC (P<0.001) and MDA (P<0.05 and P<0.001) while enhanced thiol (dose 10000 IU/Kg) (P<0.001), SOD (dose 10000 IU/kg) (P<0.001), and CAT (P<0.05 and P<0.001) compared to the LPS group. All doses of Vit D also decreased cardiac fibrosis compared to the LPS group (P<0.001). Conclusion: Vit D protected the cardiovascular against the detrimental effect of LPS. This cardiovascular protection can be attributed to the antioxidant and anti-inflammatory properties of Vit D.

Thermodynamic modeling of binary mixtures of ethylenediamine with water, methanol, ethanol, and 2-propanol by association theory.

Association theories by statistical associating fluid theory (SAFT) and cubic plus association (CPA) equation of states (EoS) have effectively handled various thermodynamic purposes thus far; they consider hydrogen bonding effects in associating compounds (those with hydrogen bonds such as water and alcohols) in a proper way. The objective of this work is to thermodynamically undertake the study of ethylenediamine (EDA)-water, EDA-methanol, EDA-ethanol, and EDA-2-propanol binary mixtures in a manner to be useful for designing separation processes by CPA EoS. Accordingly, CPA EoS was applied to model vapor-liquid equilibrium (VLE) of several practical binary mixtures including EDA-water, EDA-methanol, EDA-ethanol, and EDA-2-propanol. It should be noted that the aforementioned mixtures are being studied by CPA EoS for the first time and necessary details are presented; two different association schemes (different situations for creating hydrogen bonds), 2B and 4C schemes, were considered for EDA. Water and studied alcohols were also modeled by 4C and 2B schemes, respectively. Moreover, the capability of two different combining rules (Elliot and CR-1) was evaluated. The azeotrope point available in the phase diagram of EDA-water system was correctly identified by CPA EoS. Furthermore, the liquid phase density of EDA-water was satisfactorily predicted by CPA EoS. It has also a high level of accuracy in VLE modeling of EDA-methanol, EDA-ethanol, and EDA-2-propanol mixtures. In the end, according to all provided results, it can be said that CPA EoS along with all required parameters obtained in this study is capable of describing thermodynamic behavior of studied mixtures.

Exacerbated immune response of the brain to peripheral immune challenge in post-septic mice.

BACKGROUND: Mounting evidence indicates that sepsis can induce long-lasting brain dysfunction. Recently, it has been proposed that the brain may become more sensitive to systemic inflammation if microglial cells are already primed. Microglial priming has been demonstrated in aging, traumatic brain injury, and neurodegenerative diseases. There is evidence suggesting that systemic inflammation may also prime microglia. This study aimed to investigate the brain's response to a second immune challenge in sepsis survivors and the possible role of microglial priming. METHODS: Adult BALB/c mice were intraperitoneally (ip) injected with 5 mg/kg lipopolysaccharide (LPS) for sepsis induction. One month later, mice received a second immune challenge (LPS, 0.33 mg/kg). A cohort of mice was sacrificed 2 h post-LPS injection to measure inflammatory mediators mRNA expression. The second cohort of mice was tested on a battery of behavioral tests and then sacrificed, and brain tissues were removed for biochemical analyses. RESULTS: Results showed that in septic mice, secondary LPS challenge induced heightened neuroinflammation compared to the control mice, as evident by a significant increase of IL-1ß, TNF-α, and iNOS mRNA expression. In the immunochallenged septic mice, the anti-inflammatory cytokine IL-10 expression was also significantly increased compared to the control mice. Sepsis induction significantly disrupted the recognition ability in the novel object recognition, but the second immune challenge had no significant effect. However, immunochallenged septic mice exhibited more anxiety-like behavior in the marble burying task and intensive depressive-like behavior in the forced swim test. Additionally, the second immune challenge reduced arginase-1 levels in septic but not control mice. On the other hand, CIITA levels were increased more significantly in the LPS injected control mice compared to septic mice. Neither sepsis nor the second immune challenge significantly affected inhibitory avoidance behavior and Aß1-42 levels in brain tissue. CONCLUSION: Our finding suggests that low-grade immune challenge can induce exacerbated behavioral change and exaggerated inflammatory response in the brain of post-septic mice.

Cardiac hypertrophy and fibrosis were attenuated by olive leaf extract treatment in a rat model of diabetes.

The key role of fibrosis and hypertrophy processes in developing diabetes-induced heart injury has been demonstrated. Considering the known hypoglycemic effects of olive leaf extract (OLE), we decided to investigate its potential effect and associated mechanisms on cardiac fibrosis and myocardial hypertrophy in streptozotocin (STZ)-induced diabetic rats. Eight groups were included in this study: control, diabetic, diabetic-OLEs (100, 200 and 400 mg/kg), diabetic-metformin (300 mg/kg), diabetic-valsartan (30 mg/kg), and diabetic-metformin/valsartan (300/30 mg/kg). After a treatment period of 6 weeks, echocardiography was used to assess cardiac function. Heart-to-body weight ratio (HW/BW) and fasting blood sugar (FBS) were measured. Myocardial histology was examined by Masson's trichrome staining. Gene expressions of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), ß-myosin heavy chain (ß-MHC), TGF-ß1, TGF-ß3, angiotensin II type 1 receptor (AT1), alpha-smooth muscle actin (α-SMA), and collagen were evaluated by the quantitative real-time PCR in heart tissue. A reduction in the FBS level and HW/BW ratio in the extract groups was obvious. The improvement of left ventricular dysfunction, cardiac myocytes hypertrophy, and myocardial interstitial fibrosis was also observed in treated groups. A lowering trend in the expression of all hypertrophic and fibrotic indicator genes was evident in the myocardium of OLE treated rats. Our data indicated that OLE could attenuate fibrosis and reduce myocardial hypertrophy markers, thus improving the cardiac function and structure in the STZ-induced diabetic rats. PRACTICAL APPLICATIONS: This study demonstrates that olive leaf extract in addition to lowering blood glucose levels and the heart-to-body weight ratio (HW/BW) may also improve cardiac function and reduce cardiac hypertrophy and fibrosis in cardiac tissue, which leads to inhibition of diabetic heart damage. Thus it is possible that including olive leaf extracts in the diets of individuals with diabetes may assist in lowering cardiovascular disease risk factors.

Carvacrol attenuated neuroinflammation, oxidative stress and depression and anxiety like behaviors in lipopolysaccharide-challenged rats.

Objective: The beneficial effect of carvacrol on neuroinflammation, oxidative damage of brain tissue, and depressive- and anxiety-like behaviors after lipopolysaccharide (LPS) administration were evaluated in rats. Materials and Methods: Vehicle (1% Tween 80), 1 mg/kg of LPS, and carvacrol (25, 50, or 100 mg/kg administered prior to LPS) were injected and behavioral and biochemical tests were done. Results: The results of forced swim test revealed that carvacrol attenuated immobility time and increased activity and climbing times (p<0.05 to p<0.001). The results of elevated plus maze also revealed that treatment by carvacrol prolonged the open arms time and entries and decreased the time and entries in the closed arms (p<0.05 to p<0.01). Carvacrol enhanced crossing, time, and traveled distance in the central segment of the open field and increased total crossing and distance while attenuating the peripheral zone time (p<0.05 to p<0.001). All doses of carvacrol attenuated TNF- α (tumor necrosis factor α) and NO (nitric oxide) in the brain (p<0.01 to p<0.001). The 50 and the 100 mg/kg doses of carvacrol decreased malondialdehyde (p<0.001 for both), and the 100 mg/kg dose of carvacrol increased the content of the thiol (p<0.001). Conclusion: In conclusion, carvacrol improved the behavioral consequences of LPS challenge and attenuated neuroinflammation and brain tissue oxidative stress in rats.

Ellagic Acid Prevents Oxidative Stress and Memory Deficits in a Rat Model of Scopolamine-induced Alzheimer's Disease.

BACKGROUND: Ellagic acid (EA) has various pharmacological effects such as antiinflammatory and anti-oxidant effects. OBJECTIVE: This study aimed to investigate the effects of EA on learning and memory dysfunction as well as oxidative stress in scopolamine-induced amnesic rats. METHODS: The studied rats were treated according to the following protocol: Control (group 1) and scopolamine (group 2) groups received saline (intraperitoneal injection (i.p.)) while the treatment groups (group 3-5) were given EA (25, 50, and 100 mg/kg, i.p.) for 3 weeks. Thereafter, their behavioral performance was evaluated using Morris water maze (MWM) and passive avoidance (PA) tasks. Notably, scopolamine was injected (into groups II-V at a dose of 2 mg/kg, i.p.) before conducting the tasks. Finally, the oxidative stress indicators in the brain were measured. RESULTS: EA reduced the escape latencies and distances during the learning phase of MWM. The results of probe trials also indicated that EA improved memory retrieval and helped animals recall the platform. Moreover, EA increased delay and light time, while decreasing the frequency of entries to the dark area of PA. In the EA-treated groups, the level of malondialdehyde was decreased, while the levels of total thiol groups, superoxide dismutase, and catalase were increased. CONCLUSION: EA prevented the negative effects of scopolamine on learning and memory which is probably mediated via modulating oxidative stress. Hence, EA could be considered as a potential alternative therapy for dementia.

Losartan improved hippocampal long-term potentiation impairment induced by repeated LPS injection in rats.

Cognitive impairment has been known as a common consequence of brain inflammation. Long-term potentiation (LTP), the generally accepted cellular mechanism for memory formation in the mammalian brain, has been shown to be suppressed by inflammation. Studies have shown that angiotensin II (Ang II) through the Ang II type 1 receptor (AT1R) has a role in brain and peripheral immune system communication and brain inflammation. Here, the effect of AT1R blockade on hippocampal LTP in rats undergoing repeated lipopolysaccharide (LPS) injection was investigated. Rats received intraperitoneal (ip) injections of LPS (250 µg kg-1  day-1 ) for seven days. Treatment with losartan (ip; 3 mg kg-1  day-1 ) was started 3 days before LPS injection and continued during the LPS injections. Rats were anesthetized, and field excitatory postsynaptic potential (fEPSP) was recorded from the stratum radiatum of the CA1 area of the hippocampus in response to stimulation of the Schaffer collateral pathway. Results showed that LTP was suppressed in the LPS-injected rats as no significant differences were found in the fEPSP slope and amplitude before and after the LTP induction. AT1R blockade by losartan restored fEPSP to the control levels. These findings indicate that Ang II, through AT1R, has a role in LTP suppression induced by systemic inflammation.