Chemistry Reference
In-Depth Information
TABLE 4-3. Anti-ChE Activities of Oral HA, Donepezil, and Tacrine in Rats
Dose mg/kg
AChE Inhibition (%)
ð
n
¼
6
Þ
BuChE Inhibition (%)
ChEI
(mmol/kg)
Cortex
Hippocampus
Striatum
Serum
ð
n
¼
3
Þ
20
6
a
17
3
a
18
4
a
HA
0.36 (1.5)
18
10
16
6
a
15
3
a
16
8
a
0.24 (1.0)
16
14
10
6
a
13
10
b
0.12 (0.5)
8
7
7
12
18
6
a
12
5
a
12
8
b
33
7
a
Donepezil
6.66 (16)
11
6
a
10
4
a
10
6
b
22
1
a
5.00 (12)
3.33 (8)
9
11
6
8
8
6
8
10
20
6
a
11
10
b
11
10
b
52
5
a
Tacrine
28.2 (120)
8
6
a
8
41
a
40
20
b
21.1 (90)
9
6
14.1 (60)
7
7
2
2
2
5
24
17
a
P
<
0
:
01:
b
P
<
0
:
05 vs. saline group. Values expressed as percent inhibition (vs. saline control)
standard deviation. Data from Ref. 5.
AChE activity and serum BuChE.
42
The inhibitory action of HA on brain AChE was
less than that of donepezil after the intraventricular injection but more effective than
that of tacrine.
39
Maximal AChE inhibition in rat cortex and whole brain was reached
at 30-60 min and maintained for 360 min after oral administration of 0.36 mg/kg
HA.
40-42
The oral administration of HA produced greater AChE inhibition com-
pared with donepezil and tacrine, which indicated that it has greater bioavailability
and more easily penetrates the blood-brain barrier (Table 4-3). Repeated doses of HA
showed no significant decline in AChE inhibition as compared with that of a single
dose, which demonstrates that no tolerance to HA occurred.
43
4.4.2
Effects on Learning and Memory
HA has been found to be an effective cognition enhancer in a broad range of animal
cognitive models by Tang et al.
35,41,44-55
and in clinical trials (see Section 4.4.3).
56
The effects of HA on nucleus basalis magnocellularis lesion-induced spatial work-
ing memory impairment were tested by means of a delayed-nonmatch-to-sample
radial arm maze task. Unilateral nucleus basalis magnocellularis lesion by kainic
acid impaired the rat's ability to perform this task. This working memory impair-
ment could be ameliorated by HA.
52
HA ameliorates the impaired memory natu-
rally occurring or induced by scopolamine in aged rats. The Morris water maze
was used to investigate the effects of HA on acquisition and memory impairments.
During 7-day acquisition trials, aged rats took longer latency to find the platform.
HA at a dosage of 0.1-0.4 mg/kg subcutaneously (s.c.) could significantly reduce
the latency or reverse the memory deficits induced by scopolamine.
54
The effects of HA on the disruption of spatial memory induced by the muscarinic
antagonist scopolamine and (g-amino-n-butyric acid (GABA)) against muscimol in
the passive avoidance task was tested in chicks. The avoidance rate was evaluated
as memory retention. Both scopolamine (100 ng) and muscimol (50 ng), injected
intracranially 5 minutes before training, resulted in a decreased avoidance rate. HA
(25 ng), injected intracranially 15 minutes before training, reversed memory deficits
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