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Anesthetic Agents: Neurotoxics or Neuroprotectives?
Introduction
The National Health Statistics Report published in 2010 estimated that around 45 million inpatient surgical procedures are carried out annually in the United States with an increasing rate among older population (≥65 years old). Newborns’ data was excluded from this survey although around 1.5 million interventions per year have been reported. Therefore, a considerable number of patients are annually being exposed to potential perioperative complications.
Central nervous system (CNS) functioning is affected during anesthesia. Neurons in eloquent areas are commonly targeted by local and general anesthetic drugs, interfering with their physiologic mechanisms and autoregulation. An extensive body of evidence assessed the neuroprotective and neurotoxic effects of anesthetics.
Different individual factors should be considered to assess the actual risk of developing perioperative neurological complications. Cerebral metabolic rate is decreased as a result of anesthetic drugs use. However, correlation between cerebral blood flow (CBF) and oxygen consumption is usually conserved. Disruption of the cerebral autoregulation involves several variables related to anesthesia (exposition to anesthetics, depth of anesthesia, high plasmatic concentration of anesthetics), surgery (cardiovascular or neurologic surgery), or patient demographics and medical history (aging, comorbidities, etc.).
Molecular mechanisms involving anesthetic-induced neurotoxicity were extensively studied in animal models. Nevertheless, because of the natural limitations imposed by the clinical research it is difficult to conclude whether these processes similarly occur within human physiopathological conditions. Studies published in more than five decades have reported on neuroprotective effects of anesthetics. Decreased CBF, intracranial pressure (ICP), and rate of oxygen consumption were the first neuroprotective mechanisms described for both volatile and intravenous anesthetics. Paradoxically, anesthetics’ neuroprotective mechanisms are linked to mitochondria, the same organelle in which anesthetics’ neurotoxic effects are carried out.
Pharmacological Considerations
Neurotoxicity of Anesthetic Drugs
In general, the molecular effect of anesthetics is studied in different species including nonhuman primates. Relevant findings explaining potential neurotoxic effects in fragile brain models have been reported.
A pioneer study published by Ikonomidou et al. in 1999 associated anesthesia with neurotoxicity. Glutamate is one of the major neurotransmitter with an important role during developing brain stages. Therefore, N -methyl- d -aspartate (NMDA) antagonists (+MK801, ketamine, phencyclidine, and carboxypiperazin-4-yl-propyl-1-phosphonic acid) are able to trigger dose- and time-dependent proapoptotic responses leading to cellular degeneration in rats. Similar consequences may be responsible for neurological impairments observed in children whose mothers were exposed to comparable substances during pregnancy.
Inhaled Anesthetics
Retinal cells have shown neurodegeneration and apoptosis after isoflurane exposure in rats. Cheng et al. studied two groups of 7-day-old rats comparing mitochondrial responses in retinal cells. One of the groups was exposed for 1 h to air (control group), and the second group was exposed for 1 h to isoflurane 2% inhalation (interventional group) in 8–12 L of fresh gas flow mixture. Caspase 3 activation is the final stage after intrinsic and extrinsic apoptotic cascade initiation. Isoflurane is capable of acting on caspase 3 and initializing final apoptotic cascade throughout several mechanisms such as inactivation of proteins with antiapoptotic activity (BCL-xL and BCL-2), increase of the mitochondrial membrane permeability, and activation of caspases 8 and 9. Retinal cells seem to be a good starting point to assess the potentially deleterious effects of some anesthetics on the CNS as they may be directly observed using noninvasive techniques. Additionally, the effect of inhaled anesthetics in the progression of neurodegenerative disorders in humans is supported by studies done in animal models experiencing an increase in proinflammatory cytokines levels, such as tumor necrosis factor-α (TNF-α), after isoflurane exposure.
Wang et al. reported that sevoflurane administration for a 6-h period in 7-day-old rats causes a significant impairment in astrocytes functioning. An important reduction in GLAST (glutamate-aspartate transporter) and JAK/STAT (Janus kinase/signal transducer and activator of transcription) activity was noticed after sevoflurane administration and considered to be associated with impaired astrocytic proliferation. Neuronal cells exposure to sevoflurane triggered endoplasmic reticulum dysfunction and dysregulation of intracellular Ca 2+ homeostasis.
Schallner et al. studied the effects of sevoflurane, isoflurane, and desflurane in neuronal cells after induced hypoxia. Activation of a protein linked to cellular stress response (NF-κB) with concomitant inactivation of p75 NTR , was seen under isoflurane exposure but not after the use of sevoflurane or desflurane. In other words, isoflurane is associated with the progression of neuronal death under hypoxic conditions. This mechanism was not associated with sevoflurane or desflurane during in vitro and in vivo studies, promoting the use of these agents in patients with a history of stroke and cardiovascular interventions.
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