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Magnesium Increases the Protective Effect of Citicoline on Aluminum Chloride-induced Cognitive Impairment.

ABSTRACT: Objective:Alzheimer's disease is a popular neurodegenerative disorder which is growing in the elderly people. Exposure to environmental pollutant like aluminum could trigger or accelerate its involved mechanisms like tau phosphorylation. The current study will evaluate the effect of alone or co-administration of Citicoline or/and magnesium on the aluminum chloride induced memory impairment. Methods:Male albino mice were randomly divided into different groups (n = 7). Memory impairment was induced via orally administration of 300 mg/kg Aluminum Chloride for 28 days. Based on respective group, animals received 100, 250, 500 mg/kg of Citicoline or 50, 100, 150 mg/kg of Magnesium sulfate (MgSO4), intraperitoneally. In co-administration, 50 mg/kg of MgSO4 injected concomitantly with 100, 250, or 500 mg/kg of Citicoline. Rivastigmine (2 mg/kg intraperitoneally) was used as a positive control. Memory was evaluated using the Object Recognition Task (ORT) and Passive Avoidance Test (PAT). Results:The studied doses of Citicoline or MgSO4 when administered individually showed significant increase in the discrimination index in ORT and latency time in the PAT compared to the Aluminium chloride (AlCl3) treated group. Concomitant injection of 50 mg/kg MgSO4 with the different doses of Citicoline strongly increased the above indices values in comparison to each alone. Conclusion:The findings show, individual administration of Citicoline or MgSO4 inverted the AlCl3-induced memory impairment in a dose independent manner. The addition of MgSO4 to the Citicoline showed a synergistic effect in the PAT and likely additive effect in the ORT.

SUBMITTER: Hosseini-Sharifabad A

PROVIDER: S-EPMC7242111 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Magnesium Increases the Protective Effect of Citicoline on Aluminum Chloride-induced Cognitive Impairment.

Hosseini-Sharifabad Ali A Rabbani Mohammad M Seyed-Yousefi Yasaman Y Safavi Maryam M

Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology 20200501 2

<h4>Objective</h4>Alzheimer's disease is a popular neurodegenerative disorder which is growing in the elderly people. Exposure to environmental pollutant like aluminum could trigger or accelerate its involved mechanisms like tau phosphorylation. The current study will evaluate the effect of alone or co-administration of Citicoline or/and magnesium on the aluminum chloride induced memory impairment.<h4>Methods</h4>Male albino mice were randomly divided into different groups (n = 7). Memory impair ...[more]

PMID: 32329305

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Project description:Alzheimer's disease (AD) is a devastating neurodegenerative disorder without a cure. Hence, developing an effective treatment or protective agent is crucial for public health. The present study aims to characterize orange peel extract (OPE) through in vitro and in silico studies. Furthermore, it examines the protective effect of OPE against experimentally-induced Alzheimer's disease in rats. The total phenolic and flavonoid content of OPE was 255.86 ± 1.77 and 52.06 ± 1.74 (mg/100 g), respectively. Gallic acid, the common polyphenol in OPE detected by HPLC was 3388.60 μg/100 g. OPE antioxidant IC50 was 67.90 ± 1.05, 60.48 ± 0.91, and 63.70 ± 0.30 by DPPH, ABTS and Hydroxyl radical scavenging activity methods, respectively. In vitro anti-acetylcholinesterase (AChE) IC50 was 0.87 ± 0.025 mg/mL for OPE and 2.45 ± 0.001 mg/mL for gallic acid. Molecular docking analysis for human AChE (4EY7) with donepezil, gallic acid, and acetylcholine showed binding energy ΔG values of -9.47, -3.72, and -5.69 Kcal/mol, respectively. Aluminum chloride injection (70 mg/Kg/day for 6 weeks) induced Alzheimer's-like disease in male rats. OPE (100 and 200 mg/kg/d) and gallic acid (50 mg/kg/d) were administered orally to experimental animals for 6 weeks in addition to aluminum chloride injection (as protective). OPE was found to protect against aluminum chloride-induced neuronal damage by decreasing both gene expression and activity of acetylcholinesterase (AChE) and a decrease in amyloid beta (Aβ42) protein level, thiobarbituric acid-reactive substances (TBARS), and nitric oxide (NO), and increased reduced glutathione (GSH) level and activity of the antioxidant enzymes in the brain tissues. Additionally, gene expressions for amyloid precursor protein (APP) and beta secretase enzyme (BACE1) were downregulated, whereas those for presinilin-2 (PSEN2) and beta cell lymphoma-2 (BCL2) were upregulated. Furthermore, the reverse of mitochondrial alternation and restored brain ultrastructure might underlie neuronal dysfunction in AD. In conclusion, our exploration of the neuroprotective effect of OPE in vivo reveals that OPE may be helpful in ameliorating brain oxidative stress, hence protecting from Alzheimer's disease progression.

Project description:BackgroundAlzheimer's disease (AD) is the most prevalent neurodegenerative and remains incurable. Aluminum is a potent neurotoxin associated with AD. The main pathological features of AD are extracellular amyloid-β protein deposition and intracellular hyperphosphorylated Tau protein. A body of evidence suggest that oxidative stress and autophagy are involved in the pathogenesis of AD. Andrographis paniculata (AP) is a native plant with anti-inflammatory, anti-oxidative stress, and regulation of autophagy properties. AP significantly alleviated cognitive impairments, reduced Aβ deposition and has neuroprotective effect. However, its effects on aluminum-induced AD model have not been studied much. In this study, we investigated whether AP protect against aluminum-induced neurotoxicity through regulation of p62-Kelch-like ECH-associated protein 1(Keap1)-Nuclear factor E2 related factor 2 (Nrf2) pathway and activation autophagy in vivo and in vitro.MethodsUPLC-ESI-qTOF-MS/MS was used to identify the chemical constituents of AP ethanol extract. The mice with cognitive deficit were established by injecting aluminum chloride and D-galactose, and treated with either AP extract (200, 400, or 600 mg/kg/d) or andrographolide (2 mg/kg/2d).The spatial memory ability was detected by Morris water maze, HE staining were used to detect in brain tissue,Oxidative stress indexs and SOD activity in both serum and brain tissue were detected by kit.The expression of p62-Nrf2 pathway proteins were measured via western blotting. Furthermore, the neurotoxicity model was induced by aluminum maltolate (700 µM) in PC12 cells. Following AP and andrographolide treatment, the cell viability was detected. The relevant mRNA and protein expressions were detected in cells transfected with the p62 siRNA.ResultsThe main active components of AP included andrographolide, neoandrographolide and deoxyandrographolide as identified. AP and andrographolide significantly improved the spatial memory ability of mice, attenuated pathological changes of hippocampal cells, reduced the level of malondialdehyde, and increased superoxide dismutase activity in serum or brain tissue as compared to model control. In addition, the Nrf2, p62 and LC3B-II proteins expression were increased, and p-Tau and Keap1 proteins were decreased in the hippocampus after AP and andrographolide treatment.Furthermore, AP increased aluminum maltolate-induced cell viability in PC12 cells. Silencing p62 could reverse the upregulation expression of Nrf2 and downregulation of Keap1 and Tau proteins induced by AP in aluminum maltolate-treated cells.ConclusionsAP had neuroprotective effects against aluminum -induced cognitive dysfunction or cytotoxicity, which was involved in the activation of the p62-keap1-Nrf2 pathway and may develop as therapeutic drugs for the treatment of AD. However, this study has certain limitations, further optimize the protocol or model and study the molecular mechanism of AP improving AD.

Project description:BackgroundTo evaluate the effect of Isorhynchophylline (IRN) on the learning and memory impairments induced by aluminum chloride (AlCl3) in mice.MethodsFifty male Balb-c mice (4-month-old) were randomly divided into five groups: control, AlCl3 plus vehicle, AlCl3 plus IRN (20 mg/kg), AlCl3 plus IRN (40 mg/kg) and AlCl3 plus donepezil (5 mg/kg). Learning and memory impairments were induced in mice by subcutaneously injecting with AlCl3 (50 mg/kg) once a day for 8 consecutive weeks. At the same time, mice were intragastrically given vehicle or IRN (20 and 40 mg/kg) or donepezil (5 mg/kg) 30 min before each AlCl3 injection. The spatial learning and memory function was assessed using radial arm maze. After sacrificed, the parameters of oxidative stress and cholinergic system in the brain tissues were examined with ELISA kits. Moreover, the expression of nuclear factor kappa B (NF-κB) signaling pathway was analyzed with western blotting.ResultsThe results showed that treatment with IRN could significantly ameliorate the cognitive deficits induced by AlCl3 in mice. In addition, treatment with IRN was found to reduce the level of malondialdehyde, enhance the activities of superoxide dismutases and catalase, increase the level of glutathione, and markedly inhibit the activity of acetylcholinesterase (AChE) in the brain tissues of the AlCl3-treated mice. Moreover, IRN significantly suppressed the phosphorylation of NF-κB p65 and IκBα in the brain tissues of AlCl3-treated mice. However, IRN did not show significant effect on the activity of butyrylcholinesterase.ConclusionOur findings demonstrated for the first time that IRN could alleviate learning and memory impairments induced by AlCl3 in mice. The neuroprotective effect of IRN against AlCl3-induced AD is probably mediated, at least in part, through inhibiting the AChE activity and reducing the oxidative damage of brain tissue via suppress the NF-κB signaling pathway. These results contributed to a better understanding of the in vivo anti-AD mechanism of IRN. It was concluded that IRN could protect the learning and memory function.

Project description:Diabetes-induced cognitive impairment (DCI) presents a major public health risk among the aging population. Previous clinical attempts on known therapeutic targets for DCI, such as depleted insulin secretion, insulin resistance, and hyperglycaemia have delivered poor patient outcomes. However, recent evidence has demonstrated that the gut microbiome plays an important role in DCI by modulating cognitive function through the gut-brain crosstalk. The bioactive compound tanshinone IIA (TAN) has shown to improve cognitive and memory function in diabetes mellitus models, though the pharmacological actions are not fully understood. This study aims to investigate the effect and underlying mechanism of TAN in attenuating DCI in relation to regulating the gut microbiome. Metagenomic sequencing analyses were performed on a group of control rats, rats with diabetes induced by a high-fat/high-glucose diet (HFD) and streptozotocin (STZ) (model group) and TAN-treated diabetic rats (TAN group). Cognitive and memory function were assessed by the Morris water maze test, histopathological assessment of brain tissues, and immunoblotting of neurological biomarkers. The fasting blood glucose (FBG) level was monitored throughout the experiments. The levels of serum lipopolysaccharide (LPS) and tumor necrosis factor-α (TNF-α) were measured by enzyme-linked immunoassays to reflect the circulatory inflammation level. The morphology of the colon barrier was observed by histopathological staining. Our study confirmed that TAN reduced the FBG level and improved the cognitive and memory function against HFD- and STZ-induced diabetes. TAN protected the endothelial tight junction in the hippocampus and colon, regulated neuronal biomarkers, and lowered the serum levels of LPS and TNF-α. TAN corrected the reduced abundance of Bacteroidetes in diabetic rats. At the species level, TAN regulated the abundance of B. dorei, Lachnoclostridium sp. YL32 and Clostridiodes difficile. TAN modulated the lipid metabolism and biosynthesis of fatty acids in related pathways as the main functional components. TAN significantly restored the reduced levels of isobutyric acid and butyric acid. Our results supported the use of TAN as a promising therapeutic agent for DCI, in which the underlying mechanism may be associated with gut microbiome regulation.

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Magnesium Increases the Protective Effect of Citicoline on Aluminum Chloride-induced Cognitive Impairment.

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Magnesium Increases the Protective Effect of Citicoline on Aluminum Chloride-induced Cognitive Impairment.

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