84. Evaluation of acute bis(7)-tacrine treatment on
behavioral functions in 17-day-old and 30-day-old mice, with attention to drug
toxicity
S.Y. Pana,
, Z.L. Yub, , H. Donga,
N.T.K. Leec,
H. Wangb,
W.F. Fongb,
Y.F. Hanc
and K.M. Koc
aDepartment of
Pharmacology, Beijing University of Chinese Medicine, Beijing 100029, China bSchool of Chinese Medicine, Hong Kong Baptist
University, Kowloon Tong, Hong Kong, China cDepartment
of Biochemistry, The Hong Kong University of Science and Technology, Clear
Water Bay, Hong Kong, China
Bis(7)-tacrine was evaluated for efficacy on memory
retention in mice 17 days of age and 30 days of age. The tests used
were a passive-avoidance response test and a measure of spontaneous motor
activity. Also, possible drug-induced hepatotoxicity and acute drug toxicity
were evaluated. Behavioral studies were performed using a step-through task and
an open-field test with a 24-h interval between training and evaluation tests. Bis(7)-tacrine (0.06−20 μmol/kg) was subcutaneously
injected 30 min prior to the first session of both test types. During the
training session of the step-through task, bis(7)-tacrine treatment reduced (by
46%, P < 0.01) the number of avoidable electric shocks
(footshocks) only at a high dose of 20 μmol/kg in mice 17 days of
age, but dose-dependently decreased the number of footshocks (10–56%, P < 0.001)
in mice 30 days of age. Bis(7)-tacrine treatment at all doses tested did
not produce any detectable changes in retention latency in mice 17 days of
age, but the drug significantly prolonged retention latency at low doses (1.25
and 2.50 μmol/kg), and not high doses (5–20 μmol/kg), in mice
30 days of age. In the open-field test, bis(7)-tacrine decreased
spontaneous motor activity in the acquisition session only at a high dose of
20 μmol/kg in mice 17 days of age and 30 days of age (by 28 and
45%, respectively), but did not affect spontaneous motor activity in the recall
session. Bis(7)-tacrine treatment at a dose of 20 μmol/kg produced a more
potent hepatotoxic effect in mice 30 days of age than in mice 17 days
of age, (P < 0.05), and the drug caused acute toxicity with
comparable potencies in mice of both age groups. In conclusion, mice
30 days of age seemed to be more sensitive than mice 17 days of age
to bis(7)-tacrine-induced cognitive function
enhancement and hepatotoxicity. Bis(7)-tacrine appears
to be more potent and more selective as a cognitive function-enhancing agent
than tacrine.
Keywords: Bis(7)-tacrine;
Passive-avoidance response; Open-field memory; Spontaneous motor activity;
Hepatotoxicity; Acute toxicity