Anesthesia, calcium homeostasis and Alzheimer's disease

Abstract

While anesthetics are indispensable clinical tools generally safe and effective, in some situations there is grown concern about selective neurotoxicity of these agents; the clinical significance is unclear as of yet. The mechanisms for inhalational anesthetics mediated cell damage are still not clear, although a role for calcium dysregulation has been suggested. For example, the inhaled anesthetic isoflurane decreases endoplasmic reticulum (ER) calcium concentration and increases that in the cytosol and mitochondria. Inhibition of ER calcium release, via either IP(3) or ryanodine receptors, significantly inhibited isoflurane neurotoxicity. Neurons made vulnerable to calcium dysregulation by overexpression of mutated presenilin-1 (PS1) or huntingtin (Q-111) proteins showed enhanced apoptosis upon isoflurane exposure. Sevoflurane and desflurane were less potent than isoflurane in altering intracellular calcium, and produced less apoptosis. Short exposures to inhalational anesthetics may provide neuroprotection by preconditioning via a sublethal stress, while prolonged exposures to inhalational anesthetics may induce cell damage by apoptosis through direct cytotoxic effects.

Fig. (1). Dynamics of intracellular Ca²⁺ homeostasis and inhaled anesthetics

Ca²⁺ released from the endoplasmic reticulum (ER) via IP₃ and/or ryanodine receptors into cytosolic space is constantly pumped back to the ER by Ca²⁺ ATPase on the ER membrane. Dantrolene and xestospongin are antagonists to the ryanodine and IP₃ receptors respectively. Thapsigargin is a selective inhibitor of Ca²⁺ ATPase. Ca²⁺ released from the ER can be transferred to mitochondria as the two compartments are in close proximity.

Fig. (2). Hypothetical pathway by which isoflurane induces apoptosis and Aβ generation and aggregation

Isoflurane induces caspase-3 activation/apoptosis. Caspase activation, in turn, increases the activities of both BACE and γ-secretase, which serve to increase Aß generation/accumulation. Isoflurane also enhances Aß aggregation, which induces further caspase-3 activation and apoptosis. Elevated Aß generation/accumulation and Aß aggregation then further induce apoptosis. Cited with permission from Xie et al., J. Neurosci, 2007; 27:1247-54.