Anesthesia during perinatal brain development has been implicated as leading to learning and memory deficits in later life. We are using mice to investigate the mechanisms by which anesthetics in the neonatal period may cause social, behavioral, learning and memory changes in adolescent and adult mice. Preliminary results have found alterations in social behavior and we are examining the physiological, cellular and molecular actions of anesthetics in order to determine the mechanisms by which they cause toxicity.
We are also examining the protective effects of anesthetic preconditioning against hypoxic and ischemic brain damage in adult rats. Cerebral ischemia is a frequent consequence during cardiac and neurological surgery. In surgical procedures with a high risk of ischemia, it is important to choose an anesthetic that offers protection. A focus of our studies is to examine the effects of anesthetics and other agents to determine how the cellular and molecular changes due to these anesthetics enhance recovery after an ischemic insult. We found that the volatile anesthetic sevoflurane improves recovery after hypoxia in hippocampal slices and after global ischemia in situ. Sevoflurane activates the mTOR pathway increasing the expression of protein kinase Mζ; blocking this pathway prevents the protective effects of sevoflurane. Additionally, we found that the local anesthetic and antiarrhythmic agent lidocaine reduces neuronal damage after hypoxia in hippocampal slices and after global or focal ischemia in situ. After global ischemia we found that lidocaine not only reduced neuronal cell loss in the CA1 region of the hippocampus but improved learning and memory 4 weeks after ischemia.
In our experiments we use pharmacologic methods, western blots, immunohistochemistry, electrophysiological techniques, fluorescent dyes and behavioral studies to examine the mechanisms leading to brain damage.
Figure 1. Quantification of the number of TUNEL positive cells in the ischemic penumbra and core. There were no TUNEL positive cells in the ischemic penumbra or core 4 h after ischemia. There were significantly fewer TUNEL positive cells in the ischemic penumbra of the lidocaine-treated group 24 h after ischemia. However, there were significantly more TUNEL positive cells in the ischemic core of the lidocaine-treated group compared with the vehicle-treated group 24 h after ischemia. * P<0.05 versus the vehicle group.
Double-labeling of cytochrome C (A); active caspase 3 (C); and TUNEL (E) with NeuN (B; D and F respectively). After 90 min of focal cerebral ischemia, there were significantly less Cytochrome C and Caspase 3 cells at 4 hours and TUNEL cells at 24 hours in the lidocaine treated animals. Figures from Lei, B., et. al. 2004 (reference below).
Lei, B., Popp, S., Capuano-Waters, C., Cottrell, J. E., and Kass, I. S. (2004). Lidocaine attenuates apoptosis in the ischemic penumbra and reduces infarct size after transient focal cerebral ischemia in rats. Neuroscience 125, 691-701.
Libien, J., Sacktor, T. C., and Kass, I. S. (2005). Magnesium blocks the loss of protein kinase C, leads to a transient translocation of PKC and PKC, and improves recovery after anoxia in rat hippocampal slices. Mol. Brain Res.136,104-111.
Wang, J., Meng, F., Cottrell, J. E., and Kass, I. S. (2006). The differential effects of volatile anesthetics on electrophysiological and biochemical changes during and recovery after hypoxia in rat hippocampal slice CA1 pyramidal cells. Neuroscience 140, 957-967.
Wang, J., Lei, B., Popp, S., Meng, F., Cottrell, J. E., and Kass, I. S. (2007). Sevoflurane immediate preconditioning alters hypoxic membrane potential changes in rat hippocampal slices and improves recovery of CA1 pyramidal cells after hypoxia and global cerebral ischemia. Neuroscience 145, 1097-1107.
Lei, B., Popp, S., Cottrell, J. E., and Kass, I. S. (2009). Effects of Midazolam on Brain Injury After Transient Focal Cerebral Ischemia in Rats. Journal of Neurosurgical Anesthesiology 21, 131-139.
Wang, J., Cottrell, J. E., and Kass, I. S. (2009). Effects of desflurane and propofol on electrophysiological parameters during and recovery after hypoxia in rat hippocampal slice CA1 pyramidal cells. Neuroscience 160, 140-148.
Popp, S. S., Lei, B., Kelemen, E., Fenton, A. A., Cottrell, J. E., and Kass, I. S. (2011). Intravenous antiarrhythmic doses of lidocaine increase the survival rate of CA1 pyramidal neurons and improve cognitive outcome after transient global cerebral ischemia in rats. Neuroscience 192, 537-549.
Wang, J., Meng, F., Cottrell, J. E., Sacktor, T. C., and Kass, I. S. (2012). Metabotropic actions of the volatile anesthetic sevoflurane increase PKMζ synthesis and induce immediate preconditioning protection of rat hippocampal slices J. Physiology 590, 4093-4107.
Naito, H., Takeda, Y., Danura, T., Kass, I.S., and Morita, K. (2013). Effect of lidocaine on dynamic changes in cortical NADH fluorescence during transient focal cerebral ischemia. Neuroscience 235, 59-69.
Esenther, B. R., Ge, Z., Meng, F., Cottrell, J. E., and Kass, I. S. (2013). Sevoflurane preconditioning attenuates the fall in ATP levels, but does not alter the changes in sodium and potassium levels during hypoxia in rat hippocampal slices. Anesthesiology 119, 119-128.
Daisy Lin, Ph.D., Research Assistant Professor
Baiping Lei, M.D., Ph.D., Clinical Assistant Professor
Jinyang Liu, M.S., Research Scientist
Editorial Board: Journal of Neurosurgical Anesthesiology, Raven Press.
Member: Sub-Committee on Current Research, New York State Society of Anesthesiologists.