Permissive role of cytosolic pH acidification in neurodegeneration: A closer look at its causes and consequences

Majdi, Alireza; Mahmoudi, Javad; Sadigh-Eteghad, Saeed; Golzari, Samad Ej; Sabermarouf, Babak; Reyhani-Rad, Siamak

doi:10.1002/jnr.23757

Cited by 64 publications

(62 citation statements)

References 102 publications

(153 reference statements)

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“…In this study, diabetes increased immobility time in the forced swimming test in mice similar to findings of previous studies [19,23] , probably because immobility time is an indicator of despair which is an important symptom of depression [9] .…”

Section: Discussionsupporting

confidence: 77%

Chronic Administration of Rosa canina Hydro-Alcoholic Extract Attenuates Depressive-Like Behavior and Recognition Memory Impairment in Diabetic Mice: A Possible Role of Oxidative Stress

et al. 2017

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Objective: This study was designed to evaluate whether chronic Rosa canina (RC) extract administration could improve recognition memory and depressive-like behavior in diabetic mice. Materials and Methods: Seventy-five male albino mice (25-30 g) were randomly divided into 5 groups (15 in each group). A single intraperitoneal injection of 200 mg/kg streptozotocin (STZ) was administered to the mice to induce diabetes. The control group received normal saline, and the diabetic groups received normal saline or 50, 250, and 500 mg/kg of RC extract for 28 days. The mice were weighed each week. Recognition memory and depressive-like behavior were assessed using forced swimming and novel object recognition (NOR) tests, respectively. Malondialdehyde (MDA) levels and total antioxidant capacity (TAC) were measured in the mouse brain homogenate to evaluate oxidative stress. Statistical analysis was conducted using SPSS, version 22. Results: The groups receiving 250 or 500 mg/kg RC had significantly lower immobility time (159.4 ± 4.7 and 150.1 ± 3.1 s) compared to the sham control group (192.1 ± 7.8 s) in the forced swimming test, and a higher discrimination index (0.39 ± 0.02 and 0.48 ± 0.03) was seen in diabetic animals in the NOR task compared to the sham control group (0.2 ± 0.01). Also, the groups receiving treatment with RC (250 and 500 mg/kg) had significantly higher TAC (0.92 ± 0.04 and 0.96 ± 0.05 mmol/L) and lower MDA (0.76 ± 0.02 and 0.67 ± 0.03 nmol/mg protein) levels in the brains in comparison to the model group. In the 3rd and 4th weeks of study, the RC-treated mice (250 and 500 mg/kg) gained more weight (31.2 ± 0.3 and 32.4 ± 0.3 g, and 31.3 ± 0.2 and 33.7 ± 0.3 g, respectively) than the diabetic group (30 ± 0.2 and 29.6 ± 0.3 g). Conclusion: This study showed that RC attenuated impairment of recognition memory and depressive-like behavior probably through modulation of oxidative stress in an STZ model of diabetes in mouse brains.

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Section: Discussionsupporting

confidence: 77%

Chronic Administration of Rosa canina Hydro-Alcoholic Extract Attenuates Depressive-Like Behavior and Recognition Memory Impairment in Diabetic Mice: A Possible Role of Oxidative Stress

et al. 2017

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“…Under normal condition, there is a balance between reactive oxygen species (ROS) and the antioxidant opposing forces in the body. Once the balance was destroyed, oxidative stress happened, resulting in a sequence of irreversible damage to biological macromolecules including DNA, lipids, and proteins (Majdi et al, ). The brain is particularly vulnerable to oxidative stress because of its high consumption of oxygen, the generation of ROS, high long‐chain polyunsaturated fatty acid content (which, in turn, are vulnerable to ROS attacks), and relatively poor antioxidant capacity (Fukui, Omoi, Hayasaka, Shinnkai, & Abe, ; Xia et al, ).…”

Section: Discussionmentioning

confidence: 99%

Protective effects of Genistein on the cognitive deficits induced by chronic sleep deprivation

Lü

Jiang

et al. 2020

Phytotherapy Research

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Sleep deprivation has been widely reported to cause cognitive dysfunction, and elevation in oxidative stress and inflammation in the body, including the brain, have been suggested as the main factors. Genistein (GE) is an isoflavone widely present in leguminous plants, and it was found to exert a wide spectrum of biological activities, including antioxidant, anti‐inflammatory, hepatoprotective, neuroprotective, and antimetastatic effects. In this study, the protective effect of GE on chronic sleep deprivation (CSD)‐induced cognitive dysfunction was investigated. The mice were subjected to the sleep interruption apparatus and continuously sleep deprived for 25 days. GE was orally administrated (10, 20, and 40 mg/kg) during the sleep deprivation process totally for 25 days. Cognitive behavioral tests were conducted to study the learning and memory using the object location recognition (OLR) task, novel object recognition (NOR) test, and the Morris water maze (MWM) task. Additionally, the cortex and hippocampus were dissected to measure the oxidative stress markers and the antioxidant element nuclear erythroid‐2‐related factor 2 (Nrf2) and its downstream targets, including glutamate cysteine ligase catalytic, glutamate cysteine ligase modifier, heme oxygenase 1, and quinone oxidoreductase 1, as well as nuclear factor kappa B (NF‐κB) p65, nitric oxide synthase (iNOS), and cyclooxygenase 2 (COX‐2) protein expression. Moreover, the pro‐inflammatory cytokines (TNF‐α, interleukin [IL]‐6, and IL‐1β) level was examined in the serum. The current results showed that GE could dose‐dependently ameliorate the cognitive deficits of CSD‐treated mice in the OLR, NOR, and MWM tasks. In addition, GE treatment significantly elevated the activities of total antioxidant capacity and superoxide dismutase and the level of glutathione and lowered the content of malondialdehyde in the cortex and hippocampus of CSD‐treated mice. Furthermore, GE administration effectively activated the antioxidant element Nrf2 and its downstream targets in the cortex and hippocampus of CSD‐treated mice. Moreover, GE treatment significantly suppressed CSD‐induced NF‐κB p65, iNOS, and COX‐2 activation in the cortex and hippocampus, as well as inhibited CSD‐induced pro‐inflammatory cytokines (TNF‐α, IL‐6, and IL‐1β) release in the serum. Taken together, all these results suggested that GE has substantial potential as a therapeutic intervention for the alleviation of CSD‐induced deleterious effects.

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“…It has been suggested that pH fluctuation happens in the cellular context, where oxidative stress results in cytosolic acidification that can ultimately lead to neurodegeneration (for a review, see Ref. 71). Oxidative stress, a trigger for apoptosis, induced by the addition of hydrogen peroxide in HEK 293/Tau cells, increases active caspase-6 and caspase-3 activity (72).…”

Section: Discussionmentioning

confidence: 99%

Caspase-6 Undergoes a Distinct Helix-Strand Interconversion upon Substrate Binding

Dagbay¹,

Bolik-Coulon²,

Savinov

et al. 2017

Journal of Biological Chemistry

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Edited by Norma AllewellCaspases are cysteine aspartate proteases that are major players in key cellular processes, including apoptosis and inflammation. Specifically, caspase-6 has also been implicated in playing a unique and critical role in neurodegeneration; however, structural similarities between caspase-6 and other caspase active sites have hampered precise targeting of caspase-6. All caspases can exist in a canonical conformation, in which the substrate binds atop a ␤-strand platform in the 130's region. This caspase-6 region can also adopt a helical conformation that has not been seen in any other caspases. Understanding the dynamics and interconversion between the helical and strand conformations in caspase-6 is critical to fully assess its unique function and regulation. Here, hydrogen/deuterium exchange mass spectrometry indicated that caspase-6 is inherently and dramatically more conformationally dynamic than closely related caspase-7. In contrast to caspase-7, which rests constitutively in the strand conformation before and after substrate binding, the hydrogen/ deuterium exchange data in the L2 and 130's regions suggested that before substrate binding, caspase-6 exists in a dynamic equilibrium between the helix and strand conformations. Caspase-6 transitions exclusively to the canonical strand conformation only upon substrate binding. Glu-135, which showed noticeably different calculated pK a values in the helix and strand conformations, appears to play a key role in the interconversion between the helix and strand conformations. Because caspase-6 has roles in several neurodegenerative diseases, exploiting the unique structural features and conformational changes identified here may provide new avenues for regulating specific caspase-6 functions for therapeutic purposes.Caspases are cysteine proteases that recognize aspartatecontaining substrates and are major players in key cellular processes, including apoptosis and inflammation. Caspase active sites contain a Cys-His dyad required for cleavage of peptide bonds adjacent to aspartate residues in select protein substrates. There are two main classes of caspases, initiator and executioner caspases, classified based on their cellular function and domain organization. Initiator caspases (caspase-2, -8, and -9) function upstream in the apoptotic pathway and activate the downstream executioner caspases (caspase-3, -6, and -7) by proteolytic cleavage at an intersubunit linker between large and small subunits. Executioner caspases then cleave a select group of protein targets to promote apoptosis. Initiator caspases generally exist as monomers and are subsequently activated by dimerization mediated by interaction with a molecular platform (e.g.

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Permissive role of cytosolic pH acidification in neurodegeneration: A closer look at its causes and consequences

Cited by 64 publications

References 102 publications

Chronic Administration of Rosa canina Hydro-Alcoholic Extract Attenuates Depressive-Like Behavior and Recognition Memory Impairment in Diabetic Mice: A Possible Role of Oxidative Stress

Chronic Administration of Rosa canina Hydro-Alcoholic Extract Attenuates Depressive-Like Behavior and Recognition Memory Impairment in Diabetic Mice: A Possible Role of Oxidative Stress

Protective effects of Genistein on the cognitive deficits induced by chronic sleep deprivation

Caspase-6 Undergoes a Distinct Helix-Strand Interconversion upon Substrate Binding

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