Alyson Win

Introduction: Propofol is one of the most widely used intravenous anesthetics in the United States. While it is considered to be safe in a healthy, developed brain, there has been growing evidence that propofol is neurotoxic in neonatal animals. The general mechanism of propofol toxicity seems to be either increased neuronal apoptosis or suppression of neuronal proliferation and differentiation.^1,7,10 Dexmedetomidine, an ₂ agonist currently used as a sedative, may attenuate propofol toxicity.⁹ Methods: For in-vitro studies, healthy postnatal mice had their brains extracted and infused with propofol.⁵ For in-vivo studies, postnatal mice or pregnant mice were injected with propofol, some once and others over varying periods of time.⁸ Some mice were made to do tasks such as the Morris Water Maze test⁴ or the Open Field Test² in order to measure behavior and cognition. Western blotting was used to measure levels of signaling proteins and other molecules. TUNEL staining and the measurement of caspase-3 and Bax were used to quantify apoptosis.⁵ Probe staining was used to measure levels of Reactive oxygen species (ROS).⁵ RT-PCR testing was used to measure levels of miRNAs.⁴ Immunofluorescence staining was used to quantify Dopaminergic neurons in the brain.² Results: On a molecular level, propofol increases apoptosis through increased expression of pro-apoptotic molecules and ROS.⁵ This increase in ROS production can be attributed to the downregulation of the Pink1 pathway.⁵ Propofol inhibits neuronal stem cell development through downregulating the CaMKII/AMPK pathway and decreasing ATF5 production.⁶ Propofol also changes the levels of expression of 18 miRNAs, and these alterations of expression are associated with cell death, and neurological and psychiatric disorders.⁴ On a gross level, propofol exposure elicited decreased dopaminergic neuronal density in the ventral tegmental area (VTA), which is associated with depressive behavioral disorders.² On a behavioral level, propofol exposure was associated with less activity in the open field test², and poor performance on the Morris Water Maze test⁴, both associated with depressive behavioral disorders and impaired long-term memory respectively. Dexmedetomidine has been shown to attenuate propofol’s pro-apoptotic effects.⁹ Conclusions: Studies have found that in mice, propofol increases apoptosis, decreases neuronal stem cell development, and alters hippocampal miRNA expression to decrease neuronal density, which leads to long term memory and behavioral deficits in post-natal mice. More clinical research needs to be done to determine the extent in which these effects translate in human neonates. Dexmedetomidine is a promising treatment to reverse the pro-apoptotic effects of propofol.

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