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.
Highlights
Though general anesthesia has its undoubted role in facilitating critical surgeries, still people started to consider its double-bladed actions on CNS since its principal mechanism is to blockade nervous traffic
Recent studies have shown that fibulin-3 is capable of upregulating tissue inhibitor of metalloproteinase- (TIMP-) 1 and tissue inhibitor of metalloproteinase-3 (TIMP-3), physically interacting with TIMP-3, and downregulating matrix metalloproteinase- (MMP-) 2, Matrix metalloproteinases (MMPs)-3, and matrix metalloproteinase-9 (MMP-9) [11, 12]
Does reduced EFEMP1 expression have any effect on TIMP? And subsequently, could the activity and expression of MMPs be affected to interfere with the stability of extracellular matrix (ECM) in CNS, which hampers the development of the brain? To solve these queries, we used mass spectrometry to measure and compare the methylation level of EFEMP1 and assayed the alterations in the expression of EFEMP1 to explore whether the repeated application of propofol was capable of disturbing the stability of the living environment of neurons and thereby interfering with the development of the brain and long-term learning and memory
Summary
Though general anesthesia has its undoubted role in facilitating critical surgeries, still people started to consider its double-bladed actions on CNS since its principal mechanism is to blockade nervous traffic. Based on the current research, multiple or long-lasting anesthesia may cause some persistent neurotoxicity including deficits in memory and learning, at extreme ages [1], which is more often seen in patients with developing, immature brains. Matrix metalloproteinases (MMPs), as a family of protein-digesting enzymes, play important roles in maintenance and conversion of the ECM [13], and the activity and expression level of MMPs are strictly controlled by various mechanisms including transcription, activation of the precursor zymogens, and inhibition by the TIMP [14]. We used mass spectrometry to measure and compare the methylation level of EFEMP1 and assayed the alterations in the expression of EFEMP1 to explore whether the repeated application of propofol was capable of disturbing the stability of the living environment of neurons and thereby interfering with the development of the brain and long-term learning and memory Does reduced EFEMP1 expression have any effect on TIMP? And subsequently, could the activity and expression of MMPs be affected to interfere with the stability of ECM in CNS, which hampers the development of the brain? To solve these queries, we used mass spectrometry to measure and compare the methylation level of EFEMP1 and assayed the alterations in the expression of EFEMP1 to explore whether the repeated application of propofol was capable of disturbing the stability of the living environment of neurons and thereby interfering with the development of the brain and long-term learning and memory
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