Dexmedetomidine attenuates the propofol-induced long-term neurotoxicity in the developing brain of rats by enhancing the PI3K/Akt signaling pathway

Abstract

BackgroundPropofol induces short- and long-term neurotoxicity. Our previous study showed that dexmedetomidine (Dex) can attenuate the propofol-induced acute neurotoxicity in rodents by enhancing the PI3K/Akt signaling. However, whether treatment of young rats with Dex could protect them from long-term neurotoxicity induced by propofol is unclear.Materials and methodsSeven-day-old male Sprague Dawley rats were randomized and injected intraperitoneally with saline (100 μL, NS), propofol (100 mg/kg), Dex (75 μg/kg), propofol (100 mg/kg) plus Dex (25, 50 or 75 μg/kg), 10% dimethyl sulfoxide (DMSO, 100 μL) or TDZD-8 (a GSK3β inhibitor, 1 mg/kg), or intracerebroventricularly with DMSO (5 μL) or LY294002 (a PI3K inhibitor, 25 μg/5 μL DMSO). Other rats in the experimental group were injected with the same doses of propofol, Dex and LY294002 or TDZD-8. All the rats were monitored until they were 9 weeks old. Their spatial learning and memory were tested by Morris water maze. The neuronal apoptosis, expression of PSD95, expression and phosphorylation of Akt and GSK3β and synaptic ultrastructures were determined by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling, immunohistochemistry, Western blot and transmission electron microscopy assays, respectively.ResultsCompared with the NS control group, young rats injected with intralipid, Dex, TDZD-8, LY294002 or DMSO alone did not show any significant change as they aged. Propofol significantly increased the escape latency time, hippocampal neuroapoptosis and synaptic ultrastructural changes but decreased the relative levels of PSD95 expression, and Akt and GSK3β phosphorylation in the developing hippocampus of the rats. The neuronal toxic effects of propofol were significantly mitigated by the pretreatment with a higher dose of Dex. The neuroprotective effect of Dex was enhanced by the treatment with TDZD-8, but was completely abrogated by the treatment with LY294002.ConclusionOur results indicated that the pretreatment of young rats with Dex attenuated the propofol-induced long-term neurotoxicity in their developing hippocampus by enhancing the PI3K/Akt signaling.

Neuroprotection of the Developing Brain by Dexmedetomidine Is Mediated by Attenuating Single Propofol-induced Hippocampal Apoptosis and Synaptic Plasticity Deficits

“…This is in agreement with others, where a single injection of propofol (60 mg/kg), administered at the neonatal peak period of CNS development, was insufficient to cause cognitive dysfunction of juvenile mice [10]. However, Xiao et al [11] found that 9 week old rats showed aberrant neurological deficits after receiving the 100 mg/kg propofol (50 mg/kg, twice) at the neonatal period. The discrepant reason may be due to their different drug regimen, which somehow decreased number of neurocytes, self-renewal and differentiation capacity of neural stem cells during the period of mature brains.…”

Dexmedetomidine reduced sevoflurane‐induced neurodegeneration and long‐term memory deficits in neonatal rats

“…These results were consistent with previous similar studies (Li et al, 2014; Sanders et al, 2010, 2009), though inconsistent with others (Lee et al, 2017; Perez‐Zoghbi et al, 2017). In previous studies, DEX ameliorated the neuroapoptosis and cognitive dysfunction induced by exposure of the developing brain to isoflurane (Li et al, 2014; Sanders et al, 2010, 2009), sevoflurane (Perez‐Zoghbi et al, 2017), and propofol (Lv et al, 2017; Wang et al, 2016; Xiao et al, 2018). Sanders et.…”

“…Based on a previous study, DEX may attenuate the reduction in the expression of anti‐apoptotic signaling pathways mediated by Bcl‐2 and phosphor‐ERK1/2 induced by isoflurane anesthesia, in a similar manner to that of neonatal brain injury (Li et al, 2014). Moreover, DEX has anti‐apoptotic effects (Engelhard et al, 2002), decreases caspase‐3 elevation (Dahmani et al, 2005; Eser et al, 2008) and attenuates the activation of the PI3k/Akt/ glycogen synthase kinase (GSK)3beta pathway in propofol‐induced neuroapoptosis (Lv et al, 2017; Wang et al, 2016; Xiao et al, 2018). Further research is warranted in order to ascertain the precise neuroprotective mechanisms of DEX against neural toxicity induced by anesthesia exposure in the neonatal brain.…”

“…DEX is likely to be a protective compound that could be used to prevent or ameliorate anesthesia‐induced neurodegeneration (Walters and Paule, 2017). Based on previous studies, DEX can ameliorated the neuroapoptosis and cognitive dysfunction induced by exposure of the developing brain to ketamine (Duan et al, 2014), isoflurane (Li et al, 2014; Sanders et al, 2010, 2009), sevoflurane (Perez‐Zoghbi et al, 2017) and propofol (Lv et al, 2017; Wang et al, 2016; Xiao et al, 2018). Moreover, DEX has neuroprotective effects in the hypoxic‐ischemic neonatal brain (Ren et al, 2016; Zhou et al, 2018) and in an acute hyperoxic neonatal rat model (Endesfelder et al, 2017; Sifringer et al, 2015).…”

<p>Dexmedetomidine attenuates the neurotoxicity of propofol toward primary hippocampal neurons in vitro via Erk1/2/CREB/BDNF signaling pathways</p>

“…Based on accumulating evidence, propofol may induce developmental neurotoxicity, raising serious concerns regarding the use of propofol anesthesia in pediatric patients 5–7. Dexmedetomidine, a highly selective α2-adrenergic agonist, exerts a neuroprotective effect on propofol-induced neurotoxicity,8–10 but the associated mechanisms have not yet been fully clarified. The neuroprotective effects of dexmedetomidine are mediated by its binding to imidazoline I1 receptors and modulating histone acetylation via Erk1/2 pathways 11–13.…”