Increased production of inflammatory cytokines and activation of microglia in the fetal brain of preeclamptic mice induced by angiotensin II

Katoh, Yuki; Iriyama, Takayuki; Yano, Eriko; Sayama, Seisuke; Seyama, Takahiro; Kotajima-Murakami, Hiroko; Sato, Atsushi; Sakuma, Hiroshi; Iguchi, Yoshinobu; Yoshikawa, Midori; Inaoka, Naoko; Ichinose, Mari; Toshimitsu, Masatake; Sone, Kenbun; Kumasawa, Keiichi; Nagamatsu, Takeshi; Ikeda, Kazutaka; Osuga, Yutaka

doi:10.1016/j.jri.2022.103752

Cited by 4 publications

(2 citation statements)

References 35 publications

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“…To date, many researchers have investigated the mechanisms underlying adverse neurodevelopment in offspring attributed to intrauterine exposure to PE using various animal models of PE (3). Previous animal studies have demonstrated various alterations in (1) neuroanatomy (e.g., reduced volumes of cerebral neocortex, caudate-putamen, occipital lobe, and entorhinal cortex) and vascularization (e.g., small diameter vessels) in the central nervous system (6,7); (2) the number and localization of immune cells (e.g., microglia), apoptotic cells, and inflammatory cytokines (8,9); (3) neurogenesis, gliosis, and myelination (10); and (4) protein expression both in quality and quantity by western blotting and brain tissue pathology in the offspring of PE model animals (3). However, the pathogenesis of the increased risk of such disorders in offspring remains unclear (7,11).…”

Section: Introductionmentioning

confidence: 99%

Altered offspring neurodevelopment in an L-NAME-induced preeclampsia rat model

et al. 2023

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IntroductionTo investigate the mechanism underlying the increased risk of subsequent neurodevelopmental disorders in children born to mothers with preeclampsia, we evaluated the neurodevelopment of offspring of a preeclampsia rat model induced by the administration of N-nitro-L-arginine methyl ester (L-NAME) and identified unique protein signatures in the offspring cerebrospinal fluid.MethodsPregnant rats received an intraperitoneal injection of L-NAME (250 mg/kg/day) during gestational days 15–20 to establish a preeclampsia model. Behavioral experiments (negative geotaxis, open-field, rotarod treadmill, and active avoidance tests), immunohistochemistry [anti-neuronal nuclei (NeuN) staining in the hippocampal dentate gyrus and cerebral cortex on postnatal day 70], and proteome analysis of the cerebrospinal fluid on postnatal day 5 were performed on male offspring.ResultsOffspring of the preeclampsia dam exhibited increased growth restriction at birth (52.5%), but showed postnatal catch-up growth on postnatal day 14. Several behavioral abnormalities including motor development and vestibular function (negative geotaxis test: p < 0.01) in the neonatal period; motor coordination and learning skills (rotarod treadmill test: p = 0.01); and memory skills (active avoidance test: p < 0.01) in the juvenile period were observed. NeuN-positive cells in preeclampsia rats were significantly reduced in both the hippocampal dentate gyrus and cerebral cortex (p < 0.01, p < 0.01, respectively). Among the 1270 proteins in the cerebrospinal fluid identified using liquid chromatography-tandem mass spectrometry, 32 were differentially expressed. Principal component analysis showed that most cerebrospinal fluid samples achieved clear separation between preeclampsia and control rats. Pathway analysis revealed that differentially expressed proteins were associated with endoplasmic reticulum translocation, Rab proteins, and ribosomal proteins, which are involved in various nervous system disorders including autism spectrum disorders, schizophrenia, and Alzheimer's disease.ConclusionThe offspring of the L-NAME-induced preeclampsia model rats exhibited key features of neurodevelopmental abnormalities on behavioral and pathological examinations similar to humans. We found altered cerebrospinal fluid protein profiling in this preeclampsia rat, and the unique protein signatures related to endoplasmic reticulum translocation, Rab proteins, and ribosomal proteins may be associated with subsequent adverse neurodevelopment in the offspring.

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Section: Introductionmentioning

confidence: 99%

Altered offspring neurodevelopment in an L-NAME-induced preeclampsia rat model

et al. 2023

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“…A recent preclinical study revealed that fetal brain inflammation might be linked to the pathological mechanism connecting maternal pre-eclampsia and brain dysfunction in offspring. These findings are intriguing, as they suggest that preeclampsia in mothers might lead to altered inflammatory conditions in the fetal brain (46).…”

Section: Introductionmentioning

confidence: 99%

Modulation of vagal activity may help reduce neurodevelopmental damage in the offspring of mothers with pre-eclampsia

Abarca-Castro,

Talavera-Peña,

Reyes-Lagos

et al. 2023

Front. Immunol.

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Maternal Immune Activation (MIA) has been linked to the pathogenesis of pre-eclampsia and adverse neurodevelopmental outcomes in the offspring, such as cognitive deficits, behavioral abnormalities, and mental disorders. Pre-eclampsia is associated with an activation of the immune system characterized by persistently elevated levels of proinflammatory cytokines, as well as a decrease in immunoregulatory factors. The Cholinergic Anti-inflammatory Pathway (CAP) may play a relevant role in regulating the maternal inflammatory response during pre-eclampsia and protecting the developing fetus from inflammation-induced damage. Dysregulation in the CAP has been associated with the clinical evolution of pre-eclampsia. Some studies suggest that therapeutic stimulation of this pathway may improve maternal and fetal outcomes in preclinical models of pre-eclampsia. Modulation of vagal activity influences the CAP, improving maternal hemodynamics, limiting the inflammatory response, and promoting the growth of new neurons, which enhances synaptic plasticity and improves fetal neurodevelopment. Therefore, we postulate that modulation of vagal activity may improve maternal and fetal outcomes in pre-eclampsia by targeting underlying immune dysregulation and promoting better fetal neurodevelopment. In this perspective, we explore the clinical and experimental evidence of electrical, pharmacological, physical, and biological stimulation mechanisms capable of inducing therapeutical CAP, which may be applied in pre-eclampsia to improve the mother’s and offspring’s quality of life.

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