Hypermethylation of EFEMP1 in the Hippocampus May Be Related to the Deficit in Spatial Memory of Rat Neonates Triggered by Repeated Administration of Propofol

Abstract

It has been confirmed that repeated application of propofol, as an intravenous and short-fast-acting anesthetic, in neonatal animals or humans may produce long-term deficits in cognitive functions. With the aim of explaining the neurotoxic effects of repeated administration of propofol on neonatal rat pups from P7 to P9 especially from an epigenetic perspective, the present study used the Morris water maze to detect cognitive deficits in spatial learning and memory, Sequenom methylation on the CpG island located in the promoter region of epidermal growth factor-containing fibulin-like extracellular matrix protein 1 (EFEMP1) to assess the methylation level of this region, and Western blot to measure the expression of EFEMP1, TIMP-3, and MMP-9. As the results have shown, repeated propofol administration on neonatal rats caused significant systemic growth retardation, impairment of spatial learning and memory, and hypermethylation of the CpG sites in the promoter region of EFEMP1 accompanied by lower expression of EFEMP1 and TIMP-3 and enhanced expression of MMP-9. These data suggest that repeated propofol administration in neonatal rats may generate hypermethylation in the promoter region of EFEMP1 which results in downregulation of the expression of EFEMP1 and tissue inhibitor of metalloproteinase-3 (TIMP-3) but upregulation of the expression of matrix metalloproteinase-9 (MMP-9), which together may affect the stability of ECM to hamper the development of the central nervous system and therefore lead to deficits in cognitive functions.

EFEMP1 is a potential biomarker of choroid thickness change in myopia

“…Therefore, we speculate that the increase in EFEMP1 may be associated with the increase in EGFR and VEGF during myopia development. Moreover, EFEMP1 is important for maintaining the integrity of the basement membrane and the binding of other extracellular matrices, such as elastic fibers and basement membranes ( Zhang et al, 2020 ). Some researchers have found that EFEMP1 interacts with elastin as well as collagen 15A1 (a component of collagen fibrils) to produce proteins that affect the expression and function of these proteins ( Jorgenson et al, 2015 ).…”

Propofol-Induced Developmental Neurotoxicity: From Mechanisms to Therapeutic Strategies

“…Fibulin-3 can upregulate tissue inhibitors of metalloproteinase-1 (TIMP-1) and TIMP-3 and downregulate metalloproteinase-2 (MMP-2), MMP-3, and MMP-9. These factors are digestive enzymes of protein that participate in maintaining ECM and regulating learning and memory. , A study found that propofol exposure for 3 consecutive days from PND 7 to PND 9 in rats can lead to hypermethylation of CpG sites in the EFEMP1 promoter region, decrease the expression of fibulin-3 and TIMP-3, and increase the expression of MMP-9, thus interfering with the stability of ECM in the hippocampus and leading to growth retardation and cognitive impairment …”

“…97,98 A study found that propofol exposure for 3 consecutive days from PND 7 to PND 9 in rats can lead to hypermethylation of CpG sites in the EFEMP1 promoter region, decrease the expression of fibulin-3 and TIMP-3, and increase the expression of MMP-9, thus interfering with the stability of ECM in the hippocampus and leading to growth retardation and cognitive impairment. 99 3.8. Brain Region-Specific Neurotoxicity.…”