J Neurosurg Anesthesiol. 2016 Jan; 28(1):51-64.

Dexmedetomidine attenuates neurotoxicity induced by prenatal propofol exposure

Jing Li, MD, PhD, Ming Xiong, MD, PhD, Pratap R. Nadavaluru, MD, Wanhong Zuo, MD, PhD, Jiang Hong Ye, MD, MSc, Jean Daniel Eloy, MD, Alex Bekker, MD, PhD

Department of Anesthesiology, Rutgers New Jersey Medical School, Newark, NJ, USA.

 

Abstract

Background: Anesthetic agents (e.g., isoflurane, propofol) may cause neurodegeneration in the developing brains and impair animals’ learning ability. Dexmedetomidine, a selective alpha 2-adrenoreceptor agonist, has antiapoptotic properties in several brain injury models. Here, we tested whether dexmedetomidine can protect the brain from neurodegeneration in rats exposed to propofol in utero.

Methods: Fetal rats of embryonic day 20 were exposed in utero for 1 h to propofol anesthesia with dexmedetomidine or saline, or no anesthesia (control).  The fetal brains were harvested 6 h later. Cleaved caspase-3 levels and the relative number of ionized calcium-binding adaptor molecule 1 (IBA1)-positive cells were assessed by Western blot and immunohistochemistry. Learning and memory functions of the offspring in a separate cohort were assessed at postnatal day 35 by using an 8-arm radial maze.

Results: Propofol anesthesia in pregnant rats augmented caspase-3 activation by 217% in the brain tissues of fetal rats and increased the number of IBA1-positive cells in the cortex by 40% and in the thalamus by 270%.  Juvenile rats exposed prenatally to propofol were not different than controls on spontaneous locomotor activity, but made more errors of omission and took longer to complete visiting all eight arms on days 1, 2, and 3 across a 5-day test in the radial arm maze. This neurocognitive deficit was prevented by administration of dexmedetomidine (5.0 µg/kg, i.p.), which also significantly inhibited propofol-induced caspase-3 activation and microglial response in the fetal brains.

Conclusion:  Dexmedetomidine attenuates neuronal injury induced by maternal propofol anesthesia in the fetal brains, providing neurocognitive protection in the offspring rats.

PMID: 25844953

 

Supplementary:  

General anesthetics, such as isoflurane, sevoflurane, ketamine, or propofol administered during synaptogenesis, may trigger widespread apoptotic neurodegeneration in the developing.  We have recently shown that gestational exposure to propofol at a dose which produces a light sedation (defined as reduced activity but with intact righting reflex) could cause loss of neurons in the hippocampus, persistent learning deficits, and retardation in physical and neurological reflex development in the offspring rats (1-2).

Some anesthetics might be less toxic, such as dexmedetomidine. Dexmedetomidine (DEX) is an anesthetic/sedative that activates α2 adrenoceptors, a different mechanism of action from those of ketamine, isoflurane and propofol. Recent studies show that DEX even at high dose does not induce apoptosis in the fetal monkey (3). When co-administered with isoflurane, DEX mitigated the severity of neuroapoptosis induced by isoflurane, providing neurocognitive protection (4,5) We therefore hypothesized that DEX, co-administered with propofol, could attenuate gestational propofol anesthesia induced-apoptosis and microglial activation and cognitive impairments in offspring rats.

Using the pregnant rat model of total intravenous anesthesia, we found that administration of propofol (a bolus of propofol 8.0 mg/kg IV was given to achieve an anesthetic state with an absence of movement in response to a mosquito clamp pinch on the paw. The anesthetic level was maintained by a 1 hr continuous infusion of propofol at the rate of 1.2 ± 0.2 mg/kg/min.) in pregnant rats on gestational day 20 can induce acute neurotoxicity, including increases in the amount of cleaved caspase-3 and IBA1 protein (marker of microglia activation) (Fig.1) in the brain tissues of fetal rats. The same propofol infusion in pregnant rats also induced learning and memory impairment in the juvenile offspring rats (Fig. 2). DEX (5.0 µg/kg, i.p.) administered with propofol can prevent the maternal propofol exposure-induced caspase-3 activation and microglial response in the fetal brain (Fig. 3) and mitigate cognitive deficits in the juvenile offspring (Fig.4). In contrast to propofol (and other intravenous anesthetic agents, such as ketamine), DEX itself at the dose of 5.0 µg/kg lacks neurotoxicity.

  Importance of this study: Our data demonstrated that DEX attenuates neuronal injury induced by maternal propofol anesthesia in the fetal brains, providing neurocognitive protection in the offspring rats. These findings should promote additional studies to determine the neuroprotective effects of DEX on the anesthesia-induced neurotoxicity in the developing brain.

 

 

fig1

Fig.1. Propofol anesthesia for 1 h in pregnant rats induces caspase-3 and IBA1 activation in the brain tissues of fetal rats within 6 hours. Propofol general anesthesia or intralipid (IV, 1 h) was administered to pregnant rats at the age of gestational days 20. After six hours, fetuses were removed, and fetal brain tissues were harvested and analyzed by Western blot. (A and C) Representative Western blot analysis shows expression levels of cleaved caspase-3 and IBA1 in the fetal brain tissues exposed to propofol inutero and control condition. (B and D) Quantification of the Western blot shows that propofol anesthesia increased cleaved caspase-3 and IBA 1 levels in the rat brain tissues compared with the control condition (*P<0.001). n = 4 fetuses/group.

 

fig2

Fig.2. Effect of maternal propofol exposure on offsprings’ performance in 8 arm radial maze.  Mean (± SEM) number of errors (A and B), time taken to visit all eight arms (C), and number of correct responses made before the first error (D) for the offspring exposed to propofol, intralipid in utero or control condition. Rats exposed to propofol, but not intralipid inutero made significantly more errors than the control rats on day1, 2 and day 3 across 5-day test (A). There was also significant difference between groups in terms of the total number of errors over 5-day test (B). Rats exposed to propofol, but not intralipid inutero also took longer time to complete visiting all eight arms relatively to the controls on day1, 2 and day 3 across 5-day test (C). n = 12 rats/group; *P<0.05, **P<0.01, ***P<0.001 indicates that there is a significant difference between the control and propofol groups.

 

fig3

Fig. 3 Effect of DEX on the propofol-induced increases in cleaved caspase-3 and IBA1 levels in the brain tissues of fetal rats. Fetal rats were treated in utero with control plus saline, propofol plus saline or propofol plus DEX (5.0 µg/kg), or DEX (5.0 µg/kg) alone, as indicated. After 6 hours, fetal brain tissues were harvested and processed.  (A) Representative Western blot analysis of expression levels of cleaved caspase-3 in the fetal brain tissues. (B and C) Quantification of the Western blot shows that the propofol anesthesia plus saline increases cleaved caspase-3 and IBA1 levels compared with the control/saline (***P < 0.001), and DEX mitigates the propofol anesthesia-induced activation of caspase-3 and IBA1 (###P < 0.001, vs. propofol + saline) in fetal rat brain tissues. n = 6 fetuses/group.

 

fig4

Fig. 4 Effect of DEX on maternal propofol exposure-induced impaired memory and learning ability of offspring in 8 arm radial maze. Mean (± SEM) number of errors (A and B), time taken to visit all eight arms (C), and number of correct responses made before the first error (D) for the offspring exposed to control, propofol plus saline, propofol plus DEX  or DEX alone. *P<0.05, **P<0.01, ***P<0.001 compared with control/saline; #P<0.05, ##P<0.01, ###P<0.001 compared with propofol/DEX.  n = 18 pups for control + saline, n = 14 for propofol + saline, n = 14 for propofol + DEX and n = 14 for DEX alone group.

 

Reference:

(1)   Li J, Xiong M, Alhashem HM, et al. Effects of prenatal propofol exposure on postnatal development in rats. Neurotoxicol Teratol 2014;43: 51-8.

(2)   Xiong M, Li J, Alhashem HM, et al. Propofol exposure in pregnant rats induces  neurotoxicity and persistent learning deficit in the offspring. Brain Sci 2014;4: 356-75.

(3)   Koo E, Oshodi T, Meschter C, et al. Neurotoxic effects of dexmedetomidine in fetal cynomolgus monkey brains. J Toxicol Sci 2014;39: 251-62.

(4)   Sanders RD, Xu J, Shu Y, et al. Dexmedetomidine attenuates isoflurane-induced neurocognitive impairment in neonatal rats. Anesthesiology 2009;110: 1077-85.

(5)   Sanders RD, Sun P, Patel S, et al. Dexmedetomidine provides cortical neuroprotection: impact on anaesthetic-induced neuroapoptosis in the rat developing brain. Acta Anaesthesiol Scand 2010;54: 710-6.

 

Contact information:

Alex Bekker, M.D, Ph.D.

Professor and Chair of Department of Anesthesiology,

Rutgers New Jersey Medical School, 185 South Orange Avenue, Newark, NJ, USA 07103.  Phone: 973-972-5007.   Fax: 973-972-8202. E-mail: bekkeray@njms.rutgers.edu

 

 

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