Objective Anesthetics have been linked to widespread neuronal cell death in neonatal animals. Epidemiological human studies have associated early childhood anesthesia with long-term neurobehavioral abnormalities, raising substantial concerns that anesthetics may cause similar cell death in young children. However, key aspects of the phenomenon remain unclear, such as why certain neurons die, whereas immediately adjacent neurons are seemingly unaffected, and why the immature brain is exquisitely vulnerable, whereas the mature brain seems resistant. Elucidating these questions is critical for assessing the phenomenon’s applicability to humans, defining the susceptible age, predicting vulnerable neuronal populations, and devising mitigating strategies. Methods This study examines the effects of anesthetic exposure on late- and adult-generated neurons in newborn, juvenile, and adult mice, and characterizes vulnerable cells using birth-dating and immunohistochemical techniques. Results We identify a critical period of cellular developmental during which neurons are susceptible to anesthesia-induced apoptosis. Importantly, we demonstrate that anesthetic neurotoxicity can extend into adulthood in brain regions with ongoing neurogenesis, such as dentate gyrus and olfactory bulb. Interpretation Our findings suggest that anesthetic vulnerability reflects the age of the neuron, not the age of the organism, and therefore may potentially not only be relevant to children but also to adults undergoing anesthesia. This observation further predicts differential heightened regional vulnerability to anesthetic neuroapoptosis to closely follow the distinct regional peaks in neurogenesis. This knowledge may help guide neurocognitive testing of specific neurological domains in humans following exposure to anesthesia, dependent on the individual’s age during exposure.

Phenylketonuria is caused by specific mutations in the phenylalanine hydroxylase gene and is characterized by elevated blood phenylalanine levels, hypomyelination in forebrain structures, reduced dopamine levels, and cognitive difficulties. To determine whether brain tyrosine levels and/or myelination play a role in the up-regulation of dopamine, phenylketonuric mice were placed on a low phenylalanine diet for 4 weeks and as blood phenylalanine levels dropped to normal, the relationships between phenylalanine, tyrosine, dopamine, myelin proteins, and axonal proteins in frontal cortex and striatum were determined using gas chromatography mass spectrometry, histology, and western blotting techniques. Blood phenylalanine rapidly decreased from an eight-fold elevation to near control levels, and blood tyrosine gradually rose from about 50% to near normal values. In frontal cortex and striatum, phenylalanine levels dropped to 2-and 1.5-fold elevations above control, respectively, and tyrosine levels increased but remained less than 70% of control in both structures. In frontal cortex, increases in dopamine and myelin basic protein occurred in a similar biphasic pattern, reaching near normal levels by week 4. In striatum, dopamine and MBP dramatically increased to near normal levels in the first week. Myelination was confirmed histologically and by western blot quantification of phosphorylated neurofilaments. In summary, our results showed: (i) an increase in dopamine despite low brain tyrosine levels and (ii) similar recovery patterns for myelination and dopamine. Since myelin/axonal interactions trigger signaling pathways that result in axonal maturation, we speculate that this interaction also may trigger signals that up-regulate neurotransmitter synthesis. Keywords: axon, blood-brain barrier, dopamine, myelin, phenylketonuria, tyrosine. In the CNS, oligodendrocytes extend numerous processes, and from the distal tip of each process, a membrane sheet is assembled and wrapped around a segment of axon as an internode of myelin. Myelin is a highly metabolically active membrane that, under normal conditions, remains connected to and is supported by the oligodendrocyte cell body for the life span of the oligodendrocyte. Myelin is essential for the rapid conduction of action potentials and, therefore, there may be devastating consequences if oligodendrocytes fail to produce myelin (hypomyelination) or lose their myelin (demyelination) as a consequence of disease.One disease in which hypomyelination occurs in specific forebrain tracts, but neurons and their axons are spared, is the autosomal recessive disorder phenylketonuria (PKU) (Malamud 1966;Dyer et al. 1996). PKU is caused by a rise in blood phenylalanine (Phe) levels, due to a deficiency in the enzyme phenylalanine hydroxylase (PAH) (Jervis 1953). PAH is expressed primarily in liver and not in brain, and catalyzes the conversion of Phe to tyrosine (Hsieh and Berry 1979). Blood Phe levels normally are about 121 lM; however, in untreated individuals (and mice) ...

The present study confirms the findings of previous studies showing peak vulnerability to anaesthesia-induced neuronal cell death in the newborn forebrain. It also shows sustained susceptibility into adulthood in areas of continued neurogenesis, substantially expanding the previously observed age of vulnerability. The differential windows of vulnerability among brain regions, which closely follow regional peaks in neurogenesis, may explain the heightened vulnerability of the developing brain because of its increased number of immature neurones.

We confirm previous findings of sevoflurane-induced neuronal injury. Dexmedetomidine, even in the highest dose, did not cause similar injury, but provided lesser degrees of anaesthesia and pain control. No mitigation of sevoflurane-induced injury was observed with dexmedetomidine supplementation, suggesting that future studies should focus on anaesthetic-sparing effects of dexmedetomidine, rather than injury-preventing effects.

Volatile agent preconditioning partially protects perirhinal cortex and striatal dependent functions against moderate to severe neonatal hypoxia-ischemia.