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

Abstract

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.

Hydroxychloroquine improves manifestation of PE rats under oxidative stress by regulating the PI3K/AKT/mTOR signaling pathway to inhibit autophagy

“…To verify our hypothesis, an oxidative stress model was established in HTR8/SVneo cell line by H 2 O 2 treatment to simulate the cellular microenvironment associated with PE, and we injected pregnant rats with L-NAME [21] , an endothelial nitric oxide synthase inhibitor, to establish a PE-like rat model. As expected, our study found elevated MDA levels and decreased SOD levels in the serum of PE rats, which is consistent with the pathophysiology of PE.…”

Maternal immune suppression during pregnancy does not prevent abnormal behavior in offspring

“…It has been reported that the peak time for MBP expression in rodents is PND 20, after which expression stabilizes [ 50 ], if this is the case it might explain the lack of differences among our groups. Interestingly, PreE offspring (from the L-NAME model) that expressed impairments in spatial learning and memory, also had changes in cortical, hippocampal and striatal NeuN expression when assessed via immunohistochemistry [ 42 , 51 ]. The findings of no change in blood pressure among offspring from HDP dams in the current study is similar to another study with similar findings when offspring from PreE dams were examined [ 52 ].…”

Neurodevelopmental Disruptions in Children of Preeclamptic Mothers: Pathophysiological Mechanisms and Consequences

“…Despite this, an increase in VEGF has been observed in PE-F1 mice, which could occur to compensate for the reduced levels of PGF [37]. A well-established and commonly employed method for inducing PE in mothers is through the administration of NG-nitro-L-arginine methyl ester (L-NAME) [90][91][92]. Research from our laboratory evaluated the effect of L-NAME-induced PE on offspring at an ontogenetic stage equivalent to childhood through the cerebellar expression of VEGF and two of its receptors, pY951 VEGF R2 and pY1172 VEGF R2.…”