Anesthesia with sevoflurane in neonatal rats: Developmental neuroendocrine abnormalities and alleviating effects of the corticosteroid and Cl− importer antagonists

Abstract

Background 1.5 million children under 12 months of age are exposed to general anesthesia annually in the United States alone. Human and especially animal studies provide evidence that exposure to general anesthesia during the early postnatal period may lead to long-term neurocognitive abnormalities via poorly understood mechanisms. We investigated whether an immature stress response system and γ-aminobutyric acid (GABA) type A receptor activities are involved in mediating these abnormalities. Methods Sprague-Dawley rats at postnatal days 4, 5 or 6 were anesthetized with 2.1% sevoflurane for 6 hrs; maternally separated and house reared rats served as controls. Results Sevoflurane anesthesia markedly increased corticosterone levels in rat pups of both genders. In adulthood, these rats responded to stress with heightened secretion of corticosterone and a greater increase in corticosterone levels in males versus females. Only male rats, previously exposed to neonatal sevoflurane, had a higher frequency of miniature inhibitory postsynaptic currents in CA1 neurons, spent a shorter time in open arms of the elevated plus maze (EPM) and exhibited impaired prepulse inhibition (PPI) of startle. Pretreatment of male rats prior to sevoflurane with the Na+-K+-2Cl− cotransporter inhibitor, bumetanide, or the mineralocorticoid receptor antagonist, RU28318, normalized endocrine responses to stress and the EPM behavior in adulthood, while only those pretreated with bumetanide exhibited normalized PPI of startle responses. Neither bumetanide nor RU28318 altered the effect of sevoflurane on synaptic activity. Conclusions Sevoflurane-enhanced neuronal excitation and elevated corticosteroid levels at the time of anesthesia contribute to the mechanisms initiating neonatal sevoflurane-induced long-term endocrine and neurobehavioral abnormalities.

Subsequent maternal separation exacerbates neurobehavioral abnormalities in rats neonatally exposed to sevoflurane anesthesia

“…In order to control for prior anesthesia injections of bumetanide, all treatment groups except the Control group received equal volumes of saline (IP) at P6. Previously we have shown that saline at these volumes does not cause any obvious physiological responses [8, 9]. A separate group with bumetanide only has not been included.…”

“…Thus, neonatal anesthesia-induced neurobehavioral abnormalities in rodents were ameliorated and exacerbated by housing the exposed animals in enriched and enrichment-deprived environments, respectively [20, 21]. In addition, rats neonatally exposed to sevoflurane, an anesthetic whose polyvalent actions include enhancement of gamma-aminobutyric acid type A receptor (GABA A R) activity, exhibited exacerbated endocrine corticosterone responses to stress in adulthood (with larger increases in male rats), suggesting greater vulnerability of the exposed rats to stressful environmental factors later in life [9]. Sevoflurane-enhanced GABA A R-mediated signaling, which undergoes a fundamental transition from predominantly depolarizing/stimulatory to inhibitory in the rat brain during the first two postnatal weeks, may initiate these abnormalities as the Na + -K + -2Cl − (NKCC1) Cl − importer inhibition prior to anesthesia was protective [9].…”

“…In addition, rats neonatally exposed to sevoflurane, an anesthetic whose polyvalent actions include enhancement of gamma-aminobutyric acid type A receptor (GABA A R) activity, exhibited exacerbated endocrine corticosterone responses to stress in adulthood (with larger increases in male rats), suggesting greater vulnerability of the exposed rats to stressful environmental factors later in life [9]. Sevoflurane-enhanced GABA A R-mediated signaling, which undergoes a fundamental transition from predominantly depolarizing/stimulatory to inhibitory in the rat brain during the first two postnatal weeks, may initiate these abnormalities as the Na + -K + -2Cl − (NKCC1) Cl − importer inhibition prior to anesthesia was protective [9]. The current study has been designed to test whether developmental abnormalities programmed by a relatively short exposure of postnatal day 6 (P6) rats to sevoflurane, which may not be sufficient to induce developmental abnormalities by itself, can be further exacerbated by post-exposure stress.…”

Propofol, but not etomidate, increases corticosterone levels and induces long-term alteration in hippocampal synaptic activity in neonatal rats

“…Synapse formation in the human prefrontal cortex reaches its peak at about 5 years of age [8]. The few rodent studies on the synaptic developmental effects of neonatal anesthetic exposure report prominent alterations of synaptic structure and activity later in life [9-13]. This suggests that humans may remain vulnerable to the detrimental effects of general anesthetics at least for several years after birth, the period of intense synaptic maturation in humans.…”

“…We recently reported that adverse developmental effects of two different general anesthetics, sevoflurane, a gaseous anesthetic whose polyvalent actions include enhancement of gamma-aminobutyric acid type A receptor (GABA A R) activity, and propofol, an intravenous anesthetic with a selective GABA A R-mediated action, included long-term alterations in synaptic activity that could be detected in the form of impaired long-term potentiation [9] and increased frequencies of GABA A R-mediated miniature postsynaptic currents (mPSCs) in the hippocampus later in life [12,13]. In general, changes in mPSC frequency are linked to presynaptic events such as a change in the probability of transmitter release and/or a change in the number of functional synapses, whereas changes in amplitude are explained by a change in postsynaptic receptor number or conductance [14].…”