Dexmedetomidine attenuates isoflurane-induced neurocognitive impairment in neonatal rats.
BACKGROUND
Neuroapoptosis is induced by the administration of anesthetic agents to the young. As alpha2 adrenoceptor signaling plays a trophic role during development and is neuroprotective in several settings of neuronal injury, the authors investigated whether dexmedetomidine could provide functional protection against isoflurane-induced injury.


METHODS
Isoflurane-induced injury was provoked in organotypic hippocampal slice cultures in vitro or in vivo in postnatal day 7 rats by a 6-h exposure to 0.75% isoflurane with or without dexmedetomidine. In vivo, the alpha2 adrenoceptor antagonist atipamezole was used to identify if dexmedetomidine neuroprotection involved alpha2 adrenoceptor activation. The gamma-amino-butyric-acid type A antagonist, gabazine, was also added to the organotypic hippocampal slice cultures in the presence of isoflurane. Apoptosis was assessed using cleaved caspase-3 immunohistochemistry. Cognitive function was assessed in vivo on postnatal day 40 using fear conditioning.


RESULTS
In vivo dexmedetomidine dose-dependently prevented isoflurane-induced injury in the hippocampus, thalamus, and cortex; this neuroprotection was attenuated by treatment with atipamezole. Although anesthetic treatment did not affect the acquisition of short-term memory, isoflurane did induce long-term memory impairment. This neurocognitive deficit was prevented by administration of dexmedetomidine, which also inhibited isoflurane-induced caspase-3 expression in organotypic hippocampal slice cultures in vitro; however, gabazine did not modify this neuroapoptosis.


CONCLUSIONS
Dexmedetomidine attenuates isoflurane-induced injury in the developing brain, providing neurocognitive protection. Isoflurane-induced injury in vitro appears to be independent of activation of the gamma-amino-butyric-acid type A receptor. If isoflurane-induced neuroapoptosis proves to be a clinical problem, administration of dexmedetomidine may be an important adjunct to prevent isoflurane-induced neurotoxicity.
Sanders
Robert D
RD
Department of Anaesthetics, Pain Medicine and Intensive Care, Imperial College London, London, UK.
Xu
Jing
J
Shu
Yi
Y
Januszewski
Adam
A
Halder
Sunil
S
Fidalgo
Antonio
A
Sun
Pamela
P
Hossain
Mahmuda
M
Ma
Daqing
D
Maze
Mervyn
M
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D003072:Cognition Disorders / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control*; D020927:Dexmedetomidine / Q000494:pharmacology / Q000627:therapeutic use*; D007530:Isoflurane / Q000009:adverse effects* / Q000037:antagonists & inhibitors; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D017207:Rats, Sprague-Dawley
D020927:Dexmedetomidine; D007530:Isoflurane