Inhalational anesthetics as neuroprotectants or chemical preconditioning agents in ischemic brain

Abstract

This review will focus on inhalational anesthetic neuroprotection during cerebral ischemia and inhalational anesthetic preconditioning before ischemic brain injury. The limitations and challenges of past and current research in this area will be addressed before reviewing experimental and clinical studies evaluating the effects of inhalational anesthetics before and during cerebral ischemia. Mechanisms underlying volatile anesthetic neuroprotection and preconditioning will also be examined. Lastly, future directions for inhalational anesthetics and ischemic brain injury will be briefly discussed.

Figure 1

As described in the text, neuroprotective (in blue) and preconditioning (in green) mechanisms currently being explored for inhalational anesthetics in ischemic brain injury are depicted within the neurovascular unit. Mechanisms under investigation for both neuroprotection and preconditioning (in red) are also shown. Inhalational anesthetics administered before (preconditioning) or during (neuroprotection) perioperative brain ischemia are thought to promote and stabilize peri-ischemic rCBF as well as reduce CMR, thus increasing cerebral energy stores in ischemic brain. Neuroprotective effects of inhalational anesthetics in ischemic brain could also occur through inhibition of ROS formation from mitochondrial, nuclear, or cytoplasmic sources; scavenging of free radicals; and inhibition of membrane degeneration and lipid peroxidation. In addition, inhalational anesthetics could modulate ischemic excitotoxicity through attenuation of ischemia-induced catecholamine release, potentiation of GABAergic neurotransmission, and inhibition of glutamergic neurotransmission. Antagonism of AMPA and NMDA receptors for glutamate can subsequently lead to attenuation of ischemia-induced increases in [Ca²⁺]_i and decreases in glutamate-receptor-linked cyclic guanosine monophosphate production. Paradoxically, inhalational anesthetic-induced [Ca²⁺]_i increases may be involved with preconditioning effects in ischemic brain. Such changes in [Ca²⁺]_i can modulate calcium-dependent protective processes in ischemic brain involving calmodulin, CCPDKII, and the MAPK–ERK pathway. Inhalational anesthetics are thought to reduce or delay apoptosis through activation of Akt (protein kinase B), an antiapoptic factor downstream of the MAPK–ERK pathway, and through decreased expression of Bax, an apoptosis-inducing protein. Adenosine A₁ receptor activation may also be involved with the preconditioning effects of inhalational anesthetics in ischemic brain. Furthermore, adenosine A₁ receptor activation may possibly be a trigger for mitochondrial K_ATP channel opening and activation, which has been linked to the development of cerebral tolerance. It is speculated that K_ATP channel activation may alter ROS production, blunt intraischemic mitochondrial calcium accumulation, and improve postischemic mitochondrial energy production. Inducible nitric oxide synthase and the subsequent generation of NO may be important for inhalational anesthetic preconditioning in ischemic brain as well. Lastly, tolerance induced by inhalational anesthetic preconditioning may be mediated through p38 MAPK activation. Abbreviations: α-amino-3-hydroxyl-5-methyl-4-isoxazol propionic acid, AMPA; ATP-sensitive potassium channel, K_ATP channel; calcium/calmodulin-dependent protein kinase II, CCPDK II; cerebral metabolic rate, CMR; cyclic guanosine monophosphate, cGMP; extraceullar signal-regulated kinase, ERK; γ-amino-butyric acid, GABA; inducible nitric oxide synthase, iNOS; intracellular calcium concentration, [Ca²⁺]_i; mitogen-activated protein kinases, MAPK; nitric oxide, NO; N-methyl-D-aspartate, NMDA; reactive oxygen species, ROS; regional cerebral blood flow, rCBF.