Neonatal anesthetic neurotoxicity: Insight into the molecular mechanisms of long-term neurocognitive deficits

Abstract

Mounting animal studies have demonstrated that almost all the clinically used general anesthetics could induce widespread neuroapoptosis in the immature brain. Alarmingly, some published findings have reported long-term neurocognitive deficits in response to early anesthesia exposure which deeply stresses the potential seriousness of developmental anesthetic neurotoxicity. However, the connection between anesthesia induced neuroapoptosis and subsequent neurocognitive deficits remains controversial. It should be noted that developmental anesthesia related neurotoxicity is not limited to neuroapoptosis. Early anesthesia exposure caused transient suppression of neurogenesis, ultrastructural abnormalities in synapse and alteration in the development of neuronal networks also could contribute to the long-term neurocognitive dysfunction. Understanding the mechanisms of developmental anesthetic neurotoxicity, especially by which anesthesia impairs brain function months after exposure, may lead to development of rational preventive and therapeutic strategies. The focus of present review is on some of those potential mechanisms that have been proposed for anesthesia induced cognitive decline.

Introduction

Advances in pediatric medicine have required widespread and prolonged administration of anesthesia to millions and thousands of neonates, infants and children for surgery and diagnostic procedure in operating rooms and intensive care units every year. Conventionally, anesthesia effects are thought to be fully reversible after anesthetic drugs are washed out from our human body. Even general anesthetics are assumed to have neuroprotection effects against to ischemia-reperfusion injury on central nervous system (CNS). However, overwhelming animal data have suggested that various general anesthetics could cause extensive neuroapoptosis and long-term neurocognitive deficits in the immature brain [1], [2], [3], [4]. These preclinical data raised considerable concerns about whether potential risk exists in humans and prompted researchers to search for clinical evidence [5]. But the uncertainty of the relationship between neuroapoptosis and subsequent neurocognitive abnormalities add more obstacles on our way to extrapolate laboratory findings to clinical anesthesia [6]. The conventional concept is that anesthesia-induced neuroapoptosis is the direct cause of neurocognitive decline, but more and more researches have indicated that neuroapoptosis by itself is not sufficient to cause neurocognitive dysfunction [7]. It is now conceivable that neurocognitive outcome after neonatal anesthesia exposure is attributed to more mechanisms other than brain cell death [8]. To develop prevention strategies requires a clear understanding of the mechanisms of anesthesia induced neurocognitive abnormalities. The goal of the review is to provide a concise summary of proposed mechanisms for anesthesia induced cognitive decline (Table 1).