Preadministration of high-dose alpha-tocopherol improved memory impairment and mitochondrial dysfunction induced by proteasome inhibition in rat hippocampus.

Objective: The ubiquitin-proteasome system plays a key role in memory consolidation. Proteasome inhibition and free radical-induced neural damage were implicated in neurodegenerative states. In this study, it was tested whether alpha-tocopherol (αT) in low and high doses could improve the long-term memory impairment induced by proteasome inhibition and protects against hippocampal oxidative stress. Methods: Alpha-tocopherol (αT) (60, 200 mg/kg, i.p. for 5 days) was administered to rats with memory deficit and hippocampal oxidative stress induced by bilateral intra-hippocampal injection of lactacystin (32 ng/µl) and mitochondrial evaluations were performed for improvement assessments. Results: The results showed that lactacystin significantly reduced the passive avoidance memory performance and increased the level of malondialdehyde (MDA), reactive oxygen species (ROS) and diminished the mitochondrial membrane potential (MMP) in the rat hippocampus. Furthermore, Intraperitoneal administration of αT significantly increased the passive avoidance memory, glutathione content and reduced ROS, MDA levels and impaired MMP. Conclusions: The results suggested that αT has neuroprotective effects against lactacystin-induced oxidative stress and memory impairment via the enhancement of hippocampal antioxidant capacity and concomitant mitochondrial sustainability. This finding shows a way to prevent and also to treat neurodegenerative diseases associated with mitochondrial impairment.

Protective effects of gallic acid against methotrexate-induced toxicity in rats.

BACKGROUND: Methotrexate, as a chemotherapy drug, can cause chronic liver damage and oxidative stress. Aim of this study was to evaluate the preventive effect of gallic acid (GA) on methotrexate (MTX)-induced oxidative stress in rat liver. METHODS: Twenty-eight male rats were randomly divided into four groups as control, MTX (20 mg/kg, i.p.), MTX + GA (30 mg/kg/day, orally) and GA treated. Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) were used as biochemical markers of MTX-induced hepatic injury. Malondialdehyde (MDA) and glutathione (GSH) levels and hepatic antioxidant enzymes activities including catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx) were assayed in liver tissue. The expression of SOD2 and GPx1 genes were evaluated by real-time RT-PCR and liver histopathology was evaluated by light microscopy. RESULTS: The result obtained from current study showed that GA remarkably reduced MTX-induced elevation of AST, ALT and ALP and increased MTX-induced reduction in GSH content, GPx, CAT and SOD activity as well as GPx1 and SOD2 gene expressions. Histological results showed that MTX led to liver damage and GA could improve histological changes. CONCLUSIONS: Our results indicate that GA ameliorates biochemical and oxidative stress parameters in the liver of rats exposed to MTX.

Effect of Berberine against Cognitive Deficits in Rat Model of Thioacetamide-Induced Liver Cirrhosis and Hepatic Encephalopathy (Behavioral, Biochemical, Molecular and Histological Evaluations).

BACKGROUND: Liver cirrhosis (LC) is one of the chronic liver diseases with high disability and mortality accompanying hepatic encephalopathy (HE) followed by cognitive dysfunctions. In this work, the effect of berberine (Ber) on spatial cognition was studied in a rat model of LC induced by thioacetamide (TAA). MATERIALS AND METHODS: Male Wistar rats (200-250 g) were divided into six groups: (1) control; (2) TAA, 200 mg/kg/day, i.p.; (3-5) TAA + Ber; received Ber (10, 30, and 60 mg/kg, i.p., daily after last TAA injection); (6) Dizocilpine (MK-801) + TAA, received MK-801 (2 mg/kg/day, i.p.) 30 m before TAA injection. The spatial memory, BBB permeability, brain edema, liver enzymes, urea, serum and brain total bilirubin, oxidative stress and cytokine markers in the hippocampus were measured. Furthermore, a histological examination of the hippocampus was carried out. RESULTS: The BBB permeability, brain edema, liver enzymes, urea, total bilirubin levels in serum and hippocampal MDA and TNF-α increased significantly after TAA injection (p < 0.001); the spatial memory was impaired (p < 0.001), and hippocampal IL-10 decreased (p < 0.001). Ber reversed all the above parameters significantly (p < 0.05, p < 0.01 and p < 0.001). MK-801 prevented the development of LC via TAA (p < 0.001). CONCLUSION: Results showed that Ber improves spatial learning and memory in TAA-induced LC by improving the BBB function, oxidative stress and neuroinflammation. Ber might be a promising therapeutic agent for cognitive improvement in LC.

Sesamin alleviates diabetes-associated behavioral deficits in rats: The role of inflammatory and neurotrophic factors.

Neuroinflammation and loss of neurotrophic support have key roles in the pathophysiology of diabetes-associated behavioral deficits (DABD). Sesamin (Ses), a major lignan of sesame seed and its oil, shows anti-hyperglycemic, anti-oxidative, and neuroprotective effects. The present study was designed to assess the potential protective effects of Ses against DABD and investigate the roles of inflammatory markers and neurotrophic factors in streptozotocin (STZ)-induced diabetic rats. After confirmation of diabetes, Ses (30 mg/kg/day; P.O.) or insulin (6 IU/rat/day; S.C.) was administered to rats for eight consecutive weeks. During the eighth-week period of the study, behavioral functions of the animals were evaluated by employing standard behavioral paradigms. Moreover, inflammation status, neurotrophic factors, and histological changes were assessed in the cerebral cortex and hippocampal regions of the rats. The results of behavioral tests showed that STZ-induced diabetes increased anxiety-/depression-like behaviors, decreased locomotor/exploratory activities, and impaired passive avoidance learning and memory. These DABD were accompanied by neuroinflammation, lack of neurotrophic support, and neuronal loss in both cerebral cortex and hippocampus of the rats. Intriguingly, chronic treatment with Ses improved all the above-mentioned diabetes-related behavioral, biochemical, and histological deficits, and in some cases, it was even more effective than insulin therapy. In conclusion, the results suggest that Ses was capable of improving DABD, which might be ascribed, at least partly, to the reduction of blood glucose level, inhibition of neuroinflammation, and potentiation of neurotrophic factors.

Chrysin attenuates traumatic brain injury-induced recognition memory decline, and anxiety/depression-like behaviors in rats: Insights into underlying mechanisms.

RATIONALE: Cortical and hippocampal neuronal apoptosis and neuroinflammation are associated with behavioral deficits following traumatic brain injury (TBI). OBJECTIVES: The present study was designed to investigate the potential protective effects of flavonoid chrysin against TBI-induced vestibulomotor impairment, exploratory/locomotor dysfunctions, recognition memory decline, and anxiety/depression-like behaviors, as well as the verified possible involved mechanisms. METHODS: Chrysin (25, 50, or 100 mg/kg/day; P.O.) was administered to rats immediately after diffuse TBI induction, and it was continued for 3 or 14 days. Behavioral functions were assessed by employing standard behavioral paradigms at scheduled points in time. Three days post-TBI, inflammation status was assayed in both cerebral cortex and hippocampus using ELISA kits. Moreover, apoptosis and expression of Bcl-2 family proteins were examined by TUNEL staining and immunohistochemistry, respectively. RESULTS: The results indicated that treatment with chrysin improved vestibulomotor dysfunction, ameliorated recognition memory deficit, and attenuated anxiety/depression-like behaviors in the rats with TBI. Chrysin treatment also modulated inflammation status, reduced apoptotic index, and regulated Bcl-2 family proteins expression in the brains of rats with TBI. CONCLUSIONS: In conclusion, the results suggest that chrysin could be beneficial for protection against TBI-associated behavioral deficits, owing to its anti-apoptotic and anti-inflammatory properties.

Pretreatment with berberine protects against cisplatin-induced renal injury in male Wistar rats.

Berberine (BBR), an isoquinoline alkaloid, has been reported to be an antioxidant agent. This study was conducted to investigate the effect of BBR against nephrotoxicity induced by cisplatin (Cis) in male rats. In this experimental study, 28 Wistar male rats were randomly divided into four groups. Rats were pretreated with BBR (100 mg/kg/day, p.o.) for 7 consecutive days and Cis (7.5 mg/kg, i.p.) was administrated on the 7th day, 1 h after the last dose of BBR. Blood samples were collected to determine blood urea nitrogen (BUN) and creatinine (Cr) levels. Malondialdehyde (MDA), glutathione (GSH), protein carbonyl (PC), and nitric oxide (NO) levels and the activities of catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), and myeloperoxidase (MPO) were assessed in the left renal tissue. Also, the mRNA expression of SOD2 and PGx1 was measured in the left renal tissue. The right kidney was used for histopathological evaluation. Our results revealed that the levels of Cr, BUN, MDA, NO, and PC and the MPO activity increased by Cis administration. Also, we found that Cis decreased renal GSH level and SOD, GPx, and CAT activities. Pretreatment with BBR for 7 consecutive days significantly attenuated the Cis-induced nephrotoxicity via increasing the antioxidant capacity and reducing the oxidative stress indices in the renal tissue. Moreover, the renoprotective effect of BBR was confirmed by the histopathological evaluation of the kidneys. Our results indicated that BBR has produced amelioration in biochemical indices and oxidative stress parameters against Cis-induced nephrotoxicity.

Exposure to ambient dusty particulate matter impairs spatial memory and hippocampal LTP by increasing brain inflammation and oxidative stress in rats.

OBJECTIVES: Exposure of healthy subjects to ambient airborne dusty particulate matter (PM) causes brain dysfunction. This study aimed to investigate the effect of sub-chronic inhalation of ambient PM in a designed special chamber to create factual dust storm (DS) conditions on spatial cognition, hippocampal long-term potentiation (LTP), inflammatory cytokines, and oxidative stress in the brain tissue. METHODS: Adult male Wistar rats (250-300 g) were randomly divided into four groups: Sham (clean air, the concentration of dusty PM was <150 µg/m3), DS1 (200-500 µg/m3), DS2 (500-2000 µg/m3) and DS3 (2000-8000 µg/m3). Experimental rats were exposed to clean air or different sizes and concentrations of dust PM storm for four consecutive weeks (exposure was during 1-4, 8-11, 15-16 and 20-23 days, 30 min, twice daily) in a real-ambient dust exposure chamber. Subsequently, cognitive performance, hippocampal LTP, blood-brain barrier (BBB) permeability and brain edema of the animals evaluated. As well as, inflammatory cytokines and oxidative stress indexes in the brain tissue measured using ELISA assays. RESULTS: Exposing to dust PM impaired spatial memory (p < 0.001), hippocampal LTP (p < 0.001). These disturbances were in line with the severe damage to respiratory system followed by disruption of BBB integrity (p < 0.001), increased brain edema (p < 0.001), inflammatory cytokines (p < 0.001) excretion and oxidative stress (p < 0.001) in brain tissue. CONCLUSIONS: Our study showed that exposure to ambient dust PM increased brain edema and BBB permeability, induced memory impairment and hippocampal LTP deficiency by increasing the inflammatory responses and oxidative stress in the brain of the rats.

Neuroprotective effects of Ellagic acid against acrylamide-induced neurotoxicity in rats.

Acrylamide (ACR) is an environmental contaminant and a well-known neurotoxin. Ellagic acid (EA), a natural plant polyphenol, has shown a variety of beneficial effects. The present study was designed to explore whether EA could attenuate ACR-induced neurotoxicity in rats and to explore the underlying mechanisms. Animals were divided into five groups. Group 1 was treated with normal saline (2 mL/kg) for 30 days. Group 2 was treated with ACR (20 mg/kg, orally) for 30 days. Groups 3 and 4 were treated with ACR and EA (10 and 30 mg/kg, orally) for 30 days. Group 5 was treated with EA (30 mg/kg, orally) for 30 days. Open field, rotarod and passive avoidance test were conducted to evaluate behavioral changes, respectively. The brain cortex was used for histological examination. Different oxidative parameters and inflammatory biomarkers were assessed in the brain cortex. ACR-administered rats showed a considerable impairment in exploratory behavior, motor performance as well as cognition. Our data also showed that ACR administration significantly increases malondialdehyde, nitric oxide, interleukin-1ß and tumor necrosis factor-α levels. Moreover, it decreases brain glutathione level, superoxide dismutase, glutathione peroxidase, catalase activity. Co-administration of EA (especially 30 mg/kg, p.o.) prevented these changes; however, it did not affect the glutathione peroxidase activity. These results were supported by histopathological observations of the brain. Our results suggest that EA can be useful for protecting brain tissue against ACR-induced neurotoxicity through ameliorative effects on inflammatory indices and oxidative stress parameters.

The possible neuroprotective effect of ellagic acid on sodium arsenate-induced neurotoxicity in rats.

OBJECTIVE: Arsenic is a well-known environmental contaminant, causing toxicity in different organs. The aim of this study was to investigate the possible neuroprotective effect of ellagic acid (EA) on arsenic-induced neurotoxicity in rats. DESIGN: Animals were divided into five groups. The first group received normal saline (2 mL/kg) for 21 days as control group. Group 2 was orally treated with sodium arsenite (SA, 10 mg/kg) for 21 days. Groups 3 and 4 were orally treated with SA (10 mg/kg) for 7 days prior to EA (10 and 30 mg/kg respectively) treatment and continued up to 21 days simultaneously with SA administration. Group 5 was orally treated with EA (30 mg/kg) for 14 days. Passive avoidance test and rotarod test were done to evaluate the behavioral changes following SA and/or EA treatment. Different biochemical, histological and molecular biomarkers were assessed in the brain tissue. RESULTS: Our data showed that SA significantly elevated brain tissue arsenic levels and malondialdehyde, nitric oxide, protein carbonylation, tumor necrosis factor-alpha, and interlukein-1ß production. A decrease in the total antioxidant capacity, reduced glutathione content and glutathione peroxidase activity occurred in the brain of rats exposed to SA. SA-treated rats showed a significant impairment in long-term-memory, motor coordination and equilibrium. These results were supported by histopathological observations of the brain. Results revealed that administration of EA (30 mg/kg) reversed all neural markers alternation and ameliorated behavioral and histopathological changes induced by SA. CONCLUSION: EA can effectively protect brain tissue against SA-induced neurotoxicity via its antioxidant and anti-inflammatory effects.