Genistein Prevents Hypoxia-Induced Cognitive Dysfunctions by Ameliorating Oxidative Stress and Inflammation in the Hippocampus

Rumman, Mohammad; Pandey, Sushil; Singh, Babita; Gupta, Manisha; Ubaid, Saba; Mahdi, Abbas Ali

doi:10.1007/s12640-021-00353-x

Cited by 23 publications

(25 citation statements)

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“…In vitro data also indicated that genistein inhibited OGD/R-induced neuronal death, neuronal injury and neuronal apoptosis, consistent with a previous study (42). Furthermore, a recent study showed that genistein treatment prevents hypoxia-induced longterm cognitive dysfunction in mice (43). Our results also showed that genistein exerted long-term neuroprotective effects on the immature brain in terms of both morphology and neurological function following HI.…”

Section: Discussionsupporting

confidence: 92%

“…Genistein treatment significantly reduced the DHE fluorescence density. Moreover, MDA is a convenient biomarker for lipid peroxidation, and GSH is a key antioxidant equivalent to antioxidant enzymes that scavenge excessive oxygen free radicals (43), which was also measured in the current study. Genistein treatment decreased the levels of MDA in pups following HIBD and increased the levels of GSH following HIBD.…”

Section: Discussionmentioning

confidence: 89%

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Genistein mitigates oxidative stress and inflammation by regulating Nrf2/HO-1 and NF-κB signaling pathways in hypoxic-ischemic brain damage in neonatal mice

Li¹,

Zhang²,

Chen³

et al. 2022

Ann Transl Med

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Background: Oxidative stress and neuroinflammation play crucial roles in the progression of neonatal hypoxic-ischemic brain damage (HIBD). Genistein, a natural phytoestrogen, has been found to protect against ischemic brain injury. However, its effects and potential mechanisms in HIBD have not yet been explored.Methods: A neonatal mouse model of hypoxia-ischemia (HI) and a cell model of oxygen-glucose deprivation/reperfusion (OGD/R) were employed. In the in vivo study, genistein (10 mg/kg; ip) was administered in mice once daily for 3 consecutive days before the operation and once immediately after HI.The effects of genistein treatment on acute brain damage and long-term responses were evaluated. Neuronal injury and apoptosis were estimated using hematoxylin and eosin (H&E) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, respectively. The expression of apoptosis-related proteins were also measured by Western blot analysis. Dihydroethidium (DHE) staining and glutathione (GSH) and malondialdehyde (MDA) production were determined to assess the extent of oxidative stress. The messenger RNA (mRNA) levels of proinflammatory cytokines were detected using real-time quantitative polymerase chain reaction (RT-qPCR) to evaluate the extent of neuroinflammation. In the in vitro study, cell counting kit-8 (CCK-8) and lactate dehydrogenase (LDH) assays, as well as propidium iodide (PI) staining, were performed to analyse the neuroprotective effects of genistein on primary cortical neurons. Western blot assays were used to detect the levels of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), phosphorylated inhibitor kappa B-α (p-IκB-α) and phosphorylated nuclear factor-kappa B (p-NF-κB) both in vivo and in vitro.Results: Our results showed that genistein treatment effectively reduced cerebral infarction, attenuated neuronal injury and apoptosis, and contributed to the long-term recovery of neurological outcomes and brain atrophy in neonatal HIBD mice. Moreover, genistein ameliorated HIBD-induced oxidative stress and neuroinflammation. Meanwhile, genistein significantly increased cell viability, reversed neuronal injury and decreased cell apoptosis after OGD/R injury. Finally, the activation of the Nrf2/HO-1 pathway and inhibition of the NF-κB pathway by genistein were verified in the brain tissues of neonatal mice subjected to HIBD and in primary cortical neurons exposed to OGD/R. Conclusions: Genistein exerted neuroprotective effects on HIBD by attenuating oxidative stress and neuroinflammation through the Nrf2/HO-1 and NF-κB signalling pathways.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 89%

Genistein mitigates oxidative stress and inflammation by regulating Nrf2/HO-1 and NF-κB signaling pathways in hypoxic-ischemic brain damage in neonatal mice

Li¹,

Zhang²,

Chen³

et al. 2022

Ann Transl Med

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“…Each included study focused on different types of MI models. For example, Rumman et al [ 19 ] focused on hypoxia-induced MI while Lu et al [ 20 ] scrutinized on chronic sleep deprivation (CSD)-induced memory deficits. Two studies employed a streptozotocin (STZ)-induced model of MI, where Pierzynowska et al [ 13 ] investigated a STZ-induced Alzheimer’s disease (AD) model while Rajput et al [ 21 ] focused on STZ-induced diabetes for an MI model.…”

Section: Description Of Study Designmentioning

confidence: 99%

“…Since genistein is believed to pass the blood–brain barrier to exert its neuroprotective effect, it is extensively applied in the investigation of the treatment of neurodegenerative diseases, such as Alzheimer’s, Huntington’s, and Sanfilippo disease ( Figure 3 ) [ 11 , 12 , 13 ]. Recent investigations have focused on its effect on MI where genistein protects against MI by (1) reducing the production of β-amyloid protein (Aβ), (2) preventing neuro-inflammatory by inhibiting nuclear factor-activated B cells (NF-κB), (3) inhibiting the activity of acetylcholinesterase (AChE), (4) decreasing the hyperphosphorylation of tau protein to prevent neuronal fiber entanglement (NFT), (5) up-regulating the activity of Apolipoprotein E (ApoE) to reduce the deposition of Aβ, and (6) exerting its antioxidant properties and reducing oxidative stress by eliminating reactive oxygen species (ROS) [ 14 , 15 , 16 , 17 , 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

Genistein: A Potential Natural Lead Molecule for New Drug Design and Development for Treating Memory Impairment

et al. 2022

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Genistein is a naturally occurring polyphenolic molecule in the isoflavones group which is well known for its neuroprotection. In this review, we summarize the efficacy of genistein in attenuating the effects of memory impairment (MI) in animals. Scopus, PubMed, and Web of Science databases were used to find the relevant articles and discuss the effects of genistein in the brain, including its pharmacokinetics, bioavailability, behavioral effects, and some of the potential mechanisms of action on memory in several animal models. The results of the preclinical studies highly suggested that genistein is highly effective in enhancing the cognitive performance of the MI animal models, specifically in the memory domain, including spatial, recognition, retention, and reference memories, through its ability to reduce oxidative stress and attenuate neuroinflammation. This review also highlighted challenges and opportunities to improve the drug delivery of genistein for treating MI. Along with that, the possible structural modifications and derivatives of genistein to improve its physicochemical and drug-likeness properties are also discussed. The outcomes of the review proved that genistein can enhance the cognitive performance and ameliorate MI in different preclinical studies, thus indicating its potential as a natural lead for the design and development of a novel neuroprotective drug.

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“…Health benefits have been associated with the use of several natural compounds with estrogenic activity, such as the isoflavone genistein, which is known to exert neuroprotective actions in animal models of neurodegeneration [86][87][88]. It has been reported that genistein-and another isoflavone, formononetin-increases neuroglobin expression in primary neurons [89], suggesting that neuroglobin may participate in the neuroprotective actions of phytoestrogens and that these molecules may be used as pharmacological inductors of neuroglobin.…”

Section: Role Of Neuroglobin In the Neuroprotective Actions Of Natural And Synthetic Compounds With Estrogenic Activitymentioning

confidence: 99%

Role of Neuroglobin in the Neuroprotective Actions of Estradiol and Estrogenic Compounds

Barreto

McGovern

García‐Segura

2021

Cells

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Estradiol exerts neuroprotective actions that are mediated by the regulation of a variety of signaling pathways and homeostatic molecules. Among these is neuroglobin, which is upregulated by estradiol and translocated to the mitochondria to sustain neuronal and glial cell adaptation to injury. In this paper, we will discuss the role of neuroglobin in the neuroprotective mechanisms elicited by estradiol acting on neurons, astrocytes and microglia. We will also consider the role of neuroglobin in the neuroprotective actions of clinically relevant synthetic steroids, such as tibolone. Finally, the possible contribution of the estrogenic regulation of neuroglobin to the generation of sex differences in brain pathology and the potential application of neuroglobin as therapy against neurological diseases will be examined.

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Genistein Prevents Hypoxia-Induced Cognitive Dysfunctions by Ameliorating Oxidative Stress and Inflammation in the Hippocampus

Cited by 23 publications

References 56 publications

Genistein mitigates oxidative stress and inflammation by regulating Nrf2/HO-1 and NF-κB signaling pathways in hypoxic-ischemic brain damage in neonatal mice

Genistein mitigates oxidative stress and inflammation by regulating Nrf2/HO-1 and NF-κB signaling pathways in hypoxic-ischemic brain damage in neonatal mice

Genistein: A Potential Natural Lead Molecule for New Drug Design and Development for Treating Memory Impairment

Role of Neuroglobin in the Neuroprotective Actions of Estradiol and Estrogenic Compounds

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