Histamine H3 Receptor Antagonist Prevents Memory Deficits and Synaptic Plasticity Disruption Following Isoflurane Exposure.
BACKGROUND
Exposure to pharmacological concentration of inhaled anesthetics such as isoflurane can cause short- or long-term cognitive impairments in preclinical studies. The selective antagonists of the histamine H3 receptors are considered as a promising group of novel therapeutic agents for the treatment of cognitive disorders. In this study, we investigated whether ciproxifan, a nonimidazole antagonist of H3 histamine receptors, could overcome the functional and electrophysiological sequela associated with isoflurane anesthesia.


METHODS
Adult male Sprague Dawley rats were exposed to 1.4% isoflurane or vehicle gas for 2 h. The memory tests (novel object recognition and passive avoidance) as well as in vivo hippocampal excitatory synaptic potentials were recorded 24 h postanesthesia. Locomotor activity, anxiety, and nociception 24 h after isoflurane were also examined. The drugs (ciproxifan 3 mg/kg or saline) were intraperitoneally injected 30 min prior to the behavioral tests or long-term potentiation induction.


RESULTS
Animals that were previously (24 h) exposed to 1.4% isoflurane for 2 h displayed no preference for novel objects and had impaired retention of a passive avoidance response at 1 h after sample phase. Treating isoflurane-exposed rats with ciproxifan significantly improved the memory performance, as evidenced by an increased discrimination ratio in objects recognition and prolonged retention time in passive avoidance test. Accordingly, hippocampus long-term potentiation was reduced in animals that received isoflurane, while administration of ciproxifan completely abolished the effect of isoflurane exposure on synaptic plasticity. Neither isoflurane nor ciproxifan altered motor performance, anxiety, and nociceptive responses.


CONCLUSIONS
These results suggest that H3R in the CNS, probably in the hippocampus, may serve as therapeutic target for improvement of anesthesia-associated cognitive deficits.
Department of Anesthesiology, Peking University Shenzhen Hospital, Shenzhen, China.
Tao
http://orcid.org/0000-0002-5592-8899
T
Luo
Materials Characterization and Preparation Center, Southern University of Science and Technology, Shenzhen, China.
Ying
Y
Wang
Central Laboratory, Wuhan University Renmin Hospital, Wuhan, China.
Jian
J
Qin
Department of Anesthesiology, Wuhan University Renmin Hospital, Wuhan, China.
Zhi-Gang
ZG
Liu
Central Laboratory, Wuhan University Renmin Hospital, Wuhan, China.
Min
M
Liu
D018685:Anesthetics, Inhalation / Q000633:toxicity; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D004195:Disease Models, Animal; D006624:Hippocampus / Q000166:cytology* / Q000187:drug effects; D006633:Histamine Antagonists / Q000494:pharmacology* / Q000627:therapeutic use*; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D007530:Isoflurane / Q000633:toxicity; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000139:chemically induced / Q000517:prevention & control*; D009473:Neuronal Plasticity / Q000187:drug effects*; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018100:Receptors, Histamine H3 / Q000378:metabolism*; D021641:Recognition, Psychology / Q000187:drug effects; D018709:Statistics, Nonparametric
D018685:Anesthetics, Inhalation; D006633:Histamine Antagonists; D007093:Imidazoles; D018100:Receptors, Histamine H3; C115705:ciproxifan; D007530:Isoflurane
Ciproxifan; Hippocampus; Isoflurane; Memory; Synaptic plasticity