Rapamycin attenuated zinc-induced tau phosphorylation and oxidative stress in animal model: Involvement of dual mTOR/p70S6K and Nrf2/HO-1 pathways

Alzheimers disease is pathologically featured by abnormal accumulation of amyloid-beta plaque, neurofibrillary tangles, oxidative stress, neuroinflammation, and neurodegeneration. Metal dysregulation including excessive zinc released by presynaptic neurons plays an important role in tau pathology and oxidase activation. The activities of mammalian target of rapamycin (mTOR)/ ribosomal S6 protein kinase (p70S6K) are elevated in the brains of patients with Alzheimers disease. Zinc induces tau hyperphosphorylation via mTOR/P70S6K activation in vitro. However, the involvement of mTOR/P70S6K pathway in zinc-induced oxidative stress, tau degeneration, synaptic and cognitive impairment, has not been fully elucidated in vivo. Here we assessed in the effect of pathological concentration of zinc in SH-SY5Y cells by using biochemical assays and immunofluorescence staining. Rats (n = 18, male) were lateral ventricularly-injected with zinc and treated with rapamycin (intraperitoneal injection) for one week and assessed using Morris water maze. Evaluation of the oxidative stress, tau phorsphylation and synaptic impairment were performed using the hippocampus tissue of the rats by biochemical assays and immunofluorescence staining. Results from Morris water maze showed that the capacity of spatial memory is impaired in zinc-treated rats. Zinc sulfate significantly increased the levels of P-mTOR Ser2448, P-p70S6K Thr389, and P-tau Ser356, and decreased levels of Nrf2 and HO-1 in SH-SY5Y cells and in zinc-treated rats compared with control groups. Increased expressions of reactive oxygen species were observed in zinc sulfate-induced SH-SY5Y cells as well as in the hippocampus of zinc-injected rats. Rapamycin, an inhibitor of mTOR, rescued the zinc-induced increases in mTOR/p70S6K activations, tau phosphorylation and oxidative stress, as well as Nrf2/HO-1 inactivation, cognitive impairment and synaptic impairment reduced the expression of synapse-related proteins in zinc-injected rats. In conclusion, our findings imply that rapamycin prevents zinc-induced cognitive impairment and protects neurons from tau pathology, oxidative stress and synaptic impairment, by decreasing mTOR/p70S6K hyperactivity and increasing Nrf2/HO-1 activity.

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Lactobacilli and bifidobacteria ameliorate memory and learning deficits and oxidative stress in β-amyloid (1–42) injected rats

Applied Physiology Nutrition and Metabolism ◽

10.1139/apnm-2017-0648 ◽

2018 ◽

Vol 43 (7) ◽

pp. 718-726 ◽

Cited By ~ 49

Author(s):

Somayeh Athari Nik Azm ◽

Abolghassem Djazayeri ◽

Majid Safa ◽

Kian Azami ◽

Behzad Ahmadvand ◽

...

Keyword(s):

Oxidative Stress ◽

Alzheimer’S Disease ◽

Morris Water Maze ◽

Water Maze ◽

Oxidative Stress Biomarkers ◽

Memory And Learning ◽

Stress Biomarkers ◽

Intrahippocampal Injection ◽

Β Amyloid ◽

And Oxidative Stress

The gastrointestinal microbiota affects brain function, including memory and learning. In this study we investigated the effects of probiotics on memory and oxidative stress biomarkers in an experimental model of Alzheimer’s disease. Sixty rats were randomly divided into 5 groups: control; control-probiotics, which received probiotics for 8 weeks; sham operation, which received an intrahippocampal injection of phosphate-buffered saline; Alzheimer, which received an intrahippocampal injection of β-amyloid (Aβ1–42); and Alzheimer-probiotics, which in addition to being injected with Aβ1–42, received 2 g (1 × 1010 CFU/g) of probiotics (Lactobacillus acidophilus, L. fermentum, Bifidobacterium lactis, and B. longum) for 8 weeks. Memory and learning were measured using the Morris water maze, and oxidative stress biomarkers in the hippocampus were measured using ELISA kits. Morris water maze results indicated that compared with the Alzheimer group, the Alzheimer-probiotics group had significantly improved spatial memory, including shorter escape latency and travelled distance and greater time spent in the target quadrant. There was also improvement in oxidative stress biomarkers such as increased malondialdehyde levels and superoxide dismutase activity following the β-amyloid injection. Overall, it seems that probiotics play a role in improving memory deficit and inhibiting the pathological mechanisms of Alzheimer’s disease by modifying microbiota.

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Arachidonic acid attenuates brain damage in a rat model of ischemia/reperfusion by inhibiting inflammatory response and oxidative stress

Human & Experimental Toxicology ◽

10.1177/0960327117692134 ◽

2017 ◽

Vol 37 (2) ◽

pp. 135-141 ◽

Cited By ~ 7

Author(s):

Y Qu ◽

H-L Zhang ◽

X-P Zhang ◽

H-L Jiang

Keyword(s):

Oxidative Stress ◽

Arachidonic Acid ◽

Reperfusion Injury ◽

Morris Water Maze ◽

Water Maze ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Morris Water Maze Test ◽

Maze Test ◽

And Oxidative Stress

The aim of the present study was to study the effects of arachidonic acid (ARA) in a rat brain ischemia/reperfusion model induced by middle cerebral artery occlusion (MCAO). A total of 50 rats were randomly divided into five groups: control group, MCAO group, MCAO + ARA 0.3 g/kg group, MCAO + ARA 1 g/kg group, and MCAO + ARA 3 g/kg group. The MCAO + ARA groups received ARA by intraperitoneal injection daily for 14 consecutive days, while the rats in the control and MCAO groups were given equivalent volume of saline. We detected the Morris water maze test and pathological changes to investigate the ischemia/reperfusion injury. The protein levels of tumor necrosis factor-alpha and interleukin-6 in the hippocampus were detected by enzyme-linked immunosorbent assay kits. In addition, the activities of superoxide dismutase, glutathione peroxidase, and malondialdehyde were assayed in hippocampus homogenates to evaluate the oxidative stress after ischemia/reperfusion. The results indicated that ARA administration decreased biochemical parameters of inflammation and oxidative stress. Morris water maze test and histopathological examination further verified the protective effects of ARA on ischemia/reperfusion injury rats. These findings demonstrated that ARA could protect MCAO-induced brain injury rats by inhibition of inflammation and oxidative stress, suggesting that it may have potential as a therapy for cerebral ischemia/reperfusion injury.

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Zhuyu Annao decoction promotes angiogenesis in mice with cerebral hemorrhage by inhibiting the activity of PHD3

Human & Experimental Toxicology ◽

10.1177/09603271211008523 ◽

2021 ◽

pp. 096032712110085

Author(s):

L Wu ◽

Y Hu ◽

L Jiang ◽

N Liang ◽

P Liu ◽

...

Keyword(s):

Oxidative Stress ◽

Signaling Pathway ◽

Morris Water Maze ◽

Cerebral Hemorrhage ◽

Water Maze ◽

Luciferase Reporter ◽

Morris Water Maze Test ◽

Therapeutic Effects ◽

Vascular Endothelial ◽

Behavioral Experiments

Some traditional Chinese decoctions, such as Zhuyu Annao, exert favorable therapeutic effects on acute cerebral hemorrhage, hemorrhagic stroke, and other neurological diseases, but the underlying mechanism remains unclear. This study aimed to determine whether Zhuyu Annao decoction (ZYAND) protects the injured brain by promoting angiogenesis following intracerebral hemorrhage (ICH) and elucidate its specific mechanism. The effect of ZYAND on the nervous system of mice after ICH was explored through behavioral experiments, such as the Morris water maze and Rotarod tests, and its effects on oxidative stress were explored by detecting several oxidative stress markers, including malondialdehyde, nitric oxide, glutathione peroxidase, and superoxide dismutase. Real-time quantitative RT-PCR and WB were used to detect the effects of ZYAND on the levels of prolyl hydroxylase domain 3 (PHD3), hypoxia-inducible factor-1α (HIF-1α), and vascular endothelial growth factor (VEGF) in the brain tissues of mice. The effect of ZYAND on the NF-κB signaling pathway was detected using a luciferase reporter gene. A human umbilical cord vascular endothelial cell angiogenesis experiment was performed to determine whether ZYAND promotes angiogenesis. The Morris water maze test and other behavioral experiments verified that ZYAND improved the neurobehavior of mice after ICH. ZYAND activated the PHD3/HIF-1α signaling pathway, inhibiting the oxidative damage caused by ICH. In angiogenesis experiments, it was found that ZYAND promoted VEGF-induced angiogenesis by upregulating the expression of HIF-1α, and NF-κB signaling regulated the expression of HIF-1α by inhibiting PHD3. ZYAND exerts a reparative effect on brain tissue damaged after ICH through the NF-κB/ PHD3/HIF-1α/VEGF signaling axis.

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Protective effect of citicoline against aluminum-induced cognitive impairments in rats

Toxicology and Industrial Health ◽

10.1177/0748233716641869 ◽

2016 ◽

Vol 33 (4) ◽

pp. 308-317 ◽

Cited By ~ 9

Author(s):

Ahmed O Abdel-Zaher ◽

Mostafa M Hamdy ◽

Mahran S Abdel-Rahman ◽

Doaa H Abd El-hamid

Keyword(s):

Oxidative Stress ◽

Protective Effect ◽

Passive Avoidance ◽

Morris Water Maze ◽

Cognitive Deficits ◽

Aluminum Chloride ◽

Water Maze ◽

Cognitive Impairments ◽

Radial Arm Maze ◽

Time Required

The potential protective effect of citicoline on aluminum chloride-induced cognitive deficits was investigated in rats. In a Morris water maze, administration of aluminum chloride to rats for 90 days resulted in increased escape latency to reach the platform and decreased swimming speed in acquisition trials. Similarly, in probe trials, the time required to reach the hidden platform was increased and the time spent in the target quadrant was reduced. Also, administration of aluminum chloride to rats for 90 days increased the reference and working memory errors and time required to end the task in the radial arm maze. In addition, this treatment decreased the step-through latency in the passive avoidance test. Concurrently, treatment of rats with aluminum chloride for 90 days increased hippocampal glutamate, malondialdehyde, and nitrite levels and decreased intracellular reduced glutathione level. In the citicoline-treated group, aluminum chloride-induced learning and memory impairments as assessed by the Morris water maze, radial arm maze, and passive avoidance tests were inhibited. At the same time, treatment of rats with citicoline prevented the biochemical alterations induced by aluminum chloride in the hippocampus. It can be concluded that elevation of hippocampal glutamate level with consequent oxidative stress and nitric oxide (NO) overproduction may play an important role in aluminum-induced cognitive impairments. Also, our results suggest, for the first time, that citicoline can protect against the development of these cognitive deficits through inhibition of aluminum-induced elevation of glutamate level, oxidative stress, and NO overproduction in the hippocampus.

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Pontine Arteriolosclerosis and Locus Coeruleus Oxidative Stress Differentiate Resilience from Mild Cognitive Impairment in a Clinical Pathologic Cohort

Journal of Neuropathology & Experimental Neurology ◽

10.1093/jnen/nlab017 ◽

2021 ◽

Vol 80 (4) ◽

pp. 325-335

Author(s):

Sarah C Kelly ◽

Peter T Nelson ◽

Scott E Counts,

Keyword(s):

Oxidative Stress ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Locus Coeruleus ◽

Tau Pathology ◽

Cognitively Normal ◽

Correlation And Regression Analysis ◽

Severity Scores ◽

Stress Burden ◽

Normal Cognition

Abstract Locus coeruleus (LC) neurodegeneration is associated with cognitive deterioration during the transition from normal cognition to mild cognitive impairment (MCI) and Alzheimer disease (AD). However, the extent to which LC degenerative processes differentiate cognitively normal, “resilient” subjects bearing a high AD pathological burden from those with MCI or AD remains unclear. We approached this problem by quantifying the number of LC neurons and the percentage of LC neurons bearing AT8 tau pathology, TDP-43 pathology, or a marker for DNA/RNA oxidative damage, in well-characterized subjects diagnosed as normal cognition-low AD pathology (NC-LP), NC-high AD pathology (NC-HP), MCI, or mild/moderate AD. In addition, the severity of pontine arteriolosclerosis in each subject was compared across the groups. There was a trend for a step-wise ∼20% loss of LC neuron number between the NC-LP, NC-HP and MCI subjects despite a successive, significant ∼80%–100% increase in tau pathology between these groups. In contrast, increasing pontine arteriolosclerosis severity scores and LC oxidative stress burden significantly separated the NC-LP/HP and MCI/AD groups via comparative, correlation, and regression analysis. Pontine perfusion, as well as LC neuronal metabolic and redox function, may impact noradrenergic LC modulation of cognition during the preclinical and prodromal stages of AD.

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Comparative Effectiveness of Agmatine and Choline Treatment in Rats with Cognitive Impairment Induced by AlCl3 and Forced Swim Stress

Current Clinical Pharmacology ◽

10.2174/1574884714666191016152143 ◽

2020 ◽

Vol 15 (3) ◽

pp. 251-264

Author(s):

Hira Rafi ◽

Fahad Ahmad ◽

Javaria Anis ◽

Ruba Khan ◽

Hamna Rafiq ◽

...

Keyword(s):

Body Weight ◽

Cognitive Impairment ◽

Learning And Memory ◽

Morris Water Maze ◽

Water Maze ◽

Weight Group ◽

Novel Object ◽

Maze Test ◽

Forced Swim Stress ◽

Light Dark Box

Aim: Endogenous agmatine has a significant role in learning and memory processes as a neurotransmitter. Various studies described the physiological role of endogenous agmatine in learning and memory of multiple cognitive tasks suggesting elevated levels of agmatine during the learning process in the rat brain. Dietary intake of choline showed correlation with cognitive functions in human subjects and treatment with choline supplements validated the ability to diminish learning and cognitive impairment dementias. Methods: 36 Albino rats were equally divided into three groups previously: a) control-water, b) Test I - AlCl3 (100 mg/Kg body weight), and c) Test II - Forced swim stress (FSS) for 14 days. On the next day of AlCl3 and FSS last administration, animals were allocated into further three groups and received the following treatments: a. water was given orally to the control group, b. Agmatine (100 mg/Kg Body Weight) group, and c. Choline (100 mg/Kg Body Weight) group for the next 14 days. Behaviors were assessed in Light/Dark Box, Open Field, Novel Object Recognition Test (NOR), T Maze Test, and Morris Water Maze Test. Results: Animals administered with agmatine demonstrated increased time spent in bright areas of light/dark box and square crossed while improved spatial memory in Morris water maze and T maze test and enhanced discrimination of novel object in NOR were observed in learning and memory paradigms along with choline. Conclusion: The present study determines that agmatine at the dose of (100 mg/kg body weight) attenuates memory and cognitive impairment in comparison with choline supplements.

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