Neuroprotection by propofol in acute mechanical injury: Role of GABAergic
Hollrigel, Greg S., Katalin Toth, and Ivan Soltesz.
Department of Anatomy and Neurobiology, University of California Irvine,
Irvine, CA 92717, Department of Functional Neuroanatomy, Institute of
Experimental Medicine, Budapest, Hungary.
APStracts 3:0096N, 1996.
SUMMARY AND CONCLUSIONS
1. Whole-cell patch clamp and extracellular field recordings were obtained
from granule cells of the dentate gyrus in 400 [mu] m thick brain slices of
the adult rat to determine the actions of the intravenous general anesthetic
propofol (2,6-diisopropylphenol) on acute neuronal survival and preservation
of synaptic integrity after amputation of dendrites (dendrotomy), and to
determine the role of GABA A receptor mediated inhibition in the
neuroprotective effects of propofol. The actions of propofol were compared to
the those exerted by another widely used intravenous general anesthetic,
thiopental (5-ethyl-5-[1-methylbutyl]-2-thiobarbituric acid) . 2. Propofol (10
[mu]M) increased the frequency (control: 5.9+/-0.9Hz; propofol: 10.5+/-1.3Hz)
and the single exponential decay time constant (_ D ) (control: 4.5+/-0.2ms;
propofol: 15.3+/-1.5ms) of miniature inhibitory postsynaptic currents (mIPSCs)
recorded in control neurons. Thiopental (25 [mu]M) also increased the _ D
(14.3+/-0.9ms) of mISPCs, but had no effect on mIPSC frequency. Both
anesthetics potentiated mIPSCs at low concentrations (5 [mu] M propofol; 1
[mu] M thiopental). Propofol and thiopental did not change the peak amplitude
and rise times of mIPSCs. 3. Propofol (10 [mu] M) was able to depress the
excitability of control granule cells, as determined by the reduction in the
amplitude of the orthodromic population spikes. This depression could be
prevented by the GABA A receptor antagonist bicuculline (50 [mu] M),
indicating that propofol reduces excitability via GABA A receptor functions.
4. Propofol and thiopental were neuroprotectant (assessed by antidromic
population responses 2-5 hours following injury) if present before and during
the amputation of the granule cell dendrites. The protective actions were dose
dependent, and at high doses (200 [mu] M propofol; 400 [mu] M thiopental) the
anesthetics were as neuroprotective against dendrotomy-induced cell death as
APV and CNQX. The protective effects of the anesthetics were completely
blocked with the GABA A receptor antagonists picrotoxin or bicuculline, and
were mimicked by the GABA A receptor agonist muscimol (100 [mu] M). 5.
Propofol, in contrast to APV and CNQX, could not prevent the dendrotomy-
induced Ca 2+ -dependent and long-lasting changes in mIPSC decay kinetics
(appearance of a double exponential, prolonged decay). 6. The protective
effects of the anesthetics and those of APV and CNQX on neuronal survival were
not significant when the drugs were applied after dendrotomy, indicating that
dendrotomy carried out 150-200 [mu]m from the soma without neuroprotective
agents rapidly induces irreversible acute degeneration in most injured
neurons. The failure to rescue cells from dendrotomy-induced injury did not
result from a decreased sensitivity of the GABA A receptors to the
anesthetics, because the potentiating effects of the anesthetics on mIPSCs
from control and dendrotomized neurons were not different. 7. These data
indicate that propofol potentiates synaptic inhibition pre- and
postsynaptically, and, when present during dendrotomy, it can protect neurons
from acute mechanical injury-induced cell death via potentiation of GABA A
receptor functions. However, propofol fails to provide neuroprotection against
dendrotomy-induced changes in synaptic physiology.
Received 6 March 1995; accepted in final form 14 May 1996.
APS Manuscript Number J182-6.
Article publication pending J. Neurophysiol.
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 5 June 96