Studies on the Effect of Atractylodis rhizoma on Learning and Memory Ability in Senescence-accelerated Mice

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1 J Chin Med 14(4): , ( ) Atractylodes macrocephala Koidz. 2 7 SAMP p < % 1. % p < % % % senile dementia presenile dementia 3 cognition enhancing drug) 1997 Le Bars ext

2 Atractylodes macrocephala Koidz. SAMP8 Atractylodes macrocephala Koidz. g +95 % %.25 %.5 % 1. % senescence-accelerated mouse prone-8 SAMP delayed-discrimination learning SAM-P8 step down test SAM-P8 shuttle box test and lever press test water maze 12 SAM-P SAM-P SAM-P cm 25 ± 2 C 5 ± 5 % 7 19 light period 19 7 dark period 2 7 1

% senescence-accelerated mouse prone-8 SAMP8 7 8-15 299 1 delayed-discrimination learning

3 Table 1. Compositions of the experimental diets Ingredient g/kg diet Group Casein α- starch Sucrose Atractylodes macrocephala extracts Vitamin mixture Mineral mixture Cellulose Corn oil A = control B = Atractylodes macrocephala extract.25 % C = Atractylodes macrocephala extract.5 % D = Atractylodes macrocephala extract 1. % 1 Casein 92 % crude protein was purchased from Oriental Yeast Co. Tokyo, Japan 2 α- starch sucrose, 2 1 ratio 3 Obtained from Oriental Yeast Co. (Tokyo, Japan). The composition was as follows (g/kg): thiamin HCl, 12; riboflavin, 4; pyridoxine HCl, 8; vitamin B 12, 5; ascorbic acid, 3; D-biotin,.2; folic acid, 2; calcium pantothenate, 5; p-aminobenzoic acid, 5; niacin, ; inositol, ; choline chloride, 2; all-rac-α-tocopheryl acetate, 5; menadione, 52; retinyl acetate,.25; ergocalciferol, 1. 4 Obtained from Oriental Yeast Co. Tokyo, Japan. The composition was as follows (g/kg): CaHPO 4-2H 2 O, 14.5; KH 2 PO 4, 25.72; NaH 2 PO 4, 9.35; NaCl, 4.; Ca-lactate, 35.9; Fe-citrate, 3.19; MgSO 4, 7.17; ZnCO 3, % 1 % vitamin mixture 5 % mineral mixture 2 % cellulose powder 5 % corn oil.25 %.5 % 1. % casein 2 % casein.25 %.5 % 1. % locomotion single-trial passive avoidance test active shuttle avoidance test hippocampus ( ) Open field activity test cm activity monitor video path analyzer Coulbourn Instruments Model E1-21

25 % C = Atractylodes macrocephala extract.5 % D = Atractylodes macrocephala extract 1. % 1 Casein 92 % crude protein was purchased from Oriental Yeast Co.

4 2 7 SAMP light-dark cycle 19 7 hr locomotion sec/5 mins 5 1 ( ) Single-trial passive avoidance test 14 step-through type cm shuttle cage Coulbourn Instruments Model E cm guillotine door Coulbourn instruments Model E1-15GD 1 cm ma 1 shock

17 2 cm shuttle cage Coulbourn Instruments Model E1-15

5 ( ) Active shuttle avoidance test cm shuttle cage Coulbourn Instruments Model E cm 1 cm 1 intertrial interval 1 conditioned stimulus CS CS unconditioned ma UCS stimulus UCS escape response CS CS avoidance response 5 CS-UCS 2 ~ 25 CS UCS CS UCS ( ) Brain 1. hematoxylin H&E stain and eosin H&E stain routine staining Mayer % 2. Periodic acid schiff PAS PAS special staining.5 % schiff 1 3 2

7.5.5 cm 1 cm 1 intertrial interval 1 conditioned stimulus CS CS 1 5.3.

6 5 Mayer SPSS ± mean ± S.E.M. one-way analysis of variance ; one-way ANOVA p <.5 95 % g g 54.9 % 2 7 SAMP Body weight (g) 34 male Body weight (g) 3 female Age (month) Age (month) 7 Fig. 2. Comparisons of body weight change of 2 month-old SAMP8 mice

9 % 2 7 SAMP8 1 2 3 4 5 2 7 2 7 7 2 Body weight (g) 34 male 32 3 28 2 Body weight (g)

7 Body weight (g) male female group group A B 32 group group B C group group C D 3 Body weight (g) Age (month) Age (month) Fig. 3. Comparisons of body weight change of 7 month-old SAMP8 mice 12 g/day) 5 male (g/day) 5 female Food intake ( 4 Food intake Age (month) Age (month) Fig. 4. Comparisons of food intake of 2 month-old SAMP8 mice Food intake (g/day) 5 4 male Food intake (g/day) 5 4 female Age (month) Age (month) Fig. 5. Comparisons of food intake of 7 month-old SAMP8 mice

Comparisons of body weight change of 7 month-old SAMP8 mice 12 g/day) 5 male (g/day) 5 female Food intake ( 4 Food intake 4 3 2 3 4 5 7 Age (month) 3

8 Table 2. Comparisons of locomotion of 2 month-old SAMP8 mice after 1 weeks Male N Locomotor activity (counts/5 min) -5 min -1 min A 1 1 ± 5 94 ± 3 B 1 15 ± 4 94 ± 5 C 1 17 ± 3 95 ± 4 D 1 17 ± 9 ± 5 Female N Locomotor activity (counts/5 min) -5 min -1 min A 1 19 ± 5 94 ± 4 B ± 94 ± C ± 5 9 ± 5 D 1 11 ± 4 9 ± 4 Group A = Control Group B = Atractylodes macrocephala.25 % Group C = Atractylodes macrocephala.5 % Group D = Atractylodes macrocephala 1. % Table 3. Comparisons of locomotion of 7 month-old SAMP8 mice after 1 weeks Male N Locomotor activity (counts/5 min) -5 min -1 min A 1 94 ± 4 83 ± B 1 9 ± 7 84 ± 4 C 1 97 ± 4 85 ± 5 D 1 1 ± 5 8 ± 4 Female N Locomotor activity (counts/5 min) -5 min -1 min A 1 94 ± 81 ± 7 B 1 9 ± 85 ± 5 C 1 11 ± 4 8 ± D 1 12 ± 8 9 ± 7 A = Control B = Atractylodes macrocephala.25 % C = Atractylodes macrocephala.5 % D = Atractylodes macrocephala 1. % 2 7 SAMP

Locomotor activity (counts/5 min) -5 min -1 min A 1 19 ± 5 94 ± 4 B 1 113 ± 94 ± C 1 112 ± 5 9 ± 5 D 1 11 ± 4 9 ± 4 Group A = Control Group B = Atractylodes macrocephala.

9 SAMP8 Latency time (sec) trial 24hr 48hr 72hr 7day Fig.. Comparisons of latency time of 2 month-old male SAMP8 mice after 1 weeks by single-trial passive avoidance test Latency time(sec) Latency time (sec) Trial 24hr 48hr 72hr 7day Fig. 7. Comparisons of latency time of 2 month-old female SAMP8 mice after 1 weeks by single-trial passive avoidance test

passive avoidance test Latency time(sec) Latency time (sec) 5 4 3 2 1 Trial 24hr 48hr 72hr 7day

10 ( ) 2 SAMP Latency time(sec) (sec) Trial 24hr 48hr 72hr 7day Fig. 8. Comparisons of latency time of 7 month-old male SAMP8 mice after 1 weeks by single-trial passive avoidance test p <.5, as compared with the corresponding 5 4 Latency time (sec) Trial 24hr 48hr 72hr 7day Fig. 9. Comparisons of latency time of 7 month-old female SAMP8 mice after 1 weeks by single-trial passive avoidance test A = Control: B = Atractylodes macrocephala.25 % C = Atractylodes macrocephala.5 %: D = Atractylodes macrocephala 1. % p <.5, as compared with the corresponding

Comparisons of latency time of 7 month-old male SAMP8 mice after 1 weeks by single-trial passive avoidance test p <.

11 p <.5.5 % 1. % p < ( ) 2 SAMP Avoidance response (frequency) Avoidance response (frequency) D a y 1 D a y 2 D a y 3 D a y 4 Fig. 1. Comparisons of latency time of 2 month old male SAMP8 mice after 1 weeks by active shuttle avoidance test p <.5, as compared with the corresponding Avoidance response (frequency) Day 1 Day 2 Day 3 Day 4 Fig. 11. Comparisons of latency time of 2 month-old female SAMP8 mice after 1 weeks by active shuttle avoidance test

12 .5 %.5 % 1. % p <.5.25 %.5 % 1. % 2 7 SAMP Avoidance response (frequency) p ( q y) D a y 1 D a y 2 D a y 3 D a y 4 Fig. 12. Comparisons of latency time of 7 month-old male SAMP8 mice after 1 weeks by active shuttle avoidance test p <.5, as compared with the corresponding Avoidance response (frequency) D a y 1 D a y 2 D a y 3 D a y 4 g r o u p A g r o u p B g r o u p C g r o u p D Fig. 13. Comparisons of latency time of 7 month-old female SAMP8 mice after 1 weeks by active shuttle avoidance test A = Control: B = Atractylodes macrocephala.25 % C = Atractylodes macrocephala.5 %: D = Atractylodes macrocephala 1. % p <.5, as compared with the corresponding

Comparisons of latency time of 7 month-old female SAMP8 mice after 1 weeks by active shuttle avoidance test A = Control: B = Atractylodes macrocephala.

13 .5 % 1. % p <.5.5 % 1. % 2 7 SAMP8 ( ) SAMP8 Percentage of lipofuscin male Percentage of lipofuscin female Percentage of lipofuscin Fig. 14. Comparisons of percentage of lipofuscin of 2 month-old SAMP8 mice after 1 weeks p <.5, as compared with the corresponding Lipofuscin (%) = number of positive lipofuscin / number of total nerve cells 1 male 18 Percentage of lipofuscin female Fig. 15. Comparisons of percentage of lipofuscin of 7 month-old SAMP8 mice after 1 weeks C = Atractylodes macrocephala.5; D = Atractylodes macrocephala 1. % p <.5, as compared with the corresponding Lipofuscin (%) = number of positive lipofuscin / number of total nerve cell 1

5, as compared with the corresponding Lipofuscin (%) = number of positive lipofuscin / number of total nerve cells 1 male 18 Percentage of lipofuscin 18 15

14 % 1. % p < % 1. % p <.5.25 %.5 % 1. % p <.5 Percentage of brain spongiosis male Percentage of brain spongiosis female Fig. 1. Comparisons of spongy degeneration of 2 month-old SAMP8 mice after 1 weeks p <.5, as compared with the corresponding Assessment standard in 1X photomicroscopy: areas of brain spongiosis/areas of total file 1 Percentage of brain spongiosis Percentage of brain spongiosis male Percentage of brain spongiosis female.. Fig. 17. Comparisons of spongy degeneration of 7 month-old SAMP8 mice after 1 weeks p <.5, as compared with the corresponding Assessment standard in 1X photomicroscopy areas of brain spongiosis/areas of total file 1

spongiosis 3. 2. 5 2. 1. 5 1.. 5 male Percentage of brain spongiosis 3. 2. 5 2. 1. 5 1.. 5 female.. Fig. 17. Comparisons of spongy degeneration of 7 month-old SAMP8 mice after 1 weeks p <.

15 ( ) 2 7 SAMP % 1.% p <.5 1. % p < % 1. % p <.5 Kawamate 1 SAMP8 SAMP8.5 % 1. %.25 % NSC B Le Bars PL, Katz MM, Berman N, Itil TM, Freedman AM, Schatzberg AF, Brazin M, Ferguson J, Freedman AM, Jordan B. Mendels J, Schatzberg AF. A placebo-controlled, double-blind, randomized trial of an extract of Ginkgo biloba for dementia. J. Am. Med. Assoc. 278: ,

Le Bars PL, Katz MM, Berman N, Itil TM, Freedman AM, Schatzberg AF, Brazin M, Ferguson J, Freedman AM, Jordan

16 . 3 pp Takeda T, Hosokawa M, Takeshita S, Itino M, Higuchi K, Matsushita T, Yomita Y, Yasuhira K, Hamamoto H, Shimizu K, Ishii M, Yamamuro T. A new murine model of accelerated senescence, Mech. Ageing Der., 17: , Miyamoto M, Kiyoto Y, Yamazaki M, Nagaoka A, Matsuo T, Nagawa Y, Takeda T. Age-related changes in learning and memory in the Senescence-Accelerated Mouse (SAM). Physiol. Behav., 38: 399-4, Yagi H, Katoh S, Akiguchi I, Takeda T. Age-released deterioration of ability of acquisition in memory and learning in senescence accelerated mouse: SAM-P/8 as an animal model of disturbances in recent memory. Brain Res., 474: 8-93, Takeda T, Hosokawa M, Higuchi K. Senescence-aceelerated mouse (SAM): A novel murine model of accelerated senescence. J. Am. Geriatr. Soc., 39: , Kawamata T, Akiguchi I, Yagi H, Irino M, Sugiyama H, Akiyama H, Shimada A, Takemura M, Ueno M, Kitabayashi T, Ohinishi K, Seriu N, Higuchi K, Hosokawa M, Takeda T, Neuropathological studies on strain of senescence- Aceelerated mouse (SAM) with age-releated deficits in learning and memory. Exp. Gerntol. 32: 11-19, Flood JF, Morley JE. Learning and Memory in the SAMP8 Mouse. Neurosi. Biobehav. Rev. 22: 1-2, Okuma Y, Nomura Y. Senescence-accelerated mouse (SAM) as an animal model of senile dementia: pharmacological, neurochemical and molecular biological approach. Japanese Journal of Pharmacology. 78: , Wei X, Zhang Y, Zhou J. Alzheimer's disease-related gene expression in the brain of senescence accelerated mouse. Neurosci. Lett. 28: , Kawamate T, Akiguchi I, Yagi H, Irino M, Sugiyama H, Akiyama H, Shimada A, Takemura M, Veno M, Kitabayashi T, Ohnish K, Seriu N, Higuchi K, Kosokawa M, Takeda T. Neuropathological studies on strain of senescence accelerated mice (SAM) with age-related deficits in learning and memory. Exp. Gerontol. 32: 11-19, 1997.

Age-related changes in learning and memory in the Senescence-Accelerated Mouse (SAM). Physiol. Behav., 38: 399-4, 198. 1. Yagi H, Katoh S, Akiguchi I, Takeda T.

17 J Chin Med 14(4): , 23 EFFECT OF ATRACTYLODIS RHIZOMA ON LEARNING AND MEMORY ABILITY IN SENESCENCE-ACCELERATED MICE Ming-Fu Wang 1, Yih-Jye Du 2, Jeng-Shiow Lai 3 and Keh-Feng Huang 2 1 Institute of Food and Nutrition, 2 Institute of Applied Chemistry, 3 Department of Cosmetic Science, Providence University, Taichung, Taiwan Received 1 st August 23, revised Ms received 4 th September 23, accepted 2 th October 23 Baizhu, Rhizoma Atractylodis macrocephalae, is the dry rootstock of Atractylodes macrocephala Koidz (Asteraceae). It is listed officially in the Chinese pharmacopoeia and is recommended in traditional Chinese medicine as a digestive, diuretic and antihifrotic. In this project, we attempt to investigate the effect of Baizhu on learning and memory in two-month-old and seven-month-old senescence acceleration mice (SAM-P8) for 1 weeks. The locomotion, single-trial passive avoidance test and active shuttle avoidance test will be conducted and variation of brain histopathology will be observed. By the way, we obtained significant results of Baizhu extracts in senescence-accelerated mice. The effect doses are 2.5, 5. and 1. g/kg diet/day on seven-month-old sensecence-accelerated mice for 1 weeks with single-trail passive avoidance test (p <.5). The effective doses are 5. and 1. g/kg diet/day on two-month-old and seven-month-old senescence-accelerated mice for 1 weeks with active shuttle avoidance test (p <.5). The study of brain histopathology on seven-month-old senescence-accelerated mice also showed the significant results (p <.5). The result could be confirmed the potential of as a cognition enhancing agent. Keywords: Baizhu (Rhizoma Atractylodis macrocephalae), Senescence-accelerated mice (SAM-P8), Learning and memory. Correspondence to: Keh-Feng Huang, Providence University, Tel: ext.152, Fax:

September 23, accepted 2 th October 23 Baizhu, Rhizoma Atractylodis macrocephalae, is the dry rootstock of Atractylodes macrocephala Koidz (Asteraceae).

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人尿可 1 2 1 1 2 (1999 9 16 1999 10 13 1999 10 21 ) 91 TEL: (04) 2053366 Ext. 8306 FAX: (04) 2053764 1 7 28 0.5 g/kg 2.0 g/kg 1) 2) 3) 4 4) 5) 6) 2.0 g/kg/day 2 (Anoectochilus formosanus Hayata) (Orchidaceae)