Neuroprotection and neurotoxicity in the developing brain: an update on the effects of dexmedetomidine and xenon

Abstract

Growing and consistent preclinical evidence, combined with early clinical epidemiological observations, suggest potentially neurotoxic effects of commonly used anesthetic agents in the developing brain. This has prompted the FDA to issue a safety warning for all sedatives and anesthetics approved for use in children under three years of age. Recent studies have identified dexmedetomidine, the potent α2-adrenoceptor agonist, and xenon, the noble gas, as effective anesthetic adjuvants that are both less neurotoxic to the developing brain, and also possess neuroprotective properties in neonatal and other settings of acute ongoing neurologic injury. Dexmedetomidine and xenon are effective anesthetic adjuvants that appear to be less neurotoxic than other existing agents and have the potential to be neuroprotective in the neonatal and pediatric settings. Although results from recent clinical trials and case reports have indicated the neuroprotective potential of xenon and dexmedetomidine, additional randomized clinical trials corroborating these studies are necessary. By reviewing both the existing preclinical and clinical evidence on the neuroprotective effects of dexmedetomidine and xenon, we hope to provide insight into the potential clinical efficacy of these agents in the management of pediatric surgical patients.

Keywords: Anesthesia; Dexmedetomidine; Neuroprotection; Neurotoxicity; Pediatric; Xenon.

Figure 1.. The mechanism of action of dexmedetomidine.

Dexmedetomidine is an agonist of the α−2 adrenoceptor, a transmembrane G-protein coupled receptor. Activation of the α−2 adrenoceptor inhibits adenylyl cyclase, which causes an intracellular decrease of cAMP. This leads to a series of cellular events and many systemic effects, as listed above. Agonism of the α−2 adrenoceptor also causes an activation of the inwardly rectifying potassium channel, leading to an efflux of K+ and inhibition of voltage-gated Ca²⁺ channels. This causes membrane hyperpolarization, such as hyperpolarization of the neuronal membrane in the locus coeruleus (LC), which suppresses neuronal firing and ascending noradrenergic activity. Dexmedetomidine also binds to the “I” receptor, which may also be responsible for some of the actions listed above. ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; GTP, guanosine triphosphate; I receptor, imidazoline receptor.

Figure 2.. The mechanism of action of xenon.

The NMDA receptor is a heterotetramer receptor which consists of two NR1 and two NR2 subunits. The NR1 subunit has a binding site for glycine and NR2 has one for glutamate and Zn²⁺. Both glutamate and glycine are needed for NMDA receptor activation. It has been demonstrated that xenon can inhibit the NMDA receptor by competing with glycine at its binding site. Inhibition of the NMDA receptor prevents the influx of Ca²⁺ and Na⁺, causing different anesthetic actions. Xenon can also activate TREK-1, TASK-3 and KATP channels. Activation of these channels allows the efflux of K⁺, conferring neuroprotection. It is also noted that KATP channels can be gated by ATP, ADP and nucleotides. Xenon also upregulates the PI3K-Akt-mTOP and the MARK pathways, although the precise mechanism is not completely understood. The upregulation of these pathways increases the efficiency of the action of HIF-1α, as well as production of its downstream effectors, VEGF and erythropoietin, which are believed to play a role in neuroprotection in ischemic brain injury. ADP, adenosine diphosphate; Akt, AKT serine/threonine kinase 1; ATP, adenosine triphosphate; ERK, extracellular signal regulated kinase; HIF-1α, hypoxia inducible factor-1α; MAPK, mitogen-activated protein kinase; MEK, mitogen-activated protein kinase/extracellular signal regulated kinase; MNK, mitogen-activated protein kinase interacting serine threonine kinase; mTOR, Mammalian target of rapamycin; NMDA, N-methyl-D-aspartate; PI3K, phosphatidylinositol-3-kinase; TASK-3, potassium two pore domain channel subfamily K member 9; TREK-1, potassium two pore domain channel subfamily K member 2; VEGF, vascular endothelial growth factor.