Richard M. Kostrzewa (2000) Crucial Role of Iron in Anesthesia. Psycoloquy: 11(032) Coma Biochemistry (3)

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PSYCOLOQUY (ISSN 1055-0143) is sponsored by the American Psychological Association (APA).
Psycoloquy 11(032): Crucial Role of Iron in Anesthesia

Commentary on Smythies on Coma-Biochemistry

Richard M. Kostrzewa
Department of Pharmacology
Quillen College of Medicine
East Tennessee State University
PO Box 70, 577
Johnson City, TN 37614.


Despite the consensus that glutamatergic and GABAergic imbalance is likely to be involved in anesthesia or coma, there is little known about molecular mechanisms of action of gaseous anesthetics. The target article by Smythies (1999) is engagingly analytical and insightful, proposing novel and testable hypotheses for the molecular mechanisms of action of anesthetics as well as for processes that may be involved in coma. The most creative and convincing of his hypotheses concerns the crucial role of iron in maintaining neural respiration and energy production as well as its involvement in synaptic plasticity. Smythies' paper is certain to stimulate new ideas and experiments on the molecular mechanisms of anesthesia and coma.


anaesthetics, coma, consciousness, desferrioxamine dopamine, GABA, general glutamate iron, redox mechanisms, synapses
1. Smythies' (1999) target article is an insightful analysis of the underlying neuronal mechanisms associated not only with coma, but with anesthesia and sleep states. The author has scoured the literature, scrutinized findings from key papers, and developed hypotheses amenable to testing. It is generally conceded that an "imbalance" between GABAergic and glutamatergic neuronal inputs at defined brain sites (e.g., thalamocortical regions and tracts) is associated with anesthetic effects, and this is addressed in the Smythies paper. The author also addresses diabetic coma, thought to be an outcome of osmolality differences inside and outside neurons, resulting in cell shrinkage and de facto hyperpolarization. The most novel aspect of the paper, however, concerns the intraneuronal mechanisms associated with induction of coma and anesthesia.

2. Using the example of coma produced by combined desferrioxamine and prochlorperazine, Smythies specifically analyses findings and proposes novel mechanisms that may account for this drug-induced coma. Hydrophilic desferrioxamine, along with lipophilic prochlorperazine, could conceivably "deplete" neurons of adequate iron, altering plasma membrane function. Smythies proposes that the net effect might be interference with serotoninergic and noradrenergic function. One alternative explanation provided is that a consequence of iron depletion may be the elimination of dopamine-iron complexes in the postsynaptic cell at the glutamate synapse, so that superoxide produced in mitochondria cannot be scavenged. This would effectively produce neuronal blockade, similar to the ketamine effect at the glutamate synapse. A third possibility described in the paper is that prochlorperazine blocks the polyamine site on NMDA receptors, while lowered intracellular iron leads to downregulation of the NMDA receptor. These are unique and creative hypotheses, new light on an old subject.

3. It is surprising that the latest edition of the "bible" on Pharmacology, Goodman & Gilman's The Pharmacological Basis of Therapeutics (9th edition, McGraw Hill, 1995) [] does not allude to mechanisms of action of anesthetics. The new hypotheses could help to fill this void. Apart from this, the synthesis by Smythies should stimulate research into basic cellular mechanisms of neuronal function and iron metabolism.


Smythies, J. (1999) The biochemical basis of coma. PSYCOLOQUY 10(026) psyc.99.10.026.coma-biochemistry.1.smythies

Volume: 11 (next, prev) Issue: 032 (next, prev) Article: 3 (next prev first) Alternate versions: ASCII Summary