Propofol Administration During Early Postnatal Life Suppresses Hippocampal Neurogenesis

Abstract

Propofol is currently one of the most widely used intravenous anesthetics and has been indicated to induce cognitive dysfunction in adults. Here, we investigated the effects of propofol exposure during early postnatal life on hippocampal neurogenesis. Propofol (30 or 60 mg/kg) was administered to mice on either postnatal day (P) 7 or P7-P9; cell proliferation and neurogenesis in the dentate gyrus (DG) were evaluated on P8 or P17. It showed that exposure to propofol on P7 decreased hippocampal cell proliferation as indicated by BrdU and Sox2 immunostaining at P8 in propofol treatment at the dosage of 60 mg/kg but not at the dosage of 30 mg/kg. Western blots revealed propofol treatment decreased Akt or extracellular signal-related kinase (ERK) 1/2 phosphorylation in the hippocampus at P8. Propofol treatment on P7 to P9 reduced the numbers of newly formed neurons in the DG at P17, which was accompanied by delay of granule neuron maturation and decreased the density of dendritic spines, particularly the mushroom-shaped mature spines. Furthermore, the in vitro findings indicated propofol suppressed cell proliferation and cell mitosis and activated apoptosis of C17.2 neural stem cell line in a dose-dependent manner. These findings suggest that propofol impairs cell proliferation and inhibits neurogenesis in the immature mouse brain and thus is possibly involved in the cognitive dysfunction induced by propofol anesthesia.

Persistent neuronal apoptosis and synaptic loss induced by multiple but not single exposure of propofol contribute to long-term cognitive dysfunction in neonatal rats

“…Moreover, our results indicate that propofol-induced neuronal apoptosis could be the cause of neuronal deficit, and persistent neuronal apoptosis induced by multiple propofol exposures can lead to longlasting neuronal damage. In addition, propofol can also suppress neurogenesis in the developing brain (Erasso et al, 2013;Huang et al, 2016). Single propofol exposure may not suppress neurogenesis, or may only induce mild suppression of neurogenesis, so that neuronal density can recover rapidly in a compensatory mechanism; while multiple propofol exposures may induce severe suppression of neurogenesis, together with its more profound pro-apoptotic effect, ultimately result in persistent neuronal deficit.…”

Propofol causes neuronal degeneration in neonatal mice and long-term neurocognitive consequences in adult mice

“…However, the exact mechanisms behind anesthetic-induced neurotoxicity and damage to the neuronal signaling pathways remain unclear. Nonetheless, apoptotic modulation is identified as the main mechanism of anesthetic-mediated cellular responses, which further correlates with the activation of many cellular signaling components such as cell death signals, cleavage of cytoskeletal proteins, signaling kinases, and DNA repair enzymes in neuronal as well as nonneuronal cells [3,[8][9][10]12,22,23]. In this study, the activation of caspase-3, ultrastructural changes in the brain, and TUNEL and NeuN staining reflected the impacts of propofol on the brains of neonatal mice, causing neurotoxicity at a critical developmental stage that led to longtern neurocognitive impacts on adult mice.…”

“…Several anesthetics, including ketamine, midazolam, isoflurane, and propofol, have been reported to cause neurodegeneration in the developing brain and subsequent cognitive dysfunction in several animal models [2][3][4][5][6][7]10]. Propofol has also been reported to cause neuroapoptosis in the developing brain at clinically relevant concentrations and durations, leading to neurocognitive dysfunction [24,25].…”

“…It has also been reported to induce apoptosis by acting as an NMDA and GABAA agonist and Na + channel blocker [3,8,9]. In addition, it impairs cell proliferation and inhibits neurogenesis in the brains of immature mice, possibly also inducing cognitive dysfunction [10].…”

Detrimental effects of postnatal exposure to propofol on memory and hippocampal LTP in mice

“…These results demonstrated that AKT pathway might be important for the spine development in early phase. Other study also indicated inactivation of AKT pathway after early postnatal application of propofol, which inhibited neurogenesis in dentate gyrus (DG) region (Huang et al, 2015). Neurotropic factor was also proposed to regulate spinogenesis (Cohen-Cory et al, 2010).…”