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.

Intravenous Anesthetics

Komuro and Rakic also studied the role of the NMDA receptor and its blockade during neurological cells development. A significant disruption in cell migration was noticed using NMDA receptor antagonists (MK-801 and D-AP5), but not γ-aminobutyric acid (GABA) receptors antagonists. Cellular migration is a major stage necessary for CNS formation and functionality. These findings may explain how ketamine triggers some neurotoxic mechanisms associated with its use.

Upregulation of NMDA receptor with a consequent increase in receptor expression and activity is a well-described neuronal mechanism occurring after its exposure to several antagonists. Ketamine is responsible for an overstimulation of NMDA receptors through their natural ligand (glutamate), explaining other mechanisms related to subsequent activation of the proapoptotic cascade with a greater influx of sodium, calcium, and chloride into the cytosol.

Anesthesia-related neurodegeneration in rats is characterized by an accelerated rate of cellular genesis commonly found during developmental phases. However, with respect to clinical studies several variables might interfere. Therefore, it is important to differentiate and identify important factors involving basic research (drug-related information such as dose and length of exposure, vitals monitoring, oxygenation, and others) and general anesthesia in children undergoing surgery.

This “controlled setting” characterizing clinical research may explain some of the remaining controversies between research findings in animal models and clinical outcomes in humans. Slikker et al. compared the response of rhesus monkeys to anesthetic doses of ketamine with a control group, monitoring hemodynamics, and other physiological variables (oxygen saturation, capnography, noninvasive blood pressure, and temperature). Even under “physiological conditions,” caspase 3 expression in cortical neurons was found to be significantly increased in ketamine group, indicating stimulation of the apoptotic cascade.

Comparable in vitro results were published by Bai et al. who found that ketamine induced caspase 3 activation and increased reactive oxygen species (ROS) in human stem cells. However, cell death and degeneration also depend on some other factors such as age, dose, and duration of exposure. Even during a single exposure to ketamine, anesthetic concentrations achieved in critical periods of brain cell development may be responsible for long-term cognitive impairment.

Propofol is a well-known anesthetic drug used in pediatrics either for sedation or general anesthesia. Similar to ketamine, in vitro animal model studies using different propofol concentrations, comparable with in vivo plasmatic values reached during general anesthesia, reported unfavorable reactions of immature neuronal tissue. In fact, increased influx of calcium and chloride, mediated by GABA _A receptor activation, may stimulate proapoptotic pathways leading to programmed cell death in immature neuronal cells.

A comparable mechanism for neuronal degeneration and apoptosis in animal models has also been described with benzodiazepines use. Diazepam used at 10 mg/kg was associated with neuronal cell damage in rats during early stages of brain development. These proapoptotic reactions were not triggered when diazepam was antagonized by flumazenil administration. Additionally, cortical neurons and the caudate/putamen nuclei seem to be the most affected after midazolam use, a short-acting benzodiazepine, with greater apoptotic effects obtained during concomitant ketamine administration. The combination of these two anesthetic drugs is common in pediatric anesthesia.

Opioids have also been associated with neurotoxicity and brain cell dysfunction. Fentanyl , remifentanil , sufentanil , and other μ-agonists have been associated with brain cells damage with consequent seizure activity in animal models.

Inhaled Anesthetics

There is no consensus regarding the preference of inhaled anesthetic use during neurosurgery, although particular effects have been described for all of them. Sevoflurane has shown the ability to maintain cerebral coupling in a better way than isoflurane at anesthetic doses without significantly increasing ICP. Reduction in CBF as a result of reduced metabolism (coupling mechanism) has been reported with low doses of sevoflurane, isoflurane, and halothane . However, specific reactions may occur simultaneously within anterior and posterior cerebral circulation depending on the type of inhaled anesthetic used.

Neurological cell impairment has been described as a result of the activation of NMDA receptors. Partial inhibition of these receptors during inhalational anesthesia is linked to the neuroprotective effect conferred by isoflurane, sevoflurane, and desflurane . In vitro, isoflurane is responsible for a greater percentage of NMDA receptor inhibition when compared to other halogenated anesthetics, in preference to sevoflurane and desflurane. Moreover, studies conducted in animal models and using inhalational anesthesia with sevoflurane and isoflurane reported enhanced mitochondrial activity by decreasing the activation of crucial proapoptotic mechanisms and preconditioning to cerebral ischemia.

Intravenous Anesthetics

Systemic pathophysiological responses including exacerbation of sympathomimetic reactions and generation of ROS are triggered by the ischemia/reperfusion phenomenon in neurological cells. ROS generated during hypoxic stages will cause peroxidation of cells’ membranes during reperfusion. Malondialdehyde (MDA) is one of the metabolic markers used to quantify the intensity of these events. Propofol seems to have a significant neuroprotective role by preventing peroxidation of the membranes, its antioxidant effect being described in ischemic animal models. Propofol administration is responsible for regulation of proapoptotic and antiapoptotic genes, decreased caspase 3 activity, and regulation of other proteins such as p53 involved in programmed death of cells.

Ischemic insult in neurological cells is associated with downregulation of GABA receptors. In vitro studies have shown that stimulation of GABA receptors may be linked to cellular death. However, diazepam exerts a positive allosteric effect on GABA receptors enhancing the affinity for its ligand, and providing a neuroprotective effect in vivo by attenuating cells death. This attenuation has been explained as a result of increased local blood flow in the penumbra areas or decreased nitric oxide (NO) synthesis.

Dexmedetomidine , a well-known α ₂ agonist, has the ability to mitigate sympathomimetic effects by mediating the norepinephrine and dopaminergic effects on hippocampal cells avoiding neuronal cell death after sustainable ischemia. Moreover, inflammatory markers, ROS, and their consequent deleterious effects during ischemia-reperfusion phenomena have been found to be reduced in hippocampal and dentate gyrus cells after dexmedetomidine administration. Eser et al. reported the effects of dexmedetomidine on ischemia/reperfusion animal models by describing significant differences in levels of TNF-α, NO, MDA, and apoptotic neuronal cells with concomitant increased activity in superoxide dismutase and catalase. Moreover, an increased activation of antiapoptotic pathways involving the modulation of Bcl-2 proteins activity has also been reported in ischemia/reperfusion models after dexmedetomidine exposure. Li et al. reported an increase of 217% in caspase 3 activity in fetal rats whose mothers were exposed to propofol during pregnancy. This proapoptotic response was significantly attenuated when dexmedetomidine was used and explained by a decrease of microglial stimulation.