1.Agmatine Improves Cognitive Dysfunction and Prevents Cell Death in a Streptozotocin-Induced Alzheimer Rat Model.
Juhyun SONG ; Bo Eun HUR ; Kiran Kumar BOKARA ; Wonsuk YANG ; Hyun Jin CHO ; Kyung Ah PARK ; Won Taek LEE ; Kyoung Min LEE ; Jong Eun LEE
Yonsei Medical Journal 2014;55(3):689-699
PURPOSE: Alzheimer's disease (AD) results in memory impairment and neuronal cell death in the brain. Previous studies demonstrated that intracerebroventricular administration of streptozotocin (STZ) induces pathological and behavioral alterations similar to those observed in AD. Agmatine (Agm) has been shown to exert neuroprotective effects in central nervous system disorders. In this study, we investigated whether Agm treatment could attenuate apoptosis and improve cognitive decline in a STZ-induced Alzheimer rat model. MATERIALS AND METHODS: We studied the effect of Agm on AD pathology using a STZ-induced Alzheimer rat model. For each experiment, rats were given anesthesia (chloral hydrate 300 mg/kg, ip), followed by a single injection of STZ (1.5 mg/kg) bilaterally into each lateral ventricle (5 microL/ventricle). Rats were injected with Agm (100 mg/kg) daily up to two weeks from the surgery day. RESULTS: Agm suppressed the accumulation of amyloid beta and enhanced insulin signal transduction in STZ-induced Alzheimer rats [experimetal control (EC) group]. Upon evaluation of cognitive function by Morris water maze testing, significant improvement of learning and memory dysfunction in the STZ-Agm group was observed compared with the EC group. Western blot results revealed significant attenuation of the protein expressions of cleaved caspase-3 and Bax, as well as increases in the protein expressions of Bcl2, PI3K, Nrf2, and gamma-glutamyl cysteine synthetase, in the STZ-Agm group. CONCLUSION: Our results showed that Agm is involved in the activation of antioxidant signaling pathways and activation of insulin signal transduction. Accordingly, Agm may be a promising therapeutic agent for improving cognitive decline and attenuating apoptosis in AD.
Agmatine/*therapeutic use
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Alzheimer Disease/*chemically induced/*drug therapy
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Animals
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Cognition Disorders/*chemically induced/*drug therapy
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Disease Models, Animal
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Male
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Rats
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Streptozocin/*toxicity
2.Enhanced effect of guizhi plus Gegen Decoction on learning and memory disorder in LPS induced neuroinflammatory mice.
Ying XU ; Zong-Qi ZHANG ; Yan ZHAO ; Xian-Wen DONG ; Xing-Yu WANG ; Li-Qing ZHANG
Chinese Journal of Integrated Traditional and Western Medicine 2014;34(2):179-184
OBJECTIVETo explore the potential effect of Guizhi plus Gegen Decoction (GGD) in improving learning and memory of lipopolysaccharides (LPS) induced neuroinflammatory mice and its possible mechanisms.
METHODSTotally 63 male ICR mice were randomly divided into 5 groups, i.e., the normal control (n = 13), the model group (n = 13), the low dose GGD group (n = 10), the high dose GGD group (n = 14), and the positive control group (n = 13). Mice were intraperitoneally injected with LPS (0.33 mg/kg) to induce Alzheimer's disease (AD) model. Mice in the high and the low dose GGD groups were administered with 12 g/kg or 6 g/kg by gastrogavage for 4 successive weeks. Mice in the control group were intraperitoneally injected with minocycline (50 mg/kg) for 3 days. By the end of treatment LPS were injected 4 h before behavior test each day, and then behavior test was conducted in mice of each group. Effect of GGD on learning and memory of AD mice was observed by using open field test, novel object recognition task, and Morris water maze.
RESULTSOpen field test showed there was no statistical difference in the movement time and the movement distance among all groups (P > 0.05), suggesting that LPS and GGD had no effect on locomotor activities of mice. In novel object recognition test, AD mice spent significantly shorter time to explore novel object after they were induced by LPS (P < 0.05), while for AD mice in the low and high dose GGD groups, their capacities for exploration and memory were significantly improved (P < 0. 05, P < 0.01). Results of Morris water maze showed that AD mice exhibited increased escape latency (P < 0.05) and spent much less time in swimming across the original platform (both P < 0.05). However, AD mice in the low and high dose GGD groups had obvious shortened latency and increased time percentage for swimming (P < 0.05, P < 0.01).
CONCLUSIONGGD possessed certain improvement in learning and memory disorder of LPS induced AD mice.
Alzheimer Disease ; chemically induced ; drug therapy ; psychology ; Animals ; Drugs, Chinese Herbal ; therapeutic use ; Lipopolysaccharides ; adverse effects ; Male ; Memory Disorders ; prevention & control ; Mice ; Mice, Inbred ICR ; Neuritis ; chemically induced ; drug therapy ; psychology ; Phytotherapy
3.Effect of rutaecarpine on Alzheimer's disease-like cognitive impairments induced by high glucose in rats.
Jian Guo CHEN ; Ya Geng WU ; Xiang LI
Chinese Journal of Applied Physiology 2019;35(2):178-182
OBJECTIVE:
To investigate the effects of rutaecarpine on high glucose-induced Alzheimer's disease-like pathological and cognitive dysfunction and its mechanism in rats.
METHODS:
Adult male SD rats were randomly divided into three groups (n=20): control group, high glucose group and rutaecarpine group. Rats in the control group were fed with conventional feed and tap water. The rats in the high glucose group were fed with conventional feed and 20% sucrose water. The rutaecarpine group was fed with fodder contain 0.01% rutaecarpine and 20% sucrose water. Morris water maze test was used to detect learning and memory and cognitive function of three groups rats after 24 weeks of feeding. Western blot analysis was used to detect tau protein at Thr205 and Ser214 sites in each group. Phosphorylation levels of GSK-3β in serine 9 site (S9-GSK-3β) and PP2A at cycline 307 site (Y307-PP2AC) were also detected. Immunohistochemistry further confirmed tau protein at Thr205 site in each group both in hippocampus and cortex.
RESULTS:
Compared with the control group, Morris water maze results showed that the latency of finding the hidden platform of the rats in high glucose group was increased significantly and the number of crossing platforms and the target quadrant residence time were significantly decreased (all P<0.05). Immunohistochemistry showed that the phosphorylation level of tau protein at Thr205 site was significantly increased in the high glucose group compared with the control group, and the phosphorylation level of tau protein at Thr205 site in the rutaecarpine group was higher than that in the high glucose group. Western blot analysis showed that the phosphorylation level of tau protein in the high glucose group was significantly increased at Thr205 and Ser214 site compared with the control group, but the phosphorylation level of pS9-GSK-3β was significantly decreased (all P <0.05). Compared with the high glucose group, the latency of finding the hidden platform of the rats in rutaecarpine group was significantly decreased, and the number of crossing platforms and the target quadrant residence time were significantly increased (both P<0.05). Compared with the high glucose group, the phosphorylation levels of tau protein at Thr205 and Ser214 sites showed a significant decrease, but the phosphorylation level of pS9-GSK-3β was significantly increased (all P<0.05).
CONCLUSION
Rutaecarpine can alleviate AD-like cognitive dysfunction induced by high glucose, possibly by enhancing pS9-GSK-3β phosphorylation, down-regulating GSK-3β activity, and thus reducing hyperphosphorylation of tau-associated sites.
Alzheimer Disease
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chemically induced
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drug therapy
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Animals
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Cognitive Dysfunction
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chemically induced
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drug therapy
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Glucose
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Glycogen Synthase Kinase 3 beta
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chemistry
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Indole Alkaloids
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pharmacology
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Male
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Maze Learning
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Phosphorylation
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Quinazolines
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pharmacology
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Random Allocation
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Rats
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Rats, Sprague-Dawley
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tau Proteins
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chemistry
4.Establishment of analogous oxidative damaged Alzheimer's disease rat model and effect of tiaoxin recipe on it.
Hong QIU ; Guo-qin JIN ; Wei-kang ZHAO
Chinese Journal of Integrated Traditional and Western Medicine 2003;23(8):603-605
OBJECTIVETo establish a convenient, economical and practical analogous oxidative damaged Alzheimer's disease rat model (AD model) for exploring the effect of Tiaoxin Recipe (TXR) on the spatial memory capacity and beta-amyloid protein (A beta) deposition in the model.
METHODSThe AD model was established by left ventricular injection of DHF-FeCl3-ADP. Spatial memory and learning capacity of the model rat was observed by Morris water maze method, A beta deposition in its cerebral cortex was observed by immunohistochemistry, and the effect of TXR was analysed.
RESULTSCompared with the normal group, the spatial memory capacity in the model group was obviously decreased, with A beta widely deposited in cortex, immunohistochemical examination showed that the number of A beta positive cells and their mean optic density significantly increased. TXR displayed significantly improving effect on the above-mentioned changes.
CONCLUSIONThe oxidative damaged model could not only express the clinical characteristics (short-term memory impairment), but also partially reflex the pathological changes (A beta deposition) of AD, is an economical and practical analogous AD model. TXR has the effects of improving spatial memory impairment and lowering A beta deposition in the AD model rats.
Alzheimer Disease ; chemically induced ; drug therapy ; Amyloid beta-Peptides ; metabolism ; Animals ; Cerebral Cortex ; metabolism ; Disease Models, Animal ; Drugs, Chinese Herbal ; pharmacology ; therapeutic use ; Male ; Memory ; drug effects ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species
5.Effect of insulin on the cognizing function and expression of hippocampal Abeta1-40 of rat with Alzheimer disease.
Li-hong JIANG ; Yi-na ZHANG ; Xiao-wei WU ; Fang-fang SONG ; Da-yun GUO
Chinese Medical Journal 2008;121(9):827-831
BACKGROUNDA model of simulated Alzheimer's disease (AD) induced by aggregated amyloid protein (Abeta(1-40)) was built in Wistar rats to observe the behavioral and pathological changes of Abeta(1-40) and the effect of hypodermic insulin injected on the function of study and memory and the expression of Abeta(1-40) from the CA1 area of the hippocampus.
METHODSExperimental groups were as follows: contrast, simulated AD model, contrast of Nacl, and insulin treated. The simulated AD model was built by microinjection of aggregated Abeta(1-40) at the CA1 area of the hippocampus, and was hypodermically injected with 0.9% NaCl (1 ml/kg) and insulin (0.1 U/kg) separately the next day. Two weeks after the modeling, the four groups were tested with water maze about the study and memory function of rats. Three weeks after the injection, the expression of Abeta(1-40) at the CA1 area of the hippocampus was examined by pathological tests (HE, Congo red) and immunohistochemical methods.
RESULTSThe study and memory abilities of rats were ameliorated significantly by the place navigation test and the spatial probe test after the application of insulin. Insulin could decrease the expression of Abeta(1-40) at the CA1 area of the hippocampus to reduce the pathological damage of Abeta(1-40) to the hippocampal area of rats.
CONCLUSIONSThe injection of aggregated Abeta(1-40) to the hippocampal area could simulate the behavioral and pathological features of AD such as the difficulty of study and memory and the damage to neurons. Insulin is effective to improve the function of study and memory and amend the pathological damage of simulated AD model rats. The results give a experimental proof of insulin in the clinical treatment of AD.
Alzheimer Disease ; chemically induced ; drug therapy ; psychology ; Amyloid beta-Peptides ; analysis ; toxicity ; Animals ; Cognition ; drug effects ; Disease Models, Animal ; Hippocampus ; chemistry ; pathology ; Insulin ; pharmacology ; therapeutic use ; Male ; Peptide Fragments ; analysis ; toxicity ; Rats ; Rats, Wistar
6.Effect of melatonin on learning and memory impairment induced by aluminum chloride and its mechanism.
Acta Pharmaceutica Sinica 2002;37(9):682-686
AIMTo investigate the effect of melatonin on learning and memory impairment in mice induced by aluminum chloride and its possible mechanism.
METHODSMice were treated with intracerebroventricular (icv) injection of 2 microL 5% aluminum chloride solution, once a day for 5 d. At the same time, the mice were given intraperitoneally melatonin 0.6, 3 and 15 mg.kg-1, once a day for 14 d. The passive avoidance of the mice was assessed by step-through test on day 15 after the last icv injection, and then the place navigation and spatial probe ability by Morris water maze were tested. After the spatial probe test, the activities of total superoxide dismutase (T-SOD), CuZn superoxide dismutase (CuZn-SOD), glutathione peroxidase (GSH-Px) and the content of malondialdehyde (MDA) in the cerebral cortex and hippocampus of mice brain were determined.
RESULTSMelatonin ameliorated significantly the impairment of passive avoidance memory, the place navigation and spatial probe ability of mice induced by aluminum chloride. Melatonin was found to prevent significantly the decline of T-SOD, CuZn-SOD and GSH-Px activities, the increase of MDA content in the cortex and hippocampus of mouse brain induced by aluminum chloride.
CONCLUSIONThe results suggest that melatonin improves significantly the learning and memory impairment in mice induced by aluminum chloride, and this effect may be attributed to its antioxidation.
Aluminum Compounds ; Alzheimer Disease ; chemically induced ; metabolism ; Animals ; Antioxidants ; therapeutic use ; Cerebral Cortex ; drug effects ; metabolism ; Chlorides ; Glutathione Peroxidase ; metabolism ; Hippocampus ; drug effects ; metabolism ; Male ; Malondialdehyde ; metabolism ; Melatonin ; therapeutic use ; Memory Disorders ; drug therapy ; Mice ; Random Allocation ; Superoxide Dismutase ; metabolism
7.Hyperbaric Oxygen and Ginkgo Biloba Extract Ameliorate Cognitive and Memory Impairment via Nuclear Factor Kappa-B Pathway in Rat Model of Alzheimer's Disease.
Li-Da ZHANG ; Li MA ; Li ZHANG ; Jian-Guo DAI ; Li-Gong CHANG ; Pei-Lin HUANG ; Xiao-Qiang TIAN
Chinese Medical Journal 2015;128(22):3088-3093
BACKGROUNDHyperbaric oxygen (HBO) and Ginkgo biloba extract (e.g., EGB 761) were shown to ameliorate cognitive and memory impairment in Alzheimer's disease (AD). However, the exact mechanism remains elusive. The aim of the present study was to investigate the possible mechanisms of HBO and EGB 761 via the function of nuclear factor kappa-B (NF-κB) pathway.
METHODSAD rats were induced by injecting β-amyloid 25-35 into the hippocampus. All animals were divided into six groups: Normal, sham, AD model, HBO (2 atmosphere absolute; 60 min/d), EGB 761 (20 mg·kg-1·d-1 ), and HBO/EGB 761 groups. Morris water maze tests were used to assess cognitive, and memory capacities of rats; TdT-mediated dUTP Nick-End Labeling staining and Western blotting were used to analyze apoptosis and NF-κB pathway-related proteins in hippocampus tissues.
RESULTSMorris water maze tests revealed that EGB 761 and HBO significantly improved the cognitive and memory ability of AD rats. In addition, the protective effect of combinational therapy (HBO/EGB 761) was superior to either HBO or EGB 761 alone. In line, reduced apoptosis with NF-κB pathway activation was observed in hippocampus neurons treated by HBO and EGB 761.
CONCLUSIONSOur results suggested that HBO and EGB 761 improve cognitive and memory capacity in a rat model of AD. The protective effects are associated with the reduced apoptosis with NF-κB pathway activation in hippocampus neurons.
Alzheimer Disease ; chemically induced ; drug therapy ; physiopathology ; therapy ; Amyloid beta-Peptides ; toxicity ; Animals ; Disease Models, Animal ; Ginkgo biloba ; chemistry ; Hyperbaric Oxygenation ; Male ; Maze Learning ; drug effects ; Memory Disorders ; drug therapy ; therapy ; NF-kappa B ; metabolism ; Plant Extracts ; therapeutic use ; Rats ; Rats, Sprague-Dawley
8.Effects of Goutengsan on model of Alzheimer dementia in rats by AlCl3.
Hou-Cai HUANG ; Rong-Ling ZHONG ; Peng CAO ; Chun-Ru WANG ; De-Gong YANG
China Journal of Chinese Materia Medica 2008;33(5):553-556
OBJECTIVEObserve the effects of Goutengsan on SOD, MAO-B, GSH-PX, NO, LDH, index of brain, rate of death and so on in rats to study therapeutic effects and mechanism of Goutengsan on Alzheimer dementia (AD) model.
METHODOne hundred and twenty rats were randomly divided into 6 groups, 3 experimental groups of which were daily administrated with Goutengsan extract whereas the model and control groups were given NS (0.01 mL x g(-1)). Aniracetam at 0.1 g x kg(-1) served as a positive control. At the 5th day after administration, all groups except the control were administrated (ip) with AlCl3 (100 mg x kg(-1) ) for successive 50 days at 1 day interval. After administration, the death rate, body weight, training scores, brain index, MAO-B, SOD, GSH-Px in brain and NO, LDH in serum were determined.
RESULTThe brain index, SOD, GSH-Px activities as well as NO content of drug-treated groups were strikingly higher that of model group, and had not obvious difference from that of normal group except content of LDH was higher.
CONCLUSIONGoutengsan could increase the brain index, cut down the rate of death, stable increase of body weight, promote the endogenous antioxidant activity, enhance the clearance of lipid peroxide and other metabolic waste, inhibit the MAO-B activity, reduced the leakage of LDH and maintain the content of NO at a normal level. Therefore Goutengsan could protect cells, delay senile, improve symptoms of AD.
Aluminum Compounds ; pharmacology ; Alzheimer Disease ; chemically induced ; drug therapy ; metabolism ; Animals ; Body Weight ; drug effects ; Brain ; drug effects ; metabolism ; Chlorides ; pharmacology ; Disease Models, Animal ; Drugs, Chinese Herbal ; pharmacology ; Female ; Glutathione Peroxidase ; metabolism ; Lipid Peroxidation ; drug effects ; Male ; Malondialdehyde ; metabolism ; Memory ; drug effects ; Nitric Oxide ; metabolism ; Oxidative Stress ; drug effects ; Pyrrolidinones ; pharmacology ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Superoxide Dismutase ; metabolism
9.Protective effect of Naoyikang on the Alzheimer's disease model mice induced by D-galactose and NaNO2.
Yan ZHU ; Ai-Ling ZHOU ; Jia-Hui MAO ; Ya-E HU ; Hai-Yan SHI
Chinese Journal of Applied Physiology 2008;24(3):296-300
AIMTo investigate the mechanisms of Naoyikang (Traditional Chinese Medicine) on the Alzheimer's Disease (AD) model mice induced by D-galactose (D-gal) and NaNO2.
METHODSThe mouse model was established by intraperitoneal injection of D-gal and NaNO2. The capacity of learning and memory was tested on mice with electrical maze; the content of nitric oxide (NO) and the activity of monoamine oxidase-B (MAO-B), glutathione peroxidase (GSH-PX), Na(+) -K(+) -ATP enzyme and Ca(2+) -ATP enzyme in cerebral cortex and hippocampus were assayed by biochemical methods; expression of Bax and Bcl-2 mRNA was detested by RT-PCR.
RESULTSNaoyikang could ameliorate the capacity of learning and memory of AD model mice and reduce MAO-B activity in the brain tissue and activate the activity of Na(+) -K(+) -ATP enzyme and Ca(2+) -ATP enzyme in the brain tissue and decrease the expression of Bax mRNA, but increase the expression of Bcl-2 mRNA in the model brain tissue.
CONCLUSIONNaoyikang could protect AD model mice induced by D-gal and NaNO2. It could modify the metabolism of monoamine neurotransmitter in brain through reducing MAO-B activity and protect neurons by activating the activity of Na(+) -K(+) -ATP enzyme and Ca(2+) -ATP enzyme and decrease Bax expression and increase Bcl-2 expression in the model brain tissue.
Alzheimer Disease ; chemically induced ; drug therapy ; Animals ; Disease Models, Animal ; Drugs, Chinese Herbal ; therapeutic use ; Female ; Galactose ; Male ; Maze Learning ; Mice ; Mice, Inbred ICR ; Neuroprotective Agents ; therapeutic use ; Phytotherapy ; RNA, Messenger ; genetics ; metabolism ; Random Allocation ; Sodium Nitrite ; Sodium-Potassium-Exchanging ATPase ; metabolism ; bcl-2-Associated X Protein ; genetics ; metabolism
10.Effect of TX0201 on expression of the apoptosis signal transduction molecule caspase-3 and apoptosis associated genes bcl-2 and bax mRNA in brain tissue of rat analogue model of Alzheimer's disease.
Ge YANG ; Shui-miao LIN ; Wei-kang ZHAO
Chinese Journal of Integrated Traditional and Western Medicine 2006;26(2):147-151
OBJECTIVETo study the mechanism of TX0201, an effective fraction extracted from Tiaoxin recipe in regulating apoptosis associated genes in brain tissue of rat analogue model of Alzheimer's disease (AD) induced by beta-amyloid protein 25-35 (Abeta 25-35).
METHODSThe model of AD was induced by bilateral amygdala injection of Abeta 25-35 to study the spatial memory capacity using Morris water maze test, and by means of RT-PCR and immunohistochemistry assay, the expressions of beta-amyloid precursor protein (APP), apoptosis correlative genes (bcl-2, bax), and apoptosis signal transduction molecule (Caspase-3) in the brain, and the effect of TX0201 on expressions of these genes were examined.
RESULTSIn AD model group, the spatial capacity was damaged significantly. Caspase-3 and the expression of APP mRNA and bax/bcl-2 mRNA were increased in the cortex and hippocampus; TX0201 ameliorated all the pathologic changes mentioned above.
CONCLUSIONTX0201 could improve the oriented learning and memory capacity in AD rats by decreasing bax/bcl-2 and down-regulating Caspase-3 to reduce neurocyte apoptosis, suggesting that effective regulation of neuron apoptosis associated genes may be one of the mechanisms of TX0201.
Alzheimer Disease ; chemically induced ; drug therapy ; metabolism ; Amyloid beta-Peptides ; Animals ; Apoptosis ; drug effects ; Caspase 3 ; biosynthesis ; genetics ; Drugs, Chinese Herbal ; pharmacology ; therapeutic use ; Male ; Phytotherapy ; Proto-Oncogene Proteins c-bcl-2 ; biosynthesis ; genetics ; RNA, Messenger ; biosynthesis ; genetics ; Rats ; Rats, Sprague-Dawley ; Signal Transduction ; bcl-2-Associated X Protein ; biosynthesis ; genetics