Hypobaric Hypoxia Induces Deficits in Adult Neurogenesis and Social Interaction via Cyclooxygenase-1/ EP1 Receptor Pathway Activating NLRP3 Inflammasome

Chauhan, Garima; Kumar, Gaurav; Roy, Koustav; Kumari, Pooja; Thondala, Bhanuteja; Kishore, Krishna; Panjwani, Usha; Ray, Koushik

doi:10.1007/s12035-022-02750-5

Cited by 11 publications

(10 citation statements)

References 83 publications

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“…The results of our study show that CHH significantly reduced the number of BrdU + /NeuN + labeled cells in the hippocampal DG of male rats whereas the number of BrdU + /NeuN + labeled cells in the hippocampal DG of female rats was hardly affected. It has been confirmed by some studies (Koester-Hegmann et al, 2018;Chauhan et al, 2022) 10.3389/fnins.2022.953417 that CHH may also induce a decrease in DG neurogenesis in the hippocampus, however, with a sex difference. In addition, neuroinflammation can lead to abnormalities in adult brain neurogenesis.…”

Section: Discussionmentioning

confidence: 83%

“…In addition, neuroinflammation can lead to abnormalities in adult brain neurogenesis. Prior studies have found that hypobaric-hypoxia stimulates microglia, astrocytes, and endothelial cells, and then produces neuroinflammation and neuronal degeneration in the hippocampal DG area ( Chauhan et al, 2022 ). Microglia affects neurogenic niches by balancing pro-inflammatory and anti-inflammatory conditions, which can either promote or inhibit neurogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…Several experimental studies have reported that simulated CHH exposure contributes to emotional behavioral changes, such as anxiety-like behavior ( Nguyen et al, 2021 ; Chauhan et al, 2022 ). The hippocampus has also been heavily implicated in depression and anxiety ( Bannerman et al, 2004 ; Campbell et al, 2004 ; Mehta et al, 2013 ).…”

Section: Methodsmentioning

confidence: 99%

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The role of sex and ovarian hormones in hippocampal damage and cognitive deficits induced by chronic exposure to hypobaric hypoxia

Zhu

Zhang²,

He³

et al. 2022

Front. Neurosci.

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PurposeThis study aims to investigate the role of sex and ovarian hormones in hippocampal damage and cognitive deficits and behavioral dysfunction in rats induced by chronic exposure to hypobaric hypoxia.MethodsSix-week-old male and female SD rats were housed for 3 months either in a real altitude (4,250 m) environment as the model of chronic hypobaric-hypoxia (CHH) or in a plain as controls. The animal behavioral and hippocampal neurons at subcellular, molecular, and ultrastructural levels were characterized after CHH exposure.ResultsAfter 3 months of CHH exposure, (1) male CHH rats’ serum testosterone level was lower than male controls’ whereas female CHH rats’ serum estradiol level was higher than female controls’; (2) Morris water maze test finds that male rats showed more learning and spatial memory deficits than female rats; (3) male rats showed more severe hippocampal damage, hippocampal inflammation, oxidative stress and decreased hippocampal integrity (neurogenesis and dendritic spine density) than female rats; (4) Western blot analysis shows that, compared with the male control group, in male CHH group’s hippocampus, expression of nNOS, HO-1, and Bax protein increased whereas that of Bcl-2 protein decreased; (5) Expression of PON2 protein in male rats (CHH and controls) was lower than female rats (CHH and controls). In addition, CHH exposure decreased the expression of PON2 protein in both male and female rats; (6) qPCR analysis reveals that CHH exposure reduced the gene expression of N-methyl-D-aspartate receptor NR2A and NR2B subunits in male rats’ hippocampus. In addition, compared with the sham CHH group, the expression level of PON2 protein decreased in the OVX-CHH group’s hippocampus whereas oxidative stress, neuroinflammation, and degeneration of hippocampal neurons increased in the OVX-CHH group’s hippocampus.ConclusionAfter CHH exposure, male rats were significantly more likely than female rats to develop hippocampal damage, hippocampal neuroinflammation, and cognitive decline and deficits, suggesting that sex and ovarian hormones were significantly involved in regulating the rats’ susceptibility to CHH exposure-induced hippocampal damage.

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Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

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The role of sex and ovarian hormones in hippocampal damage and cognitive deficits induced by chronic exposure to hypobaric hypoxia

Zhu

Zhang²,

He³

et al. 2022

Front. Neurosci.

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“…Interestingly, NSAIDs of the fenamate class may be repurposed as inhibitors of the NLRP3 in ammasome which may be bene cial for AD treatment [39]. Recently, Garima et al reported that COX-1 inhibition could mitigate the detrimental effects of hypobaric hypoxia on memory by blunting in ammation mediated by NLRP3 in ammasome-related neurogenesis impairments [34]. We demonstrated that COX-1 deletion inhibited NLRP3 in ammasome in vitro and in vivo, suggesting that COX-1 played an important role in the regulation of NLRP3 in ammasome in microglia.…”

Section: De Ciency Of Cox-1 Promoted Microglia Transition From M1 To ...mentioning

confidence: 99%

“…COX-1 inhibition can mitigate the detrimental effects of hypobaric hypoxia on memory via blunting NOD-, LRR-and pyrin domain-containing 3 (NLRP3)-mediated in ammation [34]. NLRP3 in ammasome is implicated in chronic in ammatory diseases and respond to in ammatory crystals and aggregated proteins including Aβ [35].…”

Section: Introductionmentioning

confidence: 99%

Genetic Deletion of cyclooxygenase-1 ameliorates neuroinflammation and cognitive impairment in 5×FAD mice

Wang

Wei

et al. 2023

Preprint

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Background: Neuroinflammation is one of the most important contributing factors for the pathogenesis of Alzheimer’s disease (AD). Cyclooxygenase-1 (COX-1) is distinctly expressed in microglia and involved in microglia activation and neuroinflammation in the AD. However, the molecular mechanisms by which COX-1 regulated microglia activation and participated in AD progression remains unclear. This study was designed to investigate the cellular and molecular mechanisms underlying COX-1 regulation of neuroinflammation. Methods: C57BL/6J, 5×FAD and 5×FAD/COX-1 knockout (KO) mice of different ages (e.g. 3-month-old, 6-month-old, 9-month-old) were used. Motor function and cognitive ability were evaluated using the open field test, novel-object recognition test and Morris water maze tests. The deposition of amyloid beta (Aβ) was examined by Thioflavin-S fluorescence, and neuroinflammation was investigated by immunohistochemistry, immunofluorescence and immunoblotting. Results: Konock out (KO) of COX-1 improved cognitive impairment and motor deficits, and reduced the accumulation of Aβ plaques in the cerebral cortex and hippocampus. COX-1 KO promoted microglia transition from M1 to M2 status, and reduced NOD-, LRR- and pyrin domain-containing 3 (NLRP3) inflammasome. This was mediated by the inhibition of prostaglandin E2 (PGE2)/EP2 pathway and cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA)-nuclear factor-κB (NFκB) p65 axis. Conclusions: COX-1 may contribute to the impairment of clearance Aβ and exacerbation of neuroinflammation which led to cognitive deficits in 5×FAD transgenic mice. The effects of COX-1 were mediated through PGE2/EP2 pathway which activated cAMP-PKA-NFκB p65 axis and NLRP3 inflammasome. The results suggest that the inhibition of COX-1 may be a potential pharmacological approach for the treatment of AD.

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Protective effects of Eleutheroside E against high-altitude pulmonary edema by inhibiting NLRP3 inflammasome-mediated pyroptosis

Shen,

Huang,

Jia

et al. 2023

Biomedicine & Pharmacotherapy

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Hypobaric Hypoxia Induces Deficits in Adult Neurogenesis and Social Interaction via Cyclooxygenase-1/ EP1 Receptor Pathway Activating NLRP3 Inflammasome

Cited by 11 publications

References 83 publications

The role of sex and ovarian hormones in hippocampal damage and cognitive deficits induced by chronic exposure to hypobaric hypoxia

The role of sex and ovarian hormones in hippocampal damage and cognitive deficits induced by chronic exposure to hypobaric hypoxia

Genetic Deletion of cyclooxygenase-1 ameliorates neuroinflammation and cognitive impairment in 5×FAD mice

Protective effects of Eleutheroside E against high-altitude pulmonary edema by inhibiting NLRP3 inflammasome-mediated pyroptosis

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