Research reportPKA-CREB-BDNF signaling pathway mediates propofol-induced long-term learning and memory impairment in hippocampus of rats
Introduction
The developing brain is exquisitely vulnerable and susceptible to general anesthetics (Joksovic et al., 2015). Increasing studies have demonstrated that early postnatal exposure to general anesthesia may result in neuroapoptosis and subsequent neurocognitive deficits and behavioral changes in rodents. Besides, clinical studies demonstrate that neonatal and pediatric patients exposed to general anesthetics were more likely to develop learning disabilities or cognitive function impairment in the adolescent (Sprung et al., 2012, Fan et al., 2013).
Propofol (2,6-diisopropylphenol), is a alkyl phenol derivative, due to its several attractive properties including a rapid onset of action and complete recovery, it has been wildly accepted as an ideal intravenous general anesthetic agent, and routinely used for induction and maintenance of anesthesia and critical care sedation in children. However, our previous in vitro study showed that propofol could induce a robust neuroapoptosis and inhibition of cell growth and proliferation (Zhong et al., 2014). Besides, in vivo experiments of other research group also demonstrated that neonatal exposure to propofol induces neuronal cell apoptosis in the developing brain and significant long-term learning and memory deficits (Yu et al., 2013, Zhang et al., 2013). These evidences raised serious concerns regarding the safety of pediatric propofol anesthesia. Thus, we aimed to investigate the mechanism underlying propofol-induced neuroapoptosis and evaluate long-term learning and memory impairment in the mature brain.
The cyclic adenosine 3′,5′ monophosphate (cAMP)-dependent protein kinase, also known as protein kinase A (PKA), which has been discovered in 1968, is ubiquitously expressed and mediates intracellular signal transduction in central nervous system (CNS). As with other protein kinases, PKA is an enzyme that covalently decorates proteins with phosphate group. A large body of evidence shows that PKA has important effects on neuronal differentiation, survival, function and plasticity, as well as long-term learning and memory mechanisms (Kandel, 2012, Jahan et al., 2017). Inhibitors of PKA have been reported to impair long-term memory in rodents, implying that PKA is critical for the formation of long-term memory (Barco et al., 2006, Grimes et al., 2012).
Equally, cAMP response element-binding protein (CREB) is a downstream target of PKA whose phosphorylation on Ser133 can be achieved by PKA signaling cascades in a strain-dependent expression pattern (Jiang et al., 2017). CREB, known as the “memory switch” (Zhong et al., 2016), is a transcription factor binding to the promoter regions of many genes, which is activated after phosphorylation by proteins kinases, has been implicated in synaptic plasticity and memory formation. The upregulation of p-CREB cascade was shown to alter learning and memory of behavioral tasks in rodents (Benito and Barco, 2010).
Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family, which is one of the downstream target genes of CREB. Previous studies revealed that BDNF was related to CREB regulated in an activity-dependent manner, wherein its expression was involved in neuronal development, synaptic plasticity and neuroprotection (Sakamoto et al., 2011, Leal et al., 2017). BDNF influences brain functions, which has been reported to play an important role in learning and long-term memory formation (Bekinschtein et al., 2008).
Based on previous studies, we hypothesized that propofol-induced neuroapoptosis in the developing brain and significant learning and memory deficits in the adulthood via the PKA-CREB-BDNF signaling pathway.
Section snippets
Arterial blood gas analysis
As shown in Table 1, There were no significant differences in pH, PaCO2, PaO2 and SaO2 among the five groups by one-way ANOVA (for the pH: F = 1.63, P = 0.21; for the PaCO2: F = 0.99; P = 0.44; for the PaO2: F = 0.06; P = 0.99; for the SaO2: F = 0.17; P = 0.95). It was discovered that there were no significant differences between the propofol exposure and control groups, indicating that there were no metabolic or respiratory distress in all groups.
Propofol induced neuronal cell apoptosis in the hippocampus of neonatal rats
As showed in Fig. 1A, we found that propofol
Discussion
In the present study, our results demonstrate that neonatal exposure to propofol induced significant increase of FJB-positive cells, spatial learning and memory deficits, cognition impairment and long-lasting ultrastructural abnormalities in the hippocampuses of adult rats. Additionally, decreased levels of PKA, pCREB and BDNF proteins were found in both neonatal and adult rats. Thus, over all data indicate that propofol exposure to neonates induces neuroapoptosis and impairs learning and
Animals and treatment
All animals were maintained in accordance with the guidelines of Guangxi Medical University, and the animal treatment protocols were approved by the Animal Care and Use Committee of the university. P7 Sprague Dawley rats (half males and half females, average body weight 10–12 g) were used in this study. Animals were treated with propofol (Diprivan; AstraZeneca, England) or 10% intralipid (Baxter Qiaoguang Healthcare Co., Ltd., Guangzhou, China). The drugs were used according to the
Acknowledgement
This study was supported by the Natural Science Foundation of China (No. 81060277 and No. 81373498), the Science Study and Technology Development Program of Guangxi (No. 1355005-4-2), and the Science and Technology Research Project of Guangxi University (No. 2013ZD014).
Conflict of interest
The authors declare that there are no conflicts of interest.
References (56)
- et al.
Safety of anesthetics in children
J. Am. Coll. Surg.
(2017) - et al.
CREB's control of intrinsic and synaptic plasticity: implications for CREB-dependent memory models
Trends Neurosci.
(2010) - et al.
Glutamate-induced rapid induction of Arc/Arg3.1 requires NMDA receptor-mediated phosphorylation of ERK and CREB
Neurosci. Lett.
(2017) - et al.
Applications of the Morris water maze in the study of learning and memory
Brain Res. Brain. Res. Rev.
(2001) - et al.
Comparative aspects of the brain growth spurt
Early. Hum. Dev.
(1979) - et al.
A neurotrophic model for stress-related mood disorders
Biol. Psychiat.
(2006) - et al.
Disruptions in spatial working memory, but not short-term memory, induced by repeated ketamine exposure
Prog. Neuropsychopharmacol. Biol. Psychiat.
(2009) - et al.
Recovery from ketamine-induced amnesia by blockade of GABA-A receptor in the medial prefrontal cortex of mice
Neuroscience
(2017) - et al.
Neuronal nuclear antigen (NeuN): a useful marker of neuronal immaturity in sudden unexplained perinatal death
J. Neurol. Sci.
(2013) - et al.
BDNF and hippocampal synaptic plasticity
Vitam. Horm.
(2017)
Antenatal taurine supplementation improves cerebral neurogenesis in fetal rats with intrauterine growth restriction through the PKA-CREB signal pathway
Nutr. Neurosci.
BDNF: a key regulator for protein synthesis-dependent LTP and long-term memory?
Neurobiol. Learn. Mem.
Regulation of cAMP-inducible genes by CREB
Trends Neurosci.
Isoflurane impairs odour discrimination learning in rats: differential effects on short- and long-term memory
Br. J. Anaesth.
Flavonoids and cognition: the molecular mechanisms underlying their behavioural effects
Arch. Biochem. Biophys.
Attention-deficit/hyperactivity disorder after early exposure to procedures requiring general anesthesia
Mayo. Clin. Proc.
Effect of XingPiJieYu decoction on spatial learning and memory and cAMP-PKA-CREB-BDNF pathway in rat model of depression through chronic unpredictable stress
BMC. Complement. Altern. Med.
Repeated exposure to propofol potentiates neuroapoptosis and long-term behavioral deficits in neonatal rats
Neurosci. Lett.
Repeated propofol anesthesia induced downregulation of hippocampal miR-132 and learning and memory impairment of rats
Brain Res.
Rolipram-induced improvement of cognitive function correlates with changes in hippocampal CREB phosphorylation, BDNF and Arc protein levels
Neurosci. Lett.
Common molecular mechanisms in explicit and implicit memory
J. Neurochem.
BDNF is essential to promote persistence of long-term memory storage
Proc. Natl. Acad. Sci. U.S.A.
Subanesthetic doses of propofol induce neuroapoptosis in the infant mouse brain
Anesth. Analg.
Nhe5 deficiency enhances learning and memory via upregulating Bdnf/TrkB signaling in mice
Am. J. Med. Genet. B. Neuropsychiatr. Genet.
Ciproxifan, an H3 receptor antagonist, improves short-term recognition memory impaired by isoflurane anesthesia
J. Anesth.
Enhancement of LTP in aged rats is dependent on endogenous BDNF
Neuropsychopharmacology
Quantitative growth and development of human brain
Arch. Dis. Child.
Prognostic study of sevoflurane-based general anesthesia on cognitive function in children
J. Anesth.
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These authors equally contributed to this work.