Volatile anesthetics were first introduced into clinical use in 1842 [
1]. They have been the mainstay general anesthetics for millions of patients each year. The commonly used volatile anesthetics in current clinical practice include isoflurane, sevoflurane and desflurane [
1]. Halothane is no longer used in the U.S.A. but may be used in developing countries [
2].
Various theories have been developed over the years to explain the general anesthesia induced by volatile anesthetics. Most researchers now believe that anesthetics bind particular proteins and modify their functions. These effects ultimately result in anesthetic action [
1]. A variety of protein targets have been identified for volatile anesthetics. These include ion channels, muscarinic acetylcholine receptors, opioid receptors, α
2-adrenergic receptors, 5-hydroxytryptophan (HT)
2A receptors and N-methyl-D-aspartate (NMDA) receptors [
3]. Volatile anesthetics provide all components of general anesthesia including unconsciousness, amnesia, analgesia and muscle relaxation [
1]. Apart from the anesthetic property, these anesthetics have found to have multiple biological effects, such as the modulation of inflammation [
1,
4]. Recently, volatile anesthetics have found to cause mild neuroinflammation [
5]. Since inflammation is a fundamental pathological process involved in virtually all diseases acquired after birth, for example, Alzheimer’s and Parkinson’s disease [
6,
7], these effects of volatile anesthetics on inflammation may have significant biological implications.
Neuroinflammation induced by volatile anesthetics
Recently, we showed that exposure to 1.2% isoflurane for 2 h caused a small increase of IL-1β and activated caspase 3 in the hippocampi of both young adult and elderly rats. This isoflurane exposure also leaded to cognitive impairment. Lidocaine, a local anesthetic with anti-inflammatory property, inhibited isoflurane-induced IL-1β increase and cognitive impairment. Also, isoflurane did not induce cognitive impairment in the IL-1β deficient mice. These results suggest that isoflurane induces neuroinflammation that then leads to cognitive impairment [
5,
29]. Similar to our study, a more recent study showed that exposure of 6-day old mice to 3% sevoflurane for 2 h each day for 3 days increased IL-6 in the brain tissues and resulted in cognitive impairment of these mice when they were more than one month old. These IL-6 increase and cognitive impairment were blocked by ketorolac, an anti-inflammatory reagent [
30]. Despite of these lines of evidence in animals, evidence for volatile anesthetics-induced neuroinflammation is lacking up till now.
Little is known for the mechanisms of volatile anesthetics-induced neuroinflammation. Isoflurane has been shown to open the blood brain barrier [
31]. This can increase the permeation of intravascular substances to the brain tissues. A recent study showed that exposure of H4 human neuroglioma cells to 2% isoflurane or 4.1% sevoflurane for 6 h activated NF-κB [
32]. Since NF-κB is a transcription factor known to increase inflammatory cytokine production [
33], activation of NF-κB is presumably a mechanism for volatile anesthetics-induced neuroinflammation.
Prospective
Many animal studies have shown that volatile anesthetics can inhibit inflammatory process induced by various stimuli including ischemia and inflammation inducing agents. This effect is often translated into organ protection. Similar findings have been obtained in humans. However, limited animal data have suggested that volatile anesthetics can induce neuroinflammation in the absence of other stimuli. This effect is yet to be verified in humans. Nevertheless, current evidence indicates dual effects of volatile anesthetics on inflammatory process: they can inhibit inflammation induced by various potentially harmful stimuli and induce neuroinflammation in the absence of stimuli. Since volatile anesthetics are often used to provide anesthesia for surgery (a stimulus), the anti-inflammatory effect may be what we usually see with volatile anesthetic use in the clinical practice. Understandably, the type and the length of surgical procedures seem to play a role in the anti-inflammatory effect. Goto at al. reported no effect on inflammation from volatile anesthetics for patients undergoing cataract surgery [
34]. This study suggests that the inflammatory response for minor surgery is not significantly affected by volatile anesthetics.
The effects of volatile anesthetics on inflammation may have significant implications. Inflammation is a common pathological process involved in almost all diseases acquired in life. Inflammation is also involved in various processes during perioperative period, such as wound healing and infection prevention. Further studies are needed to determine the consequences of the volatile anesthetic effects on inflammation under various clinical conditions. In addition, current studies have mainly explored the role of NF-κB in these anesthetic effects. Further studies are needed to fully understand how volatile anesthetics can induce anti-inflammatory responses and neuroinflammation.