Nimodipine prevents transient cognitive dysfunction after moderate hypoxia in adult mice.
BACKGROUND
Cognitive changes associated with moderate hypoxia may be related to the elevation of cytosolic calcium (Ca) levels which may, in turn, affect neurotransmitter synthesis and metabolism. We tested whether treatment with nimodipine (NIMO), an L-type Ca channel blocker, would preserve working memory after hypoxic hypoxia.


METHODS
We randomized 157 Swiss-Webster, 30 to 35 g mice (6 to 8 wk) to 6 groups, which were exposed to the following gas mixtures for 1 hour: (1) O2 21%; (2) O2 21% followed by 0.1 mg/kg of subcutaneous NIMO; (3) O2 21% followed by vehicle (60% polyethylene glycol/40% methanol); (4) O2 10%; (5) O2 10% then NIMO; (6) O2 10% then vehicle. The Object Recognition Test (ORT) was given once either on Day 1 or Day 7 to assess changes in short-term memory. ORT exploits the tendency of mice to prefer novel over familiar objects. Two identical objects were placed in an arena for 15 minutes of training. During the testing 1 hour later, one of the objects was replaced by a new object. Recognition Index (RI) was used to compare performance. It is defined as the time spent exploring the novel object divided by the time spent exploring both objects, the novel plus the familiar, and this ratio is converted to a percentage. RI was analyzed with analysis of variance. Tukey Honestly Significant Difference tests were used for post hoc comparisons when appropriate. P values <0.05 were considered significant.


RESULTS
RI for the control group was 68.3% (SE+/-3.6%). RI was 53.7% (SE+/-3.8%) for the 10% O2 group on the first posttreatment day. O2 saturation (SpO2) for the hypoxic group was 71.7% (SE+/-0.5%). By Day 7, RI for the 10% O2 group increased to 64.2% (SE+/-4.7%), which was not significantly different from control. On Day 1, RI was 68.6% (SE+/-5.2%) for hypoxic rodents treated with NIMO. These results were statistically significant. Low RI indicates impaired working memory and high RI indicates intact working memory. These results suggest that NIMO prevented impairment of working memory after moderate hypoxia.


CONCLUSIONS
NIMO reverses the disturbance of short-term working memory caused by moderate hypoxia in mice. The results may have implications for cognitive changes linked to Ca homeostasis in the postoperative period.
Haile
Michael
M
Department of Anesthesiology, New York University, New York, NY 10016, USA.
Limson
Fred
F
Gingrich
Kevin
K
Li
Yong-Sheng
YS
Quartermain
David
D
Blanck
Thomas
T
Bekker
Alex
A
D000818:Animals; D001288:Attention / Q000187:drug effects; D001784:Blood Gas Analysis; D002121:Calcium Channel Blockers / Q000627:therapeutic use*; D020746:Calcium Channels, L-Type / Q000187:drug effects; D003072:Cognition Disorders / Q000209:etiology* / Q000517:prevention & control* / Q000523:psychology; D002534:Hypoxia, Brain / Q000150:complications* / Q000523:psychology; D008297:Male; D008568:Memory / Q000187:drug effects; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009553:Nimodipine / Q000627:therapeutic use*; D010101:Oxygen Consumption / Q000187:drug effects; D021641:Recognition, Psychology / Q000187:drug effects
D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D009553:Nimodipine