Renal protection by ellagic acid in a rat model of glycerol-induced acute kidney injury.

Studies conducted on animal models have shown that the administration of glycerol can lead to kidney tissue damage and impaired renal function. This is believed to be caused by oxidative stress and inflammation, which in turn can result in elevated levels of blood urea nitrogen (BUN) and creatinine. These metabolites are commonly used as indicators of renal function. The aim of the current experimental research was to investigate the protective efficacy of ellagic acid in a rat model of rhabdomyolysis induced by glycerol. Sixty healthy adult male Wistar rats weighing between 250 - 300 g were divided into five equal groups including control, rhabdomyolysis (administered 8.00 mL kg-1 of glycerol), and three rhabdomyolysis plus various doses of ellagic acid (25.00, 50.00 and 100 mg kg-1 per day; 72 hr after receiving glycerol for 14 days successively) groups. Serum levels of BUN, creatinine, lactate dehydrogenase, alkaline phosphatase, electrolytes and inflammatory cytokines were evaluated in all rats. Histopathological studies were also performed on kidney tissues from all groups. The administration of ellagic acid resulted in a significant increase in renal function biomarkers compared to the rats with acute kidney injury. This increase was consistent with notable reductions in tumor necrosis factor-α levels and increases in interleukin-10 levels observed in blood samples. Furthermore, the improvement in histopathological indices observed in rats received ellagic acid confirmed its nephroprotective role. The results of the current experimental study suggest that ellagic acid can improve kidney damage following glycerol injection, potentially by modulating the inflammatory process.

Effect of Gallic Acid Pretreatment and SGK1 Enzyme Inhibition on Cardiac Function and Inflammation in a Rat Model of Ischemia-Reperfusion Injury.

Background: Serum and glucocorticoid-induced kinase 1 (SGK1) is an enzyme that may play an important role in ischemic-reperfusion (I/R) injury and myocardial dysfunction. Although many studies have been conducted on individual antioxidants, little attention has been paid to the effects of co-administration of an antioxidant with an SGK1 inhibitor on cardiac function after I/R. Methods: This study aimed to determine the effects of gallic acid (as an antioxidant) combined with an SGK1 inhibitor on I/R-induced cardiac dysfunction and inflammation. Sixty male Wistar rats were randomized into 6 groups, pretreated with gallic acid or vehicle for 10 days. Subsequently, the heart was isolated and exposed to I/R. In groups that received the SGK1 inhibitor, the heart was perfused with the SGK1 inhibitor GSK650394, 5 min before induction of ischemia. After that, cardiac function, inflammatory factors, and myocardial damage were evaluated. Results: The combination of these two compounds improved cardiac contractility, heart rate, rate pressure product, left ventricular developed pressure, left ventricular systolic pressure, perfusion pressure, and QRS voltage significantly (P < 0.05). In addition, concomitant therapy of these two agents reduced tumor necrosis factor-alpha and interleukin-6, and the activity of creatine kinase-MB, lactate dehydrogenase, and troponin-I (P < 0.05). Conclusion: The results indicated that administration of gallic acid with the SGK1 inhibitor may have a potentiating effect on the improvement of cardiac dysfunction and I/R-induced inflammation.

Dose-dependent neuroprotective effects of adipose-derived mesenchymal stem cells on amyloid ß-induced Alzheimer's disease in rats.

AIM: Mesenchymal stem cells (MSCs) have emerged as an intriguing candidate in cell therapy for treating neurodegenerative diseases, including Alzheimer's disease (AD). To achieve the maximum efficiency of cell therapy, determining the optimal dose of MSCs is essential. This study was conducted to assess the dose-dependent therapeutic response of MSCs against pathological and behavioral AD-associated alterations. METHODS: Aß1-42 was injected intrahippocampally to establish an AD rat model. The MWM test was utilized to evaluate the animal's behavioral functions after receiving low and high doses of MSCs in the hippocampus region. ELISA and RT-qPCR were also employed to assess the concentration of markers related to antioxidant activity and inflammation and the gene expression related to apoptosis in the hippocampus region, respectively. RESULTS: Low-dose MSC transplantation by increasing the concentrations of the antioxidant GSH, the anti-inflammatory cytokine IL-10, as well as by lowering the concentrations of TNF-α, and the expression levels of apoptotic factors (Bax and caspase 3), exerted a neuroprotective effect in the hippocampus of AD rats and relatively ameliorated spatial learning and memory impairments. However, increasing the dose of MSCs decreased the therapeutic benefits of these cells and had no significant effect on the recovery of behavioral disorders. CONCLUSION: Our findings reveal the dose-dependent neuroprotective effect of MSCs in AD. The therapeutic response of MSCs to ameliorate the pathological and behavioral alterations associated with AD is attenuated when the dosage of MSCs is increased.

The renoprotective effects of hesperidin on kidney injury induced by exposure to severe chronic dust storm particulate matter through inhibiting the Smads/TGF-ß1 signaling in rat.

Exposure to dust storm particulate matter (PM) is detrimental to kidney tissue. In this study, the impacts of chronic intake of dusty PM were explored as a major objective in a specified compartment to make a real-like dust storm (DS) model, and the role of hesperidin (HSP) as an antioxidant on kidney tissue was assessed in rats. Thirty-two male Wistar rats (200-220 g) were randomly allocated into 4 groups: CA+NS: (clean air and normal saline as a vehicle of HSP). Dusty PM and NS (DS+NS). HSP+ CA: rats received 200 mg/kg of HSP by gavage for 28 days, once daily in addition to exposure to clean air. HSP+DS: HSP plus DS. In DS groups, the animals were exposed to dust storms at a concentration of 5000-8000 µg/m3 in the chamber for 1 h daily, for 4 consecutive weeks, except Thursdays and Fridays. At the end of the experiment, the animals were sacrificed for biochemical, inflammatory, oxidative stress, molecular parameters, and histological evaluation. DS significantly enhanced blood urea nitrogen and creatinine, inflammatory (tumor necrosis factor-α, and interleukin-1ß), and oxidative stress indexes. Likewise, a significant increase was seen in mRNA Smads, collagen-I, and transforming growth factor-ß1 (TGF-ß1) expressions in the kidney. Histological findings showed contracted glomeruli and kidney structure disorder. In addition, Masson's trichrome staining demonstrated renal fibrosis. Nevertheless, HSP could significantly reverse these changes. Our data confirmed that DS results in kidney fibrosis through enhancing Smads/TGF-ß1 signaling. However, HSP was able to inhibit these changes as confirmed by histological findings.

Anandamide improves food intake and orexinergic neuronal activity in the chronic sleep deprivation induction model in rats by modulating the expression of the CB1 receptor in the lateral hypothalamus.

Sleep deprivation alters orexinergic neuronal activity in the lateral hypothalamus (LH), which is the main regulator of sleep-wake, arousal, appetite, and energy regulation processes. Cannabinoid receptor (CBR) expression in this area is involved in modulating the function of orexin neurons. In this study, we investigated the effects of endocannabinoid anandamide (AEA) administration on improving food intake and appetite by modulating the activity of orexin neurons and CB1R expression after chronic sleep deprivation. Adult male Wistar rats (200-250 g) were randomly divided into three groups: control + vehicle (Control), chronic sleep deprivation + vehicle (SD), and chronic sleep deprivation +20 mg/kg AEA (SD + A). For SD induction, the rats were kept in a sleep deprivation device for 18 h (7 a.m. to 1 a.m.) daily for 21 days. Weight gain, food intake, the electrical power of orexin neurons, CB1R mRNA expression in hypothalamus, CB1R protein expression in the LH, TNF-α, IL-6, IL-4 levels and antioxidant activity in hypothalamus were measured after SD induction. Our results showed that AEA administration significantly improved food intake (p < 0.01), Electrical activity of orexin neurons (p < 0.05), CB1R expression in the hypothalamus (p < 0.05), and IL-4 levels (p < 0.05). AEA also reduced mRNA expression of OX1R and OX2R (p < 0.01 and p < 0.05 respectively), also IL-6 and TNF-α (p < 0.01) and MDA level (p < 0.05) in hypothalamic tissue. As a consequence, AEA modulates orexinergic system function and improves food intake by regulating the expression of the CB1 receptor in the LH in sleep deprived rats.

Preconditioning adipose-derived mesenchymal stem cells with dimethyl fumarate promotes their therapeutic efficacy in the brain tissues of rats with Alzheimer's disease.

AIM: Transplantation of mesenchymal stem cell (MSC) has been suggested to be a promising method for treating neurodegenerative conditions, including Alzheimer's disease (AD). However, the poor survival rate of transplanted MSCs has limited their therapeutic application. This study aimed to evaluate whether preconditioning MSCs with dimethyl fumarate (DMF), a Nrf2 inducer, could enhance MSC therapeutic efficacy in an amyloid-ß (Aß1-42)-induced AD rat model. METHODS: The survival and antioxidant capacity of MSCs treated with DMF were assessed in vitro. Aß1-42 intrahippocampal injection was used to create a rat model of AD. Following the transplantation of MSCs preconditioned with DMF and using the Morris blue maze test, spatial learning and memory were assessed. Using RT-qPCR, we evaluated the gene expression related to apoptosis and neurotrophins in the hippocampus region. RESULTS: Treatment with DMF enhanced cell survival and Nrf2 protein expression in MSCs in vitro. Preconditioning with DMF also enhanced the efficacy of transplanted MSCs in rescuing learning and spatial memory deficits in Aß-AD rats. Besides, DMF preconditioning enhanced the neuroprotective effect of transplanted MSCs in the hippocampus of rats treated with Aß1-42 by decreasing the expression of apoptotic markers (Bax, caspase 3, and cytochrome c), and elevating the expression of the anti-apoptotic marker Bcl2 and neurotrophins, including BDNF and NGF. CONCLUSION: Preconditioning MSCs with DMF boosted the therapeutic efficacy of these cells; therefore, it could serve as a targeted strategy for increasing the therapeutic efficacy of MSCs in treating neurodegenerative disorders, including AD.

Effects of Gallic Acid on Memory Deficits and Electrophysiological Impairments Induced by Cerebral Ischemia/Reperfusion in Rats Following Exposure to Ambient Dust Storm.

We aimed to investigate the probable protective effects of gallic acid (GA) on cognitive deficits, hippocampal long term potentiation (LTP) impairments, and molecular changes induced by cerebral ischemia/reperfusion (I/R) in rats following exposure to ambient dust storm. After pretreatment with GA (100 mg/kg), or vehicle (Veh) (normal saline, 2 ml/kg) for ten days, and 60 minutes' exposure to dust storm including PM (PM, 2000-8000 g/m3) every day, 4-vessel occlusion (4VO) type of I/R was induced. Three days after I/R induction, we evaluated behavioral, electrophysiological, histopathological, molecular and brain tissue inflammatory cytokine changes. Our findings indicated that pretreatment with GA significantly reduced cognitive impairments caused by I/R (P < 0.05) and hippocampal LTP impairments caused by I/R after PM exposure (P < 0.001). Additionally, after exposure to PM, I/R significantly elevated the tumor necrosis factor α content (P < 0.01) and miR-124 level (P < 0.001) while pre-treatment with GA reduced the level of miR-124 (P < 0.001). Histopathological results also revealed that I/R and PM caused cell death in the hippocampus CA1 area (P < 0.001) and that GA decreased the rate of cell death (P < 0.001). Our findings show that GA can prevent brain inflammation, and thus cognitive and LTP deficits caused by I/R, PM exposure, or both.

Anti-inflammatory, anti-apoptotic, and neuroprotective potentials of anethole in Parkinson's disease-like motor and non-motor symptoms induced by rotenone in rats.

Parkinson's disease (PD) is a complex neurological disorder characterized by a combination of motor and non-motor symptoms (NMS). Antioxidant and anti-inflammatory compounds are considered a potential therapeutic strategy against PD. The present study examined the neuroprotective effects of anethole as a potent antioxidant and anti-inflammatory agent against motor and non-motor deficits induced by rotenone toxicity. Rats were treated with anethole (62.5, 125, and 250 mg/kg, i.g) concomitantly with rotenone (2 mg/kg, s.c) for 5 weeks. After the treatment, behavioral tests were performed to evaluate motor function and depression-/anxiety-like behaviors. After the behavioral tests, rats were decapitated and brains were removed for histological analysis. Striatum samples were also isolated for neurochemical, and molecular analysis. Our data showed that rotenone-induced motor deficit, anxiety-and depression-like behaviors were significantly improved in rats treated with anethole. Furthermore, anethole treatment reduced inflammatory cytokines tumor necrosis factor α (TNFα) and Interleukin 6 (IL-6), and increased anti-inflammatory cytokine IL-4 in the striatum of rotenone-induced PD rats. Western blot analysis showed that treatment with anethole markedly suppressed caspase-3 activation induced by rotenone. Moreover, histological examination of striatum showed an increase in the number of surviving neurons after treatment with anethole. Anethole also significantly enhanced the striatal levels of dopamine in rotenone-induced PD rats. In addition, treatment with L-Dopa as a positive control group had effects similar to those of anethole on histological, neurochemical, and molecular parameters in rotenone-induced parkinsonian rats. Our results suggested the neuroprotective effects of anethole through anti-inflammatory, anti-apoptotic, and antioxidant mechanisms against rotenone-induced toxicity in rats.

Exogenous growth hormone administration during total sleep deprivation changed the microRNA-9 and dopamine D2 receptor expressions followed by improvement in the hippocampal synaptic potential, spatial cognition, and inflammation in rats.

RATIONALE: Disorders caused by total sleep deprivation can be modulated by the administration of growth hormone, which could affect the expression of microRNA-9 and dopamine D2 receptor expressions followed by improvement in the hippocampal synaptic potential, spatial cognition, and inflammation in rats. OBJECTIVES: The present study aimed to elucidate the putative effects of exogenous growth hormone (GH) against total sleep deprivation (TSD)-induced learning and memory dysfunctions and possible involved mechanisms. METHODS: To induce TSD, rats were housed in homemade special cages equipped with stainless steel wire conductors to induce general and inconsistent TSD. They received a mild repetitive electric shock to their paws every 10 min for 21 days. GH (1 mg/kg, sc) was administered to adult young male rats once daily for 21-day-duration induction of TSD. Spatial learning and memory performance, inflammatory status, microRNA-9 (miR-9) expression, dopamine D2 receptor (DRD2) protein level, and hippocampal histological changes were assayed at scheduled times after TSD. RESULTS: The results indicated that TSD impaired spatial cognition, increased TNF-α, decreased level of miR-9, and increased DRD2 levels. Treatment with exogenous GH improved spatial cognition, decreased TNF-α, increased level of miR-9, and decreased DRD2 levels after TSD. CONCLUSIONS: Our findings suggest that GH may play a key role in the modulation of learning and memory disorders as well as the ameliorating abnormal DRD2-related functional disorders associated with miR-9 in TSD.

Administration of growth hormone ameliorates adverse effects of total sleep deprivation.

Total sleep deprivation (TSD) causes several harmful changes including anxiety, inflammation, and increased expression of extracellular signal-regulated kinase (ERK) and tropomyosin receptor kinase B (TrkB) genes in the hippocampus. The current study was conducted to explain the possible effects of exogenous GH against the above parameters caused by TSD and the possible mechanisms involved. Male Wistar rats were divided into 1) control, 2) TSD and 3) TSD + GH groups. To induce TSD, the rats received a mild repetitive electric shock (2 mA, 3 s) to their paws every 10 min for 21 days. Rats in the third group received GH (1 ml/kg, sc) for 21 days as treatment for TSD. The motor coordination, locomotion, the level of IL-6, and expression of ERK and TrkB genes in hippocampal tissue were measured after TSD. The motor coordination (p < 0.001) and locomotion indices (p < 0.001) were impaired significantly by TSD. The concentrations of serum corticotropin-releasing hormone (CRH) (p < 0.001) and hippocampal interleukin-6 (IL-6) (p < 0.001) increased. However, there was a significant decrease in the interleukin-4 (IL-4) concentration and expression of ERK (p < 0.001) and TrkB (p < 0.001) genes in the hippocampus of rats with TSD. Treatment of TSD rats with GH improved motor balance (p < 0.001) and locomotion (p < 0.001), decreased serum CRH (p < 0.001), IL-6 (p < 0.01) but increased the IL-4 and expression of ERK (p < 0.001) and TrkB (p < 0.001) genes in the hippocampus. Results show that GH plays a key role in modulating the stress hormone, inflammation, and the expression of ERK and TrkB genes in the hippocampus following stress during TSD.

The effects of gallic acid and vagotomy on motor function, intestinal transit, brain electrophysiology and oxidative stress alterations in a rat model of Parkinson's disease induced by rotenone.

INTRODUCTION: The neuropathology of Parkinson's disease (PD) is complex and affects multiple systems of the body beyond the central nervous system. This study examined the effects of gallic acid (GA) and gastrointestinal vagotomy (VG) on motor, cognitive, intestinal transit time, and thalamic nuclei electrical power in an animal model of PD induced by rotenone. MATERIALS AND METHODS: Male Wistar rats were divided into 4 groups: Sham, ROT, ROT+GA, VG + ROT. Sham rats received vehicle, those in ROT received rotenone (5 mg/kg/2 ml, ig), PD rats in ROT+GA were treated with GA (100 mg/kg, gavage/once daily, for 28 days), and in VG + ROT, the vagal nerve was dissected. Stride length, motor coordination and locomotion, intestinal transit time, cognitive and pain threshold, and thalamic local EEG were evaluated. Oxidative stress indexes in striatal tissue were also measured. RESULTS: Rotenone diminished significantly the stride length (p < 0.001), motor coordination (p < 0.001), power of thalamic EEG (p < 0.01) and pain (p < 0.001). MDA increased significantly (p < 0.001) while GPx activity decreased (p < 0.001). Intestinal transit time rose significantly (p < 0.01). PD rats treated with GA improved all above disorders (p < 0.001, p < 0.01). Vagotomy prevented significant alterations of motor and non-motor parameters by rotenone. CONCLUSION: According to current findings, rotenone acts as a toxin in GI and plays a role in the pathogenesis of PD through gastric vagal nerve. Thus, vagotomy could prevent the severity of toxicity by rotenone. In addition, GA improved symptoms of PD induced by rotenone. Therefore, GA can be regarded as a promising therapeutic candidate for PD patients.

Curcumin attenuates memory impairments and long-term potentiation deficits by damping hippocampal inflammatory cytokines in lipopolysaccharide-challenged rats.

Neuroinflammation is a key pathological event triggering neurodegenerative process, resulting in neurologic sequelae. Curcumin (cur) has recently received increasing attention due to its anti-inflammatory properties. Therefore, we investigated the protective effects of curcumin on lipopolysaccharide (LPS)-induced memory impairments, long-term potentiation (LTP) deficits, hippocampal inflammatory cytokines, and neuronal loss in male rats. Rats were randomly divided into four groups as follows: (1) Vehicle; (2) cur; (3) LPS; and (4) cur/LPS. Following curcumin pretreatment (50 mg/kg, per oral via gavage, 14 consecutive days), animals received a single dose of LPS (1 mg/kg, intraperitoneally) or saline. Twenty-four hours after LPS/or saline administration, passive avoidance test (PAT), hippocampal LTP, inflammatory cytokines (TNFα, IL-1ß), and neuronal loss were assessed in hippocampal tissue of rats. Our results indicated that pretreatment with curcumin in LPS-challenged rats attenuates memory impairment in PAT, which was accompanied by significant increase in the field excitatory post-synaptic potential (fEPSP) slope and population spike (PS) amplitude. Hence, pretreatment with curcumin in LPS-treated rats decreased hippocampal concentration of tumor necrosis factor-alpha (TNF-α) and interleukin-1ß (IL-1ß), as well as reduced neuronal loss in the hippocampal tissue. This study provide evidence that pretreatment with curcumin attenuates LPS-induced memory impairment and LTP deficiency, which may be partly related to the amelioration of inflammatory cytokines and neuronal loss in the hippocampal tissue.

Curcumin Ameliorates Neurobehavioral Deficits in Ambient Dusty Particulate Matter-Exposure Rats: The Role of Oxidative Stress.

It has been consistently found that exposure to ambient air pollution, such as particulate matter (PM), results in cognitive impairments and mental disorders. This study aimed to investigate the possible neuroprotective effects of curcumin, a polyphenol compound, on the neurobehavioral deficits and to identify the role of oxidative stress in dusty PM exposure rats. Rats received curcumin (50 mg/kg, daily, gavage, 2 weeks) 30 min before placing animals in a clean air chamber (≤ 150 µg/m3, 60 min daily, 2 weeks) or ambient dusty PM chamber (2000-8000 µg/m3, 60 min daily, 2 weeks). Subsequently, the cognitive and non-cognitive functions of the animals were evaluated using standard behavioral tests. Moreover, blood-brain barrier (BBB) permeability, brain water content (BWC), oxidative-antioxidative status, and histological changes were determined in the cerebral cortex and hippocampal areas of the rats. Our results showed that curcumin administration in dusty PM exposure rats attenuates memory impairment, decreases anxiety-/depression-like behaviors, and improves locomotor/exploratory activities. These findings were accompanied by reduced BBB permeability and BWC, decreasing oxidative stress, and lessening neuronal loss in the cerebral cortex and different hippocampal areas. The results of this study suggest that curcumin's antioxidant properties may contribute to its efficacy in improving neurobehavioral deficits and preventing neuronal loss associated with dusty PM exposure.

Therapeutic effects of growth hormone in a rat model of total sleep deprivation: Evaluating behavioral, hormonal, biochemical and electrophysiological parameters.

OBJECTIVE: Total sleep deprivation (TSD) causes several harmful changes in the brain, including memory impairment, increased stress and depression levels, as well as reduced antioxidant activity. Growth hormone (GH) has been shown to boost antioxidant levels while improving memory and depression. The present study was conducted to explain the possible effects of exogenous GH against behavioral and biochemical disorders caused by TSD and the possible mechanisms involved. MAIN METHODS: To induce TSD, rats were housed in homemade special cages equipped with stainless steel wire conductors to induce general and inconsistent TSD. They received a mild repetitive electric shock to their paws every 10 min for 21 days. GH (1 ml/kg, sc) was administered to rats during induction of TSD for 21 days. Memory retrieval, anxiety, depression-like behaviors, pain behaviors, antioxidant activity, hippocampal level of BDNF, and simultaneously brain electrical activity were measured at scheduled times after TSD. KEY FINDINGS: The results showed that GH treatment improved memory (p < 0.001) in the PAT test of rats exposed to TSD. These beneficial effects were associated with lowering the level of anxiety and depression-like behavior (p < 0.001), rising the pain threshold (p < 0.01), increasing the activity of antioxidants (p < 0.01), hippocampal BDNF (p < 0.001), and regular brain electrical activity. SIGNIFICANCE: Our findings show that GH plays a key role in modulating memory, anxiety and depression behaviors, as well as reducing oxidative stress and improve hippocampal single-unit activity in the brain during TSD.

Sesamin: Insights into its protective effects against lead-induced learning and memory deficits in rats.

BACKGROUND: Lead (Pb) is one of the most hazardous pollutants that induce a wide spectrum of neurological changes such as learning and memory deficits. Sesamin, a phytonutrient of the lignan class, exhibits anti-inflammatory, anti-apoptotic, and neuroprotective properties. The present study was designed to investigate the effects of sesamin against Pb-induced learning and memory deficits, disruption of hippocampal theta and gamma rhythms, inflammatory response, inhibition of blood δ-aminolevulinic acid dehydratase (δ-ALA-D) activity, Pb accumulation, and neuronal loss in rats. METHODS: Sesamin treatment (30 mg/kg/day; P.O.) was started simultaneously with Pb acetate exposure (500 ppm in standard drinking water) in rats, and they continued for eight consecutive weeks. RESULTS: The results showed that chronic exposure to Pb disrupted the learning and memory functions in both passive-avoidance and water-maze tests, which was accompanied by increase in spectral theta power and theta/gamma ratio, and a decrease in spectral gamma power in the hippocampus. Additionally, Pb exposure resulted in an enhanced tumor necrosis factor-alpha (TNF-α) content, decreased interleukin-10 (IL-10) production, inhibited blood δ-ALA-D activity, increased Pb accumulation, and neuronal loss of rats. In contrast, sesamin treatment improved all the above-mentioned Pb-induced pathological changes. CONCLUSION: This data suggests that sesamin could improve Pb-induced learning and memory deficits, possibly through amelioration of hippocampal theta and gamma rhythms, modulation of inflammatory status, restoration of the blood δ-ALA-D activity, reduction of Pb accumulation in the blood and the brain tissues, and prevention of neuronal loss.

Thymoquinone improves cognitive and hippocampal long-term potentiation deficits due to hepatic encephalopathy in rats.

OBJECTIVES: Hepatic encephalopathy (HE) is a neuropsychiatric syndrome that causes brain disturbances. Thymoquinone (TQ) has a wide spectrum of activities such as antioxidant, anti-inflammatory, and anticancer. This study aimed to evaluate the effects of TQ on spatial memory and hippocampal long-term potentiation (LTP) in rats with thioacetamide (TAA)-induced liver injury and hepatic encephalopathy. MATERIALS AND METHODS: Adult male Wistar rats were divided into six groups randomly: 1) Control; 2) HE, received TAA (200 mg/kg); 3-5) Treated groups (HE+TQ5, HE+TQ10, and HE+TQ20). TQ (5, 10, and 20 mg/kg) was injected intraperitoneally (IP) for 12 consecutive days from day 18 to 29. Subsequently, spatial memory performance was evaluated by the Morris water maze paradigm and hippocampal LTP was recorded from the dentate gyrus (DG) region. Activity levels of Malondialdehyde (MDA) and superoxide dismutase (SOD) were measured in the hippocampal tissue. RESULTS: Data showed that the hippocampal content of MDA was increased while SOD activities were decreased in TAA-induced HE. TQ treatment significantly improved spatial memory and LTP. Moreover, TQ restored the levels of MDA and SOD activities in the hippocampal tissue in HE rats. CONCLUSION: Our data confirm that TQ could attenuate cognitive impairment and improve LTP deficit by modulating the oxidative stress parameters in this model of HE, which leads to impairment of spatial cognition and LTP deficit. Thus, these results suggest that TQ may be a promising agent with positive therapeutic effects against liver failure and HE defects.

Therapeutic Effects of Resveratrol on Ischemia-Reperfusion Injury in the Nervous System.

Resveratrol is a phenol compound produced by some plants in response to pathogens, infection, or physical injury. It is well-known that resveratrol has antioxidant and protective roles in damages potentially caused by cancer or other serious disorders. Thus, it is considered as a candidate agent for the prevention and treatment of human diseases. Evidence has confirmed other bioactive impacts of resveratrol, including cardioprotective, anti-tumorigenic, anti-inflammatory, phytoestrogenic, and neuroprotective effects. Ischemia-reperfusion (IR) can result in various disorders, comprising myocardial infarction, stroke, and peripheral vascular disease, which may continue to induce debilitating conditions and even mortality. In virtue of chronic ischemia or hypoxia, cells switch to anaerobic metabolism, giving rise to some dysfunctions in mitochondria. As the result of lactate accumulation, adenosine triphosphate levels and pH decline in cells. This condition leads cells to apoptosis, necrosis, and autophagy. However, restoring oxygen level upon reperfusion after ischemia by producing reactive oxygen species is an outcome of mitochondrial dysfunction. Considering the neuroprotective effect of resveratrol and neuronal injury that comes from IR, we focused on the mechanism(s) involved in IR injury in the nervous system and also on the functions of resveratrol in the protection, inhibition, and treatment of this injury.

Naringin and trimetazidine improve baroreflex sensitivity and nucleus tractus solitarius electrical activity in renal ischemia-reperfusion injury / Naringin and trimetazidine improve baroreflex sensitivity and nucleus tractus solitarius electrical activity in renal ischemia-reperfusion injury

Resumo Fundamento: O núcleo do trato solitário (NTS) é uma área do cérebro que desempenha um papel fundamental na regulação renal e cardiovascular através dos impulsos dos barorreceptores. Objetivos: O objetivo deste estudo foi avaliar o efeito da Naringina (NAR) e trimetazidina (TMZ), isoladamente e combinadas, na atividade elétrica do NTS e na sensibilidade barorreflexa (SBR) na lesão de isquemia e reperfusão (I/R) renal. Métodos: Foram utilizados quarenta ratos machos Sprague-Dawley (200-250 g), alocados em 5 grupos com 8 ratos cada. Grupos: 1) Sham; 2) I/R; 3) TMZ 5 mg/kg; 4) NAR 100 mg/kg; e 5) TMZ5 + NAR100. A veia femoral esquerda foi canulada para infundir a solução salina ou droga e avaliar a SBR. A I/R foi induzida por oclusão dos pedículos renais por 45 min, seguida de reperfusão de 4 horas. O eletroencefalograma local do NTS foi registrado antes, durante a isquemia e durante a reperfusão. A fenilefrina foi injetada por via intravenosa para avaliar a SBR ao final do tempo de reperfusão. Os dados foram analisados por ANOVA de duas vias com medidas repetidas seguida pelo teste post hoc de Tukey. Um valor de p<0,05 foi considerado como significativo. Resultados: As ondas elétricas do NTS não se alteraram durante o tempo de isquemia, mas diminuíram significativamente durante todos os tempos de reperfusão. A atividade elétrica do NTS e a SBR foram reduzidas drasticamente em ratos com lesão I/R; no entanto, a administração de NAR e TMZ, isoladamente e combinadas, melhorou significativamente essas alterações em ratos com lesão I/R. Conclusões: Os resultados mostraram que a lesão de I/R leva à redução da atividade elétrica da SBR e do NTS, e pode haver uma ligação entre a I/R e a diminuição da SBR. Além disso, a NAR e a TMZ são agentes promissores para tratar complicações de I/R.

Abstract Background: Nucleus tractus solitarius (NTS) is a brain area that plays a key role in kidney and cardiovascular regulation via baroreceptors impulses. Objectives: The aim of this study was to evaluate the effect of naringin (NAR) and trimetazidine (TMZ) alone and their combination on NTS electrical activity and baroreceptor sensitivity (BRS) in renal ischemia- reperfusion (I/R) injury. Methods: Forty male Sprague-Dawley rats (200- 250 g) were allocated into 5 groups with 8 in each. 1) Sham; 2) I/R; 3) TMZ 5 mg/kg; 4) NAR 100 mg/kg; and 5) TMZ5+ NAR100. The left femoral vein was cannulated to infuse saline solution or drug and the BRS was evaluated. I/R was induced by occlusion of renal pedicles for 45 min, followed by 4 hours of reperfusion. The NTS local electroencephalogram (EEG) was recorded before, during ischemia and throughout the reperfusion. Phenylephrine was injected intravenously to evaluate BRS at the end of reperfusion time. The data were analyzed by two-way repeated measurement ANOVA followed by Tukey's post hoc test. A p-value <0.05 was considered significant. Results: NTS electrical waves did not change during ischemia time, while they significantly decreased during the entire reperfusion time. NTS electrical activity and BRS dramatically reduced in rats with I/R injury; however, administration of NAR, TMZ alone or their combination significantly improved these changes in rats with I/R injury. Conclusions: The results showed that I/R injury leads to reduced BRS and NTS electrical activity and there may be an association between I/R and decreased BRS. In addition, NAR and TMZ are promising agents to treat I/R complications.

Enriched environment and social isolation differentially modulate addiction-related behaviors in male offspring of morphine-addicted dams: The possible role of µ-opioid receptors and ΔFosB in the brain reward pathway.

Prenatal opioids exposure negatively affects the neurobehavioral abilities of children born from dependence dams. Adolescent housing conditions can buffer the detrimental impacts of early life experiences or contradictory can worsen individual psychosocial functions. The present study investigated the effects of maternal morphine dependence and different rearing conditions on behaviors and protein expression in brain reward circuits of male pups. Female Wistar rats a week before conception, during pregnancy and lactation were injected twice daily with escalating doses of morphine or saline. On a postnatal day 21, male pups were weaned and subjected to three different environments for two months: standard (STD), isolated (ISO), or enriched environment (EE). The anxiety and drug-related reward were measured using elevated plus maze, open field test, and conditioned place preference. Western blotting was used to determine the protein level of ΔFosB and µ-opioid receptor proteins in the striatum and the midbrain of male offspring, respectively. Results showed that maternal morphine administration dramatically increased anxiety-like and morphine place preference behaviors in offspring. Also, ISO condition aggravated these behavioral outcomes. While, rearing in EE could attenuate anxiety and morphine conditioning in pups. At molecular levels, maternal morphine exposure and social isolation markedly increased both of ΔFosB and µ-opioid receptor proteins expression. However, rearing in the EE declined ΔFosB protein expression. Together, these findings help to elucidate long lasting impacts of early life morphine exposure and rearing environment on the behavioral and molecular profile of addicted individuals.

The effects of thymoquinone on memory impairment and inflammation in rats with hepatic encephalopathy induced by thioacetamide.

Hepatic encephalopathy (HE) is a prevalent complication of the central nervous system (CNS) that is caused by acute or chronic liver failure. This study was designed to evaluate the effects of thymoquinone (TQ) on thioacetamide (TAA)-induced HE in rats, and determine the consequential behavioral, biochemical, and histological changes. HE was induced in male Wistar rats by intraperitoneal (i.p.) injection of 200 mg/kg TAA once every 48 h for 14 consecutive days. Control groups received the normal saline containing 5 % DMSO. Thymoquinone (5, 10, and 20 mg/kg) was administered for ten consecutive days intraperitoneally (i.p.) after HE induction and it was continued until the end of the tests. Then, the passive avoidance memory, extracellular single unit, BBB permeability, and brain water content were evaluated. Moreover, hippocampal tissues were used for evaluation of oxidative stress index, inflammatory biomarkers, and histological parameters following HE. As result of the treatment, TQ improved passive avoidance memory, increased the average number of simultaneous firing of spikes/bins, improved the integrity of BBB, and decreased brain water content in the animal model of HE. Furthermore, the results indicated that treatment with TQ decreased the levels of inflammatory cytokines (TNF-α and IL-1ß) but increased the levels of glutathione (GSH) and anti-inflammatory cytokine (IL-10) of the surviving cells in the hippocampal tissues. This study demonstrates that TQ may have beneficial therapeutic effects on cognitive, oxidative stress, neuroinflammatory, and histological complications of HE in rat.