From Drug-Induced Developmental Neuroapoptosis to Pediatric Anesthetic Neurotoxicity—Where Are We Now?

Abstract

The fetal and neonatal periods are critical and sensitive periods for neurodevelopment, and involve rapid brain growth in addition to natural programmed cell death (i.e., apoptosis) and synaptic pruning. Apoptosis is an important process for neurodevelopment, preventing redundant, faulty, or unused neurons from cluttering the developing brain. However, animal studies have shown massive neuronal cell death by apoptosis can also be caused by exposure to several classes of drugs, namely gamma-aminobutyric acid (GABA) agonists and N-methyl-d-aspartate (NMDA) antagonists that are commonly used in pediatric anesthesia. This form of neurotoxic insult could cause a major disruption in brain development with the potential to permanently shape behavior and cognitive ability. Evidence does suggest that psychoactive drugs alter neurodevelopment and synaptic plasticity in the animal brain, which, in the human brain, may translate to permanent neurodevelopmental changes associated with long-term intellectual disability. This paper reviews the seminal animal research on drug-induced developmental apoptosis and the subsequent clinical studies that have been conducted thus far. In humans, there is growing evidence that suggests anesthetics have the potential to harm the developing brain, but the long-term outcome is not definitive and causality has not been determined. The consensus is that there is more work to be done using both animal models and human clinical studies.

Role of environmental stressors in determining the developmental outcome of neonatal anesthesia

“…Most retrospective epidemiological studies of patients, who had medical procedures requiring general anesthesia before 1–4 years of age, found significant subsequent neurocognitive deficiencies in late childhood or adolescence ( for review see Creeley, 2016). The possibility of anesthetic-induced developmental abnormalities is strongly supported by the results of numerous laboratory studies of healthy animals, though the full range of neonatal anesthesia-induced changes and underlying mechanisms remain poorly understood even in animal models ( for review see Walters and Paule, 2016).…”

Toxic Effects of Trichloroethylene on Rat Neuroprogenitor Cells

“…One of the important parameters studied in the present research is apoptosis (programmed cell death) which is a crucial process for neurodevelopment. It prevents redundant and unused neurons from disarrangement and cluttering of the developing brain ( Creeley and Basavarajappa, 2016 ). On the other hand, necrosis had been claimed to be an unregulated mode of cell death but recently the term “necroptosis” has been used to describe a programmed, caspase-independent cell death with necrotic morphology.…”

Neurotoxicity of Inhalation Anesthetics in the Neonatal Rat Brain: Effects on Behavior and Neurodegeneration in the Piriform Cortex

“…There is accumulating evidence that, during synaptogenesis, the brain is sensitive to toxicity from many environmental agents, potentially resulting in neurological injury manifesting as neuroapoptosis [ 1 ]. Of those prescribed drugs in common clinical use, concerns particularly abound in relation to anesthetic, sedative, and analgesic agents.…”