Abstract SNACC-41

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Dexmedetomidine Attenuates Neurotoxicity in Rats Exposed to Propofol In Utero during Gestation

Li J, Xiong M, Zuo W, Ye J, Reyes J, Pisklakov S, Tilak V, Bekker A
Rutgers-New Jersey Medical School, Newark, NJ, U.s.a.

Background: The commonly used general anesthetics including propofol can have adverse effects on the developing brain by triggering apoptotic neurodegeneration, as has been documented in rodents and nonhuman primates. Preclinical and clinical evidence suggests that dexmedetomi¬dine (Dex), a highly selective α2 adrenergic agonist, exerts anti-inflammatory and neuroprotective properties in several setting of neuronal injury [1-2]. We hypothesized that Dex could attenuate neuronal damage in the offspring rats exposed to propofol anesthesia in utero.
Methods: With IACUC approval, pregnant rats (gestational day 20) were treated with propofol anesthesia for 1 h with Dex or saline. Propofol was administered to pregnant rats by continuous infusion via a tail vein catheter. Dex (5.0 µg/kg, i.p.) or saline were administered 10 minutes before the 1-h propofol infusion. Control pregnant rats had catheter placed in the tail vein, but no infusion. Another group of pregnant rats received only Dex (5.0 µg/kg, i.p.). C-sections were performed 6 hours after stopping infusion or Dex treatment and fetal brain tissues were harvested. The tissue samples were subjected to the Western blot and immunofluorescence staining to assess interleukin-6 (IL-6), tumor necrosis factor α (TNFα), cleaved caspase-3 levels and the amount of ionized calcium-binding adaptor molecule 1 (IBA1)-positive cells, the marker of microglia activation.

Results: Maternal propofol anesthesia increased cleaved caspase-3 levels (317 ± 15.2% vs. 100 ± 18.9%), IL-6 (139 ± 8.10% vs. 100 ± 5.82%) and TNFα levels (141 ± 4.9% vs. 100 ± 19.4%) in the brain tissue and the amount of IBA1-positive cells in the cortex (control 7.0 ± 0.7 vs. propofol 9.7 ± 0.8) and thalamus regions (control 5.4 ± 0. vs. propofol 20.0 ± 2.4) in the fetal rats. Caspase-3 activation occurred primarily in the cerebral cortex and thalamic region of the exposed rodent brains. Double staining with antibodies to cleaved caspase-3 and antibodies to NeuN demonstrated that most of the cleaved caspase-3 positive cells were neurons. Dex, when was administered before propofol anesthesia, attenuated the propofol-induced increases in interleukin-6 (propofol + saline: 181.8 ± 14.7% vs. propofol + Dex: 83.7% ± 3.6%), TNFα levels (propofol + saline: 149 ± 7.5% vs. propofol + Dex: 112% ± 7.8%), cleaved caspase-3 levels (propofol + saline: 275.2 ± 34.7% vs. propofol + Dex: 63.8 ± 11.9%) in the brain tissue of fetal rats. The amount of IBA1-positive cells in the cortex and thalamus regions of the fetal rats exposed to propofol with Dex was less than that exposed to propofol with saline. Dex itself did not affect either the TNFα or cleaved caspase-3 levels in the brain and the amount of IBA1-positive cells in the cortex and thalamus regions of the fetal rats.

Conclusion: Maternal propofol anesthesia caused neuroinflamation and caspase-3 activation in the brain of fetal rats. Co-administration of Dex attenuates these untoward effects of propofol.

1. Sanders, RD., et al. Acta Anaesthesiol Scand, 2010. 54(6):710-6.
2. Bekker, A., et al. J Neurosurg Anesthesiol, 2013. 25(1): 16-24.

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