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AMPAkines protect young brains
Numerous studies have suggested that exposure to anesthesia in early childhood adversely affects subsequent brain development, but the use of neonatal anesthesia can be unavoidable, for example, in situations where urgent surgery is needed. By studying neonatal mice, Huang et al. demonstrated impaired neuronal activity resulting from early exposure to ketamine anesthesia. The authors then treated the mice with AMPAkines, a class of drugs that can potentiate synaptic transmission of neuronal impulses. Treatment with AMPAkines shortly after exposure to anesthesia not only restored the animals’ neuronal activity but also prevented subsequent learning deficits even after repeated episodes of anesthesia exposure. Although this study was performed entirely in mice, the promising results suggest that AMPAkines may be worth evaluating as neuroprotective agents for human patients exposed to anesthesia as well.
Accumulating evidence has shown that repeated exposure to general anesthesia during critical stages of brain development results in long-lasting behavioral deficits later in life. To date, there has been no effective treatment to mitigate the neurotoxic effects of anesthesia on brain development. By performing calcium imaging in the mouse motor cortex, we show that ketamine anesthesia causes a marked and prolonged reduction in neuronal activity during the period of post-anesthesia recovery. Administration of the AMPAkine drug CX546 [1-(1,4-benzodioxan-6-ylcarbonyl)piperidine] to potentiate AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor activity during emergence from anesthesia in mice enhances neuronal activity and prevents long-term motor learning deficits induced by repeated neonatal anesthesia. In addition, we show that CX546 administration also ameliorates various synaptic deficits induced by anesthesia, including reductions in synaptic expression of NMDA (N-methyl-d-aspartate) and AMPA receptor subunits, motor training–evoked neuronal activity, and dendritic spine remodeling associated with motor learning. Together, our results indicate that pharmacologically enhancing neuronal activity during the post-anesthesia recovery period could effectively reduce the adverse effects of early-life anesthesia.
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