Effects of pramipexole on beta-amyloid1–42 memory deficits and evaluation of oxidative stress and mitochondrial function markers in the hippocampus of Wistar rat

Salman, Mohammad; Akram, Mohd.; Shahrukh, Mohd.; Ishrat, Tauheed; Parvez, Suhel

doi:10.1016/j.neuro.2022.07.006

Cited by 14 publications

(8 citation statements)

References 48 publications

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“…Moreover, as believed, it is excessive mitochondrial ROS production as a result of mitochondrial dysfunction that leads to the development of many pathologies including AD [ 66 , 67 ]. Analysis of the different thus far described models have shown that AD is characterized by mitochondrial dysfunction, as inferred from the decreased mitochondrial membrane potential, respiration and ATP/ADP ratio, impaired mitochondrial trafficking in neurons [ 65 , 68 ], excessive mitochondrial fragmentation [ 69 , 70 , 71 ], and enhanced ROS production as a result of an imbalance between ROS formation and clearance [ 72 , 73 ].…”

Section: Discussionmentioning

confidence: 99%

Altered Mitochondrial Morphology and Bioenergetics in a New Yeast Model Expressing Aβ42

Epremyan

Рогов

Goleva

et al. 2023

IJMS

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Alzheimer’s disease (AD) is an incurable, age-related neurological disorder, the most common form of dementia. Considering that AD is a multifactorial complex disease, simplified experimental models are required for its analysis. For this purpose, genetically modified Yarrowia lipolytica yeast strains expressing Aβ42 (the main biomarker of AD), eGFP-Aβ42, Aβ40, and eGFP-Aβ40 were constructed and examined. In contrast to the cells expressing eGFP and eGFP-Aβ40, retaining “normal” mitochondrial reticulum, eGFP-Aβ42 cells possessed a disturbed mitochondrial reticulum with fragmented mitochondria; this was partially restored by preincubation with a mitochondria-targeted antioxidant SkQThy. Aβ42 expression also elevated ROS production and cell death; low concentrations of SkQThy mitigated these effects. Aβ42 expression caused mitochondrial dysfunction as inferred from a loose coupling of respiration and phosphorylation, the decreased level of ATP production, and the enhanced rate of hydrogen peroxide formation. Therefore, we have obtained the same results described for other AD models. Based on an analysis of these and earlier data, we suggest that the mitochondrial fragmentation might be a biomarker of the earliest preclinical stage of AD with an effective therapy based on mitochondria- targeted antioxidants. The simple yeast model constructed can be a useful platform for the rapid screening of such compounds.

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Section: Discussionmentioning

confidence: 99%

Altered Mitochondrial Morphology and Bioenergetics in a New Yeast Model Expressing Aβ42

Epremyan

Рогов

Goleva

et al. 2023

IJMS

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“…We only used male mice to explore the protection of Mep-S. Notably, both sexes are appropriate in AD research, and female animals may be more prominent since AD shows a higher incidence in women [48,49]. Evidence shows that male and female animals exhibit similar variability of proxies for physiological and neurological outputs across multiple timescales [50].…”

Section: Discussionmentioning

confidence: 99%

A Multifunctional (-)-Meptazinol-Serotonin Hybrid Ameliorates Oxidative Stress-Associated Apoptotic Neuronal Death and Memory Deficits via Activating the Nrf2/Antioxidant Enzyme Pathway

Zhao

Zhou

et al. 2023

Oxidative Medicine and Cellular Longevity

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The pathogenesis of Alzheimer’s disease (AD) involves multiple pathophysiological processes. Oxidative stress is a major cause of AD-associated neuronal injury. The current research was designed to examine whether a novel (-)-meptazinol-serotonin hybrid (Mep-S) with potent antioxidant activity and additional inhibitory properties for acetylcholinesterase (AChE) activity could attenuate oxidative neuronal damage and cognitive deficits. In human SH-SY5Y cells, Mep-S suppressed H2O2-induced apoptosis by restoring mitochondrial membrane potential and inhibiting caspase-3 activation. Meanwhile, it attenuated oxidative stress elicited by H2O2 through lessening generation of reactive oxygen species as well as enhancing production of glutathione (GSH) and activity of superoxide dismutase (SOD). Mechanistically, Mep-S promoted nuclear translocation of a transcription factor nuclear factor E2-related factor-2 (Nrf2) in H2O2-challenged cells. This effect was accompanied by reduction in Kelch-like ECH-associated protein-1 (Keap1) levels as well as augmentation of Akt phosphorylation and expression of heme oxygenase-1 (HO-1) and NAD(P)H quinine oxidoreductase-1 (NQO-1). Molecular docking analysis revealed that Mep-S may disrupt the protein-protein interactions between Keap1 and Nrf2. In an in vivo mouse model, Mep-S attenuated scopolamine-caused cognitive deficits with inhibition of apoptotic neuronal death and brain AChE activity. Furthermore, the scopolamine-induced impairment of total antioxidant capacity and reduction in SOD1, SOD2, and γ-glutamate-cysteine ligase expression in the brain were counteracted by Mep-S, accompanied by decreased Keap1 levels, increased Akt catalytic subunit and Nrf2 phosphorylation, and decreased Nrf2, HO-1, and NQO-1 expression. Collectively, our results suggest that Mep-S ameliorates apoptotic neuronal death and memory dysfunction associated with oxidative stress by regulating the Nrf2/antioxidant enzyme pathway through inactivating Keap1 and phosphorylating Nrf2 via Akt activation. Therefore, Mep-S may be a potential lead for multitarget neuroprotective agents to treat AD-like symptoms.

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“…Exposure of Aβ to HT22 immortalised mouse primary hippocampal cells increased mitochondrial density and reduced mitochondrial length [ 45 ], suggesting mitochondrial fragmentation. Similarly, treatment of Wistar rats with Aβ 1–42 induced a decrease in the levels of mitofusin-2 protein and translocation of Drp-1 to mitochondria [ 46 ], correlating with increased mitochondrial fragmentation. Primary hippocampal and cortical neurons from Tg2576 mice evidenced increased mitochondrial fission, decreased fusion and abnormal mitochondrial function [ 47 ].…”

Section: Discussionmentioning

confidence: 99%

Uncovering the Early Events Associated with Oligomeric Aβ-Induced Src Activation

Mota,

Fão,

Coelho

et al. 2023

Antioxidants

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Soluble Aβ1–42 oligomers (AβO) are formed in the early stages of Alzheimer’s disease (AD) and were previously shown to trigger enhanced Ca2+ levels and mitochondrial dysfunction via the activation of N-methyl-D-aspartate receptors (NMDAR). Src kinase is a ubiquitous redox-sensitive non-receptor tyrosine kinase involved in the regulation of several cellular processes, which was demonstrated to have a reciprocal interaction towards NMDAR activation. However, little is known about the early-stage mechanisms associated with AβO-induced neurodysfunction involving Src. Thus, in this work, we analysed the influence of brief exposure to oligomeric Aβ1–42 on Src activation and related mechanisms involving mitochondria and redox changes in mature primary rat hippocampal neurons. Data show that brief exposure to AβO induce H2O2-dependent Src activation involving different cellular events, including NMDAR activation and mediated intracellular Ca2+ rise, enhanced cytosolic and subsequent mitochondrial H2O2 levels, accompanied by mild mitochondrial fragmentation. Interestingly, these effects were prevented by Src inhibition, suggesting a feedforward modulation. The current study supports a relevant role for Src kinase activation in promoting the loss of postsynaptic glutamatergic synapse homeostasis involving cytosolic and mitochondrial ROS generation after brief exposure to AβO. Therefore, restoring Src activity can constitute a protective strategy for mitochondria and related hippocampal glutamatergic synapses.

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Effects of pramipexole on beta-amyloid1–42 memory deficits and evaluation of oxidative stress and mitochondrial function markers in the hippocampus of Wistar rat

Cited by 14 publications

References 48 publications

Altered Mitochondrial Morphology and Bioenergetics in a New Yeast Model Expressing Aβ42

Altered Mitochondrial Morphology and Bioenergetics in a New Yeast Model Expressing Aβ42

A Multifunctional (-)-Meptazinol-Serotonin Hybrid Ameliorates Oxidative Stress-Associated Apoptotic Neuronal Death and Memory Deficits via Activating the Nrf2/Antioxidant Enzyme Pathway

Uncovering the Early Events Associated with Oligomeric Aβ-Induced Src Activation

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