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Active physical exercise can effectively alleviate the pathological process of chronic cerebral ischemia(CCH)and improve learning and memory ability.This paper reviews the possible biological mechanisms of aerobic exercise to delay the pathological process of chronic cerebral ischemia and improve learning and memory.Previous studies have found that aerobic exercise can improve the neuroprotective effect,enhance the plasticity of hippocampal synapses,improve the activity of the upper and lower pathways of hippocampal tissue,and improve learning and memory ability.However,the intervention effect of aerobic exercise on chronic cerebral ischemia should be fully considered at the intervention time,and the intervention effect is also different.
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BACKGROUND:Exercise improves Alzheimer's disease,dementia,and age-related cognitive abilities.A potential mediator between exercise and these health benefits may be adult hippocampal neurogenesis.Therefore,it is of great significance to explore whether and how exercise affects the adult hippocampal neurogenesis process in Alzheimer's disease mice. OBJECTIVE:To observe the effect of aerobic exercise on adult hippocampal neurogenesis of Alzheimer's disease mice,and to explore whether aerobic exercise can promote their adult hippocampal neurogenesis. METHODS:Three-month-old wild-type(C57BL/6Jnju)and APP/PS1 double transgenic Alzheimer's disease mice were randomly divided into four groups:wild control group,wild exercise group,Alzheimer's disease control group and Alzheimer's disease exercise group,with 20 mice in each group.The control group did not do exercise,and the exercise group did aerobic exercise for 5 months.After exercise intervention,real-time PCR,immunofluorescence and western blot assay were used to detect the expression levels of DCX,Ki67,βIII-tubulin and NeuN in the hippocampal tissue of mice in each group. RESULTS AND CONCLUSION:The expressions of DCX,βIII-tubulin and NeuN in the hippocampal dentate gyrus in the Alzheimer's disease control group were significantly lower than those in the wild control group(P<0.05).The expressions of DCX,Ki67,βIII-tubulin and NeuN were significantly higher in the hippocampal dentate gyrus in the Alzheimer's disease exercise group than those in the Alzheimer's disease control group(P<0.05).It is indicated that long-term aerobic exercise intervention can strengthen the proliferation,migration and differentiation of neurons during adult hippocampal neurogenesis and significantly increase the number of neuronal precursor cells and new neurons in Alzheimer's disease mice.
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BACKGROUND:β-amyloid protein and Tau protein have adverse effects on the cognitive function of Alzheimer's disease patients,and Notch1 and Caspase-3 can regulate the expression of β-amyloid protein and Tau protein.It is not clear whether Notch1 and Caspase-3 mediate the process of aerobic exercise to improve the cognitive ability of Alzheimer's disease patients.At present,there is a lack of studies on the effect of long-term aerobic exercise on the expression of Notch1 and Caspase-3 in the hippocampus of Alzheimer's disease mice. OBJECTIVE:To observe the expression of Notch1 and Caspase-3 in the hippocampus of Alzheimer's disease mice undergoing long-term aerobic exercise and to investigate the effects of Notch1 and Caspase-3 in Alzheimer's disease mice. METHODS:Wild type and APP/PS1 double-transgenic Alzheimer's disease mice aged 3 months were randomly divided into four groups:wild control group,wild exercise group,Alzheimer's disease control group and Alzheimer's disease exercise group,with 20 mice in each group.Mice in the control groups were not subjected to exercise,while those in the exercise groups received aerobic exercise intervention for 5 months.After the exercise intervention,Morris water maze was used to detect the spatial learning and memory ability of mice.Real-time PCR,immunofluorescence and western blot were used to detect the expressions of Aβ1-42,Tau,Notch1 and Caspase-3 in the hippocampal tissues of mice in each group. RESULTS AND CONCLUSION:The spatial learning and memory ability of Alzheimer's mice was significantly worse than that of wild-type mice(P＜0.05).The spatial learning and memory ability of mice in the exercise groups were significantly better than that in the corresponding control groups(P＜0.05).The expressions of Aβ1-42,Tau,Notch1 and Caspase-3 in the hippocampus were significantly higher in the Alzheimer's disease control group than the wild control group(P＜0.05)and were significantly lower in the Alzheimer's disease exercise group than the Alzheimer's disease control group(P＜0.05).To conclude,long-term aerobic exercise can improve the spatial learning and memory ability of Alzheimer's disease mice,which may be related to the decreased expression of Notch1,Caspase-3,Aβ1-42 and Tau protein in the hippocampus of Alzheimer's disease mice.
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AIM To explore the effects of Shiquan Dabu Decoction on the synaptic function and cognitive impairment in a mouse model of Alzheimer's disease(AD).METHODS Sixty mice were randomly divided into the control group,the model group,the memantine group(5 mg/kg)and the high,medium and low dose Shiquan Dabu Decoction groups(6.24,3.12 and 1.56 g/kg),with 10 mice in each group.Except for those of the control group,the mice of other groups underwent their 70-day AD models induction by intraperitoneal injection of D-galactose and gavage feeding of AlCl3,followed by 42-day corresponding dosing of drugs by gavage on the 29th day.The mice had their spatial learning and associative memory detected by Morris water maze test and conditioned fear test;their morphological changes of hippocampal neurons observed by HE staining;their serum SOD activity,MDA level,and SOD,AChE activities and MDA,ACh,TNF-α and IL-1β levels in hippocampus detected by kits;and their PSD-95,Shank3,NR1,NR2A,NR2B,AMPK and p-AMPK protein expressions in hippocampus detected by Western blot.RESULTS Compared with the model group,the high-dose Shiquan Dabu Decoction group displayed improved spatial learning and memory ability and associative memory(P<0.05,P<0.01);reduced pathological damage of hippocampal neurons,decreased levels of oxidative stress and inflammation(P<0.05,P<0.01);enhanced cholinergic transmission(P<0.05,P<0.01),and increased protein expressions of PSD-95,Shank3,NR1,NR2A,NR2B,and p-AMPK in hippocampal tissue(P<0.05,P<0.01).CONCLUSION Shiquan Dabu Decoction can improve the cognitive impairment of in the mouse model of AD,and its mechanism may be related to AMPK activation and synaptic function restoration.
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OBJECTIVE@#To observe the effects of moxa smoke through olfactory pathway on learning and memory ability in rapid aging (SAMP8) mice, and to explore the action pathway of moxa smoke.@*METHODS@#Forty-eight six-month-old male SAMP8 mice were randomly divided into a model group, an olfactory dysfunction group, a moxa smoke group and an olfactory dysfunction + moxa smoke group, with 12 mice in each group. Twelve age-matched male SAMR1 mice were used as the blank group. The olfactory dysfunction model was induced in the olfactory dysfunction group and the olfactory dysfunction + moxa smoke group by intraperitoneal injection of 3-methylindole (3-MI) with 300 mg/kg, and the moxa smoke group and the olfactory dysfunction + moxa smoke group were intervened with moxa smoke at a concentration of 10-15 mg/m3 for 30 min per day, with a total of 6 interventions per week. After 6 weeks, the emotion and cognitive function of mice was tested by open field test and Morris water maze test, and the neuronal morphology in the CAI area of the hippocampus was observed by HE staining. The contents of neurotransmitters (glutamic acid [Glu], gamma-aminobutyric acid [GABA], dopamine [DA], and 5-hydroxytryptamine [5-HT]) in hippocampal tissue of mice were detected by ELISA.@*RESULTS@#The mice in the blank group, the model group and the moxa smoke group could find the buried food pellets within 300 s, while the mice in the olfactory dysfunction group and the olfactory dysfunction + moxa smoke group took more than 300 s to find them. Compared with the blank group, the model group had increased vertical and horizontal movements (P<0.05) and reduced central area residence time (P<0.05) in the open field test, prolonged mean escape latency on days 1-4 (P<0.05), and decreased search time, swimming distance and swimming distance ratio in the target quadrant of the Morris water maze test, and decreased GABA, DA and 5-HT contents (P<0.05, P<0.01) and increased Glu content (P<0.05) in hippocampal tissue. Compared with the model group, the olfactory dysfunction group had increased vertical movements (P<0.05), reduced central area residence time (P<0.05), and increased DA content in hippocampal tissue (P<0.05); the olfactory dysfunction + moxa smoke group had shortened mean escape latency on days 3 and 4 of the Morris water maze test (P<0.05) and increased DA content in hippocampal tissue (P<0.05); the moxa smoke group had prolonged search time in the target quadrant (P<0.05) and increased swimming distance ratio, and increased DA and 5-HT contents in hippocampal tissue (P<0.05, P<0.01) and decreased Glu content in hippocampal tissue (P<0.05). Compared with the olfactory dysfunction group, the olfactory dysfunction + moxa smoke group showed a shortened mean escape latency on day 4 of the Morris water maze test (P<0.05). Compared with the moxa smoke group, the olfactory dysfunction + moxa smoke group had a decreased 5-HT content in the hippocampus (P<0.05). Compared with the blank group, the model group showed a reduced number of neurons in the CA1 area of the hippocampus with a disordered arrangement; the olfactory dysfunction group had similar neuronal morphology in the CA1 area of the hippocampus to the model group. Compared with the model group, the moxa smoke group had an increased number of neurons in the CA1 area of the hippocampus that were more densely packed. Compared with the moxa smoke group, the olfactory dysfunction + moxa smoke group had a reduced number of neurons in the CA1 area of the hippocampus, with the extent between that of the moxa smoke group and the olfactory dysfunction group.@*CONCLUSION@#The moxa smoke could regulate the contents of neurotransmitters Glu, DA and 5-HT in hippocampal tissue through olfactory pathway to improve the learning and memory ability of SAMP8 mice, and the olfactory is not the only effective pathway.
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Masculino , Animales , Ratones , Vías Olfatorias , Humo/efectos adversos , Serotonina , Envejecimiento , Dopamina , Trastornos del Olfato/etiologíaRESUMEN
Background Formaldehyde and benzene homologues are common environmental pollutants, and their neurotoxicity has aroused widespread concern. Objective To investigate the effect of taurine on cognitive impairment after exposure to formaldehyde and benzene analogues in young rats. Methods Twenty four-week old SD rats were randomly divided into four groups, with six rats in each group: control group (clean air), model group (5 mg·m−3 formaldehyde + 5 mg·m−3 benzene + 10 mg·m−3 toluene + 10 mg·m−3 xylene), low-dose taurine intervention group (5 g·L−1 taurine + mixture of formaldehyde and benzene analogues), and high-dose taurine intervention group (10 g·L−1 taurine + formaldehyde and mixture of benzene analogues), and the exposure was administered by oral and nasal aerosol inhalation for 28 d. At the end of exposure, the learning and memory ability of rats in each group was measured by Morris water maze test. After the behavioral test, the rats were anesthetized and neutralized, and the brain tissue was harvested for histopathological and molecular biological tests. The apoptosis rate of neurons in hippocampal CA1 area was detected by Tunel assay, and the expression levels of apoptosis-related proteins such as caspase 3, bax, and bcl-2 in hippocampal tissue were detected by Western blotting. Results The growth and development of rats in each group were good during inhalation. During the Morris water maze experiment, the escape latencies of rats in the taurine intervention groups were not different from that in the control group (P>0.05) from day 3 to day 5 of training, while the escape latency of rats in the model group was significantly higher than that in the control group (P <0.05). The number of crossing platform and the target quadrant residence time in the high-dose taurine intervention group were not different from those in the control group (P>0.05), while the two variables in the model group and low-dose taurine intervention group were significantly lower than those in the control group (P <0.05). The apoptotic rates of neurons in the hippocampal CA1 area of rats in the control group, model group, and low-dose and high-dose taurine intervention groups were 5.11%, 18.87%, 9.39%, and 4.63%, respectively. The apoptotic rate in the model group was higher than those in the control group and low-dose and high-dose taurine intervention groups (P<0.05). The expression levels of caspase 3, bax, and bcl-2 in the hippocampus of rats in the low-dose and high-dose taurine intervention groups showed no difference compared with the control group (P>0.05). The expression levels of caspase 3 and bax in the model group were higher than those in the control group and low-dose or high-dose taurine intervention groups (P<0.05), and the expression levels of bcl-2 was lower (P<0.05). Conclusion The mixed exposure to formaldehyde and benzene analogues can damage the learning and memory ability of young rats, and increase the apoptosis of neurons in hippocampal CA1 region. Taurine can reverse the damage induced by formaldehyde and benzene analogues.
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Background The altered expressions of hippocampal N-methyl-D-aspartate (NMDA) receptors induced by benzo[ɑ]pyrene (BaP) causes short-term spatial learning and memory impairment in humans and animals, but whether BaP causes alterations of NMDA receptor subunits in other brain regions and the associated neurotoxic mechanism is still essentially unknown. Objective To observe the mRNA expressions of NR1, NR2A, and NR2B of NMDA receptor subunits in different brain regions in SD rat model with subchronic exposure to BaP, and to provide a basis for in-depth study of the mechanism of BaP-induced neurotoxicity. Methods Forty male SD rats were selected and randomly divided into a control group and 1.00, 2.50, and 6.25 mg·kg−1 BaP exposure groups with 10 rats in each group. The exposure rats received intraperitoneal injection of BaP every other day for 90 d.The average latency to platform, the average total distance, and the duration spent in previous quadrant were measured by the Morris Water Maze. Real-time fluorescence quantitative PCR was used to detect the mRNA expressions of NR1, NR2A, and NR2B in hippocampus, cortex, cerebellum, and striatum of rats. Results The average latency to platform and the average total distance in the 2.50 and 6.25 mg·kg−1 BaP groups were significantly prolonged compared with the control group (P<0.05), and the duration that rats spent in previous quadrant in the 6.25 mg·kg−1 BaP group was significantly shortened (P<0.05). Compared with the control group, the mRNA expressions of NR1 and NR2B in the hippocampus in the 2.50 and 6.25 mg·kg−1 BaP groups were significantly reduced (P<0.05), and the NR2A mRNA expression in the hippocampus in the 6.25 mg·kg−1 BaP group was significantly reduced (P<0.05); the mRNA expressions of NR1 and NR2B in the cortical tissue in the 6.25 mg·kg−1 BaP group were significantly reduced (P<0.05), and the mRNA expression of NR2A in the cortical tissue in the 1.00 mg·kg−1 BaP group was reduced; the mRNA expression of NR2B in the cerebellar tissue in the 6.25 mg·kg−1 BaP group was significantly reduced (P<0.05); there were no differences in the mRNA expressions of NMDA receptor subunits in the striatum tissue (P>0.05). Conclusion Subchronic BaP exposure can cause short-term spatial learning and memory impairment in rats, which may be related to the down-regulation of mRNA expressions of NR1, NR2A, and NR2B in hippocampus, changes of mRNA expressions of NR1, NR2A, and NR2B in cortical area, and the down-regulation of NR2B mRNA expression in cerebellum.
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Objective:To explore the underlying protective mechanism of Kaixinsan on learning， memory， and synaptic function in APP/PS1 mice. Method:Sixty APP/PS1 mice were randomly divided into a model group， a donepezil （2 mg·kg<sup>-1</sup>·d<sup>-1</sup>） group， and low- （0.7 g·kg<sup>-1</sup>·d<sup>-1</sup>）， medium- （1.4 g·kg<sup>-1</sup>·d<sup>-1</sup>）， and high-dose （2.8 g·kg<sup>-1</sup>·d<sup>-1</sup>） Kaixinsan groups， and the wild-type mice of the same age in the same litter were assigned to the normal group， with 12 mice in each group. After continuous intragastric administration for two months， the Morris water maze experiment was performed. The ultrastructure of hippocampal neurons was observed by transmission electron microscopy. The colorimetric assay was used to detect serum content of acetylcholine （ACh）， choline acetyltransferase （ChAT）， acetylcholinesterase （AChE）， and levels of hippocampal reactive oxygen species （ROS）， malondialdehyde （MDA）， superoxide dismutase （SOD）， and glutathione peroxidase （GSH-Px）. Real-time fluorescence-based quantitative polymerase chain reaction （Real- time PCR） was used to detect the mRNA expression of hippocampal brain-derived neurotrophic factor （BDNF）， beta-nerve growth factor （NGFB）， discs large homolog (DLG)2， DLG4， and synaptophysin （SYP）. Result:Compared with the normal group， the model group showed prolonged escape latency， reduced number of crossing platforms， shortened stay in the target quadrant （<italic>P</italic><0.01）， decreased number of mitochondria with different shapes and irregular arrangement， some swollen and deformed mitochondria with broken mitochondrial cristae， endolysis， and cytoplasm vacuole， and more cell debris. Additionally， the model group also displayed reduced serum levels of ACh and ChAT， increased AChE （<italic>P</italic><0.01）， elevated hippocampal ROS and MDA （<italic>P</italic><0.05，<italic>P</italic><0.01）， declining SOD and GSH-Px （<italic>P</italic><0.01）， and diminished hippocampal BDNF， NGFB， DLG2， DLG4， and SYP mRNA levels （<italic>P</italic><0.05，<italic>P</italic><0.01）. Compared with the model group， the donepezil group， and the medium- and high-dose Kaixinsan groups showed shortened escape latency， increased number of crossing platforms， prolonged stay in the target quadrant （<italic>P</italic><0.05，<italic>P</italic><0.01）， improved mitochondrial damage with a regular shape （mainly oval shape）， relieved mitochondrial swelling and deformation， and clear mitochondrial cristae. Furthermore， the donepezil group， and the medium- and high-dose Kaixinsan groups also exhibited increased serum ACh and ChAT levels （<italic>P</italic><0.05，<italic>P</italic><0.01）， blunted AChE activity （<italic>P</italic><0.05）， reduced hippocampal ROS level （<italic>P</italic><0.05，<italic>P</italic><0.01）， declining MDA level （<italic>P</italic><0.05）， potentiated SOD and GSH-Px activities， and up-regulated hippocampal BDNF， NGFB， DLG2， DLG4， and SYP mRNA levels （<italic>P</italic><0.05，<italic>P</italic><0.01）. In the low-dose Kaixinsan group， the stay time in the target quadrant was prolonged and the expression of hippocampal SYP mRNA was elevated significantly （<italic>P</italic><0.05）. There was no statistical difference in swimming speed between the groups. Conclusion:Kaixinsan can improve the learning and memory ability of APP/PS1 mice by increasing the expression of synaptic plasticity-related proteins， reducing the ultrastructural damage to hippocampal neurons， resisting oxidative stress， and regulating cholinergic neurotransmitters， thereby exerting neuroprotective effects.
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Objective:To study the effect of Schisandrae Chinensis Fructus lignans (SCL) on learning and memory ability of D-galactose（D-gal）-induced aging model mice. Method:ICR mice were randomly divided into 4 groups: normal group (distilled water, subcutaneous injection with normal saline), model group (distilled water, subcutaneous injection with 200 mg·kg-1D-gal), piracetam group (oral administration with 200 mg·kg-1 piracetam, subcutaneous injection with 200 mg·kg-1D-gal), low-dose SCL group (oral administration with 50 mg·kg-1·d-1 SCL, subcutaneous injection with 200 mg·kg-1·d-1 D-gal), medium-dose SCL group (oral administration with 100 mg·kg-1·d-1 SCL, subcutaneous injection with 200 mg·kg-1·d-1D-gal), high-dose SCL group (oral administration with 200 mg·kg-1·d-1 SCL, subcutaneous injection with 200 mg·kg-1·d-1 D-gal). The drugs were administered continuously for 10 weeks. Dark test and Morris water maze test were performed to observe the effect of SCL on the learning and memory ability of D-gal-induced aging mice. The activities of superoxide dismutase (SOD) and malondialdehyde (MDA) in mouse brain tissue were detected by chemical colorimetry. The expressions of peroxiredoxin-6（Prdx6） and glutathione peroxidase 1（GSH-Px1） mRNA in mouse brain tissue were detected by polymerase chain reaction (PCR). The expressions of Prdx6 and GSH-Px1 protein in mouse tissues were detected by Western blot. Result:In behavioral experiments, compared with normal group, the number of dark avoidance errors in model group significantly increased (P<0.05), the latency was significantly reduced (P<0.01), and the number of mouse passes and the target quadrant residence time were significantly reduced (P<0.01), which can be used as an indicator of successful modeling. Compared with the model group, the number of errors in the piracetam group, and medium and high-dose SCL groups was significantly reduced (P<0.05，P<0.01), and the latency was significantly prolonged (P<0.05，P<0.01). At the same time, the number of water maze passes and the target quadrant retention time in the high-dose SCL group increased significantly (P<0.01). The results of biochemical indicators showed that compared with normal group, the SOD activity in brain tissue of model group mice was significantly reduced (P<0.01), while the MDA content was increased (P<0.05). Compared with the model group, SOD activity in the brain tissues of piracetam group, and low, medium and high-dose piracetam groups was significantly increased (P<0.05), whereas the level of MDA was reduced (P<0.05). The expressions of Prdx6 and GSH-Px1 were significantly increased (P<0.05，P<0.01), indicating that the SCL administration group was dose-dependent. Conclusion:SCL can improve the learning and memory ability of D-gal-induced aging mice, which may be related to the anti-oxidation ability of SCL and the up-regulation of Prdx6 and GSH-Px1 expressions in mouse brain tissue.
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Objective:To investigate whether astragaloside (AST) IV can improve spatial learning and memory abilities by alleviating oxidative stress damage to the frontal cortex and hippocampus in vascular dementia (VD) rats induced by chronic cerebral ischemia.Methods:Totally, 72 adult male Wistar rats were randomly assigned to four groups: sham-operated group ( n=12), model group ( n=20), AST-IV 10 mg group ( n=20), and AST-IV 20 mg group ( n=20); chronic cerebral ischemia-induced VD models in the later three groups were established by permanent bilateral common carotid artery occlusion (BCCAO); 3 h after BCCAO, these rats were administered with saline, 10 mg/kg AST-IV, or 20 mg/kg AST-IV once daily for a consecutive 90 d. Ninety-four d after modeling, spatial learning and memory abilities were assessed by Morris water maze; the activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT), and malondialdehyde (MDA) levels were measured by enzyme linked immunosorbent assay (ELISA). The levels of lipid peroxidation and oxidative DNA damage were assessed by immunohistochemical staining for 4-hydroxynonenal (4-HNE) and 8-hydroxy20-deoxyguanosine (8-OhdG), respectively. Results:(1) On the 3 rd, 4 th and 5 th d of place navigation test, the escape latency in rats of the model group was significantly longer than that in the sham-operated group, and that in the AST-IV 20 mg group was significantly shorter than that in the model group ( P<0.05); spatial probe test showed that the time percentage of rats spending in platform region in the model group (20.3%±1.7%) was significantly smaller than that in the sham-oprated group (48.2%±3.6%), and that in the AST-IV 20 mg group (39.7%±3.2%) was significantly larger than that in the model group ( P<0.05). (2) As compared with those in the sham-operated group, the SOD, GSH-Px and CAT activities were statistically decreased while MDA level was significantly increased in the frontal cortex and hippocampal CA1 area of rats in the model group ( P<0.05); as compared with those in the model group, the SOD, GSH-Px and CAT activities were statistically increased while MDA level was significantly decreased in the frontal cortex and hippocampal CA1 area of rats in the AST-IV 20 mg group ( P<0.05). (3) As compared with those in the model group, the numbers of 4-HNE and 8-oHdG positive cells in the frontal cortex and hippocampal CA1 area of rats in the AST-IV 20 mg group were significantly smaller ( P<0.05). Conclusion:Intraperitoneal injection of high dose AST-IV can ameliorate oxidative damage in the frontal cortex and hippocampal CA1 area in chronic cerebral ischemia-induced VD models, and has the potential to reverse spatial learning damages and memory dysfunction.
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@#To investigate the neuroprotective effect and possible molecular mechanism of PNU-282987 on rats subjected to ischemia and reperfusion. In this study, middle cerebral artery occlusion/reperfusion(MCAO/R)in rats was used as the animal model. The 44 Sprague-Dawley(SD)rats were divided into 4 groups, sham group, model group, low-dose of PNU-282987(1. 2 mg/kg)and high-dose of PNU-282987(2. 4 mg/kg)treatment group. Y-maze test was tested for the learning and memory abilities of rats, and we also examined the brain infarct size, brain edema and neurological dysfunction in rats. Furthermore, HE staining was used to evaluate the neuronal injury and TUNEL assay was used to evaluate the neuronal apoptosis in the rat brain. The results revealed that the learning and memory abilities of rats in treatment group improved significantly, and treatment with PNU-282987 reduced brain infarct size, lessoned brain edema, lessened neurological dysfunction, ameliorated pathological injury and prevented neuronal apoptosis. The above results suggest that the underlying mechanism of PNU-282987 on improving learning and memory abilities of rats after cerebral ischemia and reperfusion may include the inhibition of neuronal apoptosis.
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OBJECTIVE@#To compare the therapeutic effect of electroacupuncture (EA) combined with donepezil hydrochloride and donepezil hydrochloride alone on improving learning-memory ability in patients with Alzheimer's disease (AD), and to explore its action mechanism.@*METHODS@#Sixty patients of AD were randomly divided into an observation group and a control group, 30 cases in each group. The patients in the observation group were treated with EA at governor vessel (GV) combined with donepezil hydrochloride. EA was applied at Baihui (GV 20) and Fengfu (GV 16) with dilatational wave (10 Hz/50 Hz of frequency, 0.5 to 5.0 mA of intensity), and the needles were kept for 40 min, EA was given once a day; the donepezil hydrochloride tablet was taken orally, 5 mg, once a day, and after 4 weeks the dosage might be increased to 10 mg per day according to the specific situation. All the treatment was given for 8 weeks. The patients in the control group were only treated with donepezil hydrochloride with the identical procedure as the observation group. The Montreal cognitive assessment (MoCA) and Alzheimer's disease assessment scale cognitive part (ADAS-Cog) were evaluated before and after treatment; P300 (latency and amplitude of N2 and P3) was detected by EEG/ERP system brain event related potential instrument, and amyloid precursor protein (APP) and β-amyloid protein 1-42 (Aβ) were detected by ELISA.@*RESULTS@#Compared before treatment, the MoCA scores were increased after treatment in the two groups (<0.05), and the MoCA score in the observation group was higher than that in the control group (<0.05). Compared before treatment, the ADAS-Cog scores were decreased after treatment in the two groups (<0.05), and the ADAS-Cog score in the observation group was lower than that in the control group (<0.05). Compared before treatment, the latency of N2 and P3 was shortened and the amplitude was increased after treatment in the two groups (<0.05); after treatment, the latency of N2 and P3 in the observation group was shorter than that in the control group and the amplitude was higher than that in the control group (<0.05). Compared before treatment, the serum levels of APP and Aβ were lower after treatment in the two groups (<0.05), and the serum levels of APP and Aβ in the observation group were lower than those in the control group (<0.05).@*CONCLUSION@#EA at Baihui (GV 20) and Fengfu (GV 6) combined with donepezil hydrochloride can effectively reduce the serum levels of APP and Aβ and improve the scores of MoCA and ADAS-Cog and the levels of N2 and P3 of P300 in AD patients, which has superior effect to donepezil hydrochloride alone in improving the learning-memory of AD patients.
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Humanos , Enfermedad de Alzheimer , Sangre , Terapéutica , Péptidos beta-Amiloides , Sangre , Precursor de Proteína beta-Amiloide , Sangre , Cognición , Donepezilo , Usos Terapéuticos , Electroacupuntura , Aprendizaje , Memoria , Fragmentos de Péptidos , SangreRESUMEN
Objective: To study the effects of prescriptions including Ginseng Decoction, Xixin Decoction, and Dabuyuan Decoction for tonifying spleen and stomach on learning and memory ability and PKA/ERK/p-CREB pathway in hippocampus of SAMP8 mice, and explore the mechanism in the prevention and treatment of Alzheimer's disease (AD). Methods: Three-month-old SAMP8 mice were randomly divided into model group, Donepezil Hydrochloride group, prescription group of Tonifying Spleen and Stomach Yuanqi Prescription (Ginseng, Xixin Decoction, and Dabuyuan Decoction). Moreover, three-month-old SAMR1 mice were recruited as a normal control group, six groups in total. Related indices were detected after 10 weeks continuous gastrogavage. The spatial learning-memory deficit of mice was detected by Morris water maze test. The expression levels of PKA protein in hippocampal region of mice were detected by immunohistochemistry, and the expression levels of ERK and p-CREB protein in hippocampal region of mice were detected by immunofluorescence. The protein expression levels of PKA, ERK, and p-CREB in hippocampus were detected by Western blotting. Results: Compared with the model group, the escape latency of the prescription group of tonifying spleen and stomach was decreased (P < 0.05, P < 0.01), while the swimming time and the times of crossing the platform in the target quadrant were increased (P < 0.01). Results of immunohistochemistry showed that the protein expression of PKA was significantly increased and the expression of ERK and p-CREB in hippocampal region was significantly increased (P < 0.05, P < 0.01). The results of Western blotting were consistent with those of immunohistochemistry and immunofluorescence (P < 0.05, P < 0.01). Conclusion: The Tonifying Spleen and Stomach Yuanqi Prescription showed obvious improvement on the spatial learning-memory deficit in SAMP8 mice, which might be associated with affecting the PKA/ERK/p-CREB pathway in hippocampal region.
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Objective: To compare the effect and mechanism of Compound Danshen Tablets and its disassembled prescription on learning and memory ability of rats with vascular dementia (VD). Methods: Rats with normal learning and memory ability were screened through the shuttle box, and then divided into seven groups: sham group, model group, contrast group (dihydroergotaminemesylate 0.65 g/kg), Danshen group (ethanol extract of Salvia miltiorrhiza 0.3 g/kg), Senqi group (Panax notoginseng powder 0.3 g/kg), Compound Danshen Tablets group (low dose 0.3 g/kg, high dose 0.6 g/kg), ig administration, once daily one time, after 7 d of continuous administration, the VD rat model was established by bilateral common carotid artery ligation and reperfusion. After 7 d of continuous administration, the shuttle box test and neurological deficit score were performed; TTC staining and Nissl staining were used to detect the area of cerebral ischemia and the pathological changes of rat in the cerebral cortex respectively. The changes of SOD, MDA, Ach, 5-HT in the brain and VEGF, ET, eNOS, IL-6 in the serum were detected by kit. Results: Compared with the model group, the Compound Danshen Tablets group increased the number of conditional stimulation avoidance in VD rats, reduced the neurological function score and cerebral ischemia area, and reduced the MDA in rat brain tissue and ET, eNOS, IL-6 in rat serum, and increased Ach, 5-HT, SOD in the brain and VEGF in the serum. S. miltiorrhiza extract had better performance in reducing MDA in rat brain tissue and ET, eNOS, IL-6 in rat serum, SOD in the brain than in P. notoginseng; P. notoginseng was more advantageous in improving the content of Ach and 5-HT in rat brain tissue. The high-dose group of Compound Danshen Tablets had significant differences in SOD, MDA, ACH, 5-HT, and VEGF compared with Danshen group or Senqi group (P < 0.05, P < 0.01). Conclusion: Compound Danshen Tablets can improve the cognitive learning and memory ability of VD rats. The mechanism maybe enhance the secretion of Ach by the central cholinergic nervous system, improve the content of the monoamine neurotransmitters 5-HT in the hippocampus and hypothalamus, reduce the lipid peroxidation damage of the brain tissue, inhibit the inflammatory injury reaction and promote angiogenesis. In the compound, S. miltiorrhiza extract as the role of “Jun medicine”, plays a major role, while P. notoginseng assists “Jun medicine” in treating VD.
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Aim To assess the effects of Trillium Tschonoskii Maxim ( TTM ) decoction on Tau protein phosphorylation and synaptic development in AD model rats induced by high activity GSK-3β. Methods The SD rats were divided into five groups of ten animals, named sham-operated group ( blank group) , AD model group, TTM group (0. 5, 0. 25, 0. 125 g·kg-1 · d-1 ) . Treatment group received gavage once a day for seven days with TTM decoction, while other groups by gavage once a day for seven days with drinking water. On 2nd day by gavage, Morris water maze test was used to assess the spatial learning and memory ability of the rats. After five days' training, rats in the treat-ment groups and AD model group were injected wort-mannin ( WT, PI3K specific inhibitor ) and GF-109203X (GFX, PKC specific inhibitor) (100 μmol ·L-1 of each, total volume of 10 μL) into the right lateral ventricle. Western blot was used to detect the levels of phosphorylation Tau protein at multiple sites and the expression level of PI3K, Akt, PKC, GSK-3β(S9, T216) and synapse-associated proteins. Immu-nohistochemical method was used to detect the hyper-phosphorylation of Tau protein in hippocampus of rats. Golgi staining was applied to detect the number and morphological changes of synaptic development and dendritic spines. Nissl' s staining was employed to ob-serve the development of neonatal neurons in hippo-campus and cortex. Results Western blot showed that the phosphorylation level of Tau in hippocampus increased in model group, and the activity of GSK-3βwas up-regulated. Among them, however, in middle dose TTM group, the phosphorylation level of Tau in hippocampus decreased and the activity of GSK-3βde-creased. The expression levels of p-PKC and p-Akt in low and middle dose treatment group were higher than those in model group, thus increasing the activity of PKC and Akt to inhibit the activity of GSK-3β kinase. Immunohistochemistry also indicated that TTM could decrease the biological effects of Tau phosphorylation in hippocampus of AD rats. Western blot showed that TTM could increase the expression levels of synapsin-1 , syn-aptophysin and GluR-1 in hippocampus of AD rats. Nissl staining showed that the number of Nissl bodies in hippocampal neurons of AD model group were signif-icantly fewer than those of sham operation group, which could be increased by TTM middle and high dose group, and the complexity and dendritic spine density of hippocampal neurons in AD rats could be en-hanced as well. Conclusion TTM can effectively im-prove the cognitive function of AD rats induced by the increase of GSK-3β activity, and its possible mecha-nism may be via down-regulating the activity of GSK-3β and inhibiting the phosphorylation of tau protein and promoting the development of neurons.
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Objective To investigate the effect of Jin's 3-needling therapy on executive function and spatial learning and memory abilities and their mechanism in frontal lobe injury rats. Methods Thirty-two male Sprague-Dawley rats were randomly divided into sham-operated group, Jin's 3-needling group, model group and medoba treatment group (n=8). The rats in the sham-operated group only underwent craniotomy to remove the bone flap and no impact was performed on the frontal lobe; the frontal lobe injury models of model group, Jin's 3-needling group and medoba treatment group were established by eCCI-6.3 device; rats in the Jin's 3-needling group were treated with Jin's 3-needling therapy, and rats in the madopa treatment group were given 2 mL of madopa suspension by perfusion once daily. The behavior of rats in each group was evaluated by GO/NO GO task and Morris water maze test, and apoptosis of cells was detected by TUNEL, dopamine receptor D1 (DRD1) expression was determined by immunohistochemistry, and the content of dopamine in frontal tissues was analyzed by high performance liquid chromatography. Results The accuracy rate of GO/NO GO task in Jin's 3 needling group was significantly higher than that in madopa treatment group (P<0.05); and that in madopa treatment group was significantly higher than that in model group (P<0.05). On the 3rd and 4th d of place navigation test, the escape latency in the Jin's 3 needling group and madopa treatment group was significantly decreased as compared with that in the model group (P<0.05); the escape latency in the Jin's 3 needling group was significantly decreased as compared with that in the madopa treatment group (P<0.05). In spatial probe test, the number of times of crossing the platform in the Jin's 3 needling group and madopa treatment group was significantly larger as compared with that in the model group (P<0.05). As compared with those in the model group, the number of apoptotic neurons in the frontal lobes was significantly larger, the content of dopamine in the frontal lobes and the DRD1 expression were significantly increased in the madopa treatment group and Jin's 3-needling group (P<0.05); the number of apoptotic neurons in the Jin's 3 needling group was significantly smaller as compared with that in the madopa treatment group (P<0.05); the content of dopamine in the frontal lobes and the DRD1 expression in the Jin's 3 needling group were significantly increased as compared with those in the madopa treatment group (P<0.05). Conclusion Jin's 3-needling therapy can effectively improve the executive function and spatial learning and memory abilities of frontal lobe damaged rats, and their mechanism may be related to decreased apoptosis of frontal tissue cells and increased dopamine content and increased DRD1 expression.
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Objective To investigate the effect of esmolol pretreatment on Toll like receptor-4 (TLR4)/nuclear factor-kappa-B (NF-кB) pathway in rats with repeated cerebral ischemia/reperfusion (IR) injury. Methods Forty-eight adult male Sprague-Dawley rats were randomly allocated into sham-operated group, IR group and esmolol group (n=16). Rats in the IR group and esmolol group were injected intravenously with esmolol at a dose of 200 g/(kg?min) or normal saline for one h before surgery, and then, bilateral common carotid arteries were clipped to establish the repeated IR injury models. Bilateral common carotid arteries in rats of sham-operated group were only isolated but not clipped, and injected intravenously with normovolemic normal saline for one h. Learning and memory abilities of rats were measured by Morris water maze test before, and one, 3 and 7 d after surgery. Rats were euthanized and hippocampus tissues were excised. The wet to dry (W/D) ratio of the hippocampus was tested. The permeability of blood-brain barrier was determined by Evans blue (EB) method. The levels of tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6 and IL-1β in the hippocampus were tested by enzyme linked immunosorbent assay (ELISA). The NF-кB p65 and TLR4 mRNA expressions in the hippocampus were determined by reverse transcription-polymerase chain reaction (RT-PCR). The NF-кB p65 and TLR4 protein expressions in hippocampus were detected by Western blotting. Results As compared with those in the sham-operated group, the escape latency was significantly prolonged and swimming distance was signficantly longer in rats of IR group one, 3 and 7 d after surgery (P<0.05), the W/D ratio of the hippocampus and the content of EB in brain tissues were significantly increased in the IR group (P<0.05), the levels of TNF-α, IL-6 and IL-1β in hippocampus were significantly increased in the IR group (P<0.05), and the NF-кB p65 or TLR4 mRNA and protein expressions in the hippocampus of IR group were statistically higher (P<0.05). As compared with IR group, the escape latency and swimming distance of rats in the esmolol group were significantly shortened one, 3 and 7 d after surgery (P<0.05), the W/D ratio of the hippocampus and content of EB in brain tissues of esmolol group were significantly decreased (P<0.05), the levels of TNF-α, IL-6 and IL-1β in the hippocampus of esmolol group were signficantly lower(P<0.05), and the NF-кB p65 or TLR4 mRNA and protein expressions in hippocampus of esmolol group were statistically lower in the esmolol group (P<0.05). Conclusion Esmolol preconditioning can alleviate cerebral injury and improve learning and memory abilities of rats with repeated cerebral IR injury, which may be involved in alleviating inflammation and suppressing TLR4/NF-кB pathway.
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Objective To observe the effect of curcumin on behavior,blood brain barrier(BBB)and ex-pression of glial fibrillary acidic protein(GFAP)and cyclic nucleotide 3′phosphohydrolase(CNPase)in hippocam-pus of radiation injured brain(RIB)rats. Methods SD rats were divided into radiation group,treatment group and negative control group. RIB rats model were established by X ray,and rats in treatment group were treated by curcumin. Morris water maze test were taken to study learning memory of rats in each group. The expression of Ev-ans blue(EB)in brain tissue and the expression of GFAP and CNPase in hippocampus were detected to observe the effect of curcumin on the BBB of RIB rats. Results In RIB rats,learning memory were decreased significant-ly,permeability of BBB were increased. GFAP expression in brain tissue was increased,and CNPase was de-creased(P < 0.05). After the treatment of curcumin,learning memory of rats were improved,the permeability of BBB was decreased,GFAP was decreased,and CNPase expression was increased(P < 0.05). Conclusion Cur-cumin can significantly reduce the damage of BBB in RIB rats,decrease the expression of GFAP and increase the expression of CNPase in hippocampal,which indicate that curcumin has curative effect on radiation injured brain.
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Objective To observe the effects of electroacupuncture on the learning and memory ability and cerebral cortex inflammatory factor of rats with vascular cognitive impairment (VCI); To discuss the mechanism of electroacupuncture for preventing and treating VCI. Methods VCI rat models were made in microemboli injection through internal carotid artery method. The successful modeled rats were randomly divided into model group, positive medicine group and electroacupuncture group, and normal rats were taken as control group. Three days after rat models were established, the positive medicine group was given donepezil hydrochlorideby gavage, and electroacupuncture group was given electroacupuncture at "Baihui" and "Zusanli" acupoints. After treatment, the learning and memory ability was detected by Morris water maze test. The contents of TNF-α, IL-6 and IL-1β in rat brain tissue were detected by ELISA. Results The water maze results showed that with the increase of the number of training, the average escape latency of rats to find platform in positive medicine group and electroacupuncture group all had different degrees of shortening in positioning cruise experiment; in space exploration experiment, positive medicine group and electroacupuncture group to cross the platform area for the first time were significantly reduced compared with the model group; compared with the control group, the contents of TNF-α, IL-6 and IL-1β in the model group were increased significantly; compared with the model group, the contents of TNF-α, IL-6 and IL-β in postive medicine group and electroacupuncture group were decreased. Conclusion Electroacupuncture at "Baihui"and "Zusanli" acupoints can decrease the contents of TNF-α, IL-1 and IL-6 in the cortex of VCI rats, and improve the learning and memory ability of rats.
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Objective To explore the effect ofthymosin alpha-1 (Ta1) on postnatal systemic inflammation-induced learning and memory impairment in mice and their relevant mechanism.Methods (1) Twenty-four neonatal C57BL/6 mice were randomly assigned into normal saline group,lipopolysaccharide (LPS,0.3 mg/kg) group,LPS (0.6 mg/kg) group,and LPS (0.9 mg/kg) group.And the animals were intraperitoneally injected with different doses of LPS or equal volume of saline for 5 days.The variations of body weight,liver weight relative to the body and tumor necrosis factor-α (TNF-α) level in serum and brain tissues were observed to determine the appropriate dose of LPS for simulating neonatal clinical infection.(2) A total of 60 newborn mice were randomly divided into three groups:control group,LPS group and Ta1 treatment group;mice in each group were continuously injected with equal volume saline,LPS (0.6 mg/kg) and Tal (0.4 mg/kg)+LPS (0.6 mg/kg) for 5 days.On day 28 and on day 56,Morris water maze was used to measure the spatial learning and memory abilities of mice;the concentrations of TNF-α,interleukin-1β (IL-1β),brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in the hippocampus were examined by ELISA,and the expressions of toll-like receptor 4 (TLR4) and nuclear factor-κB (NF-κB) were measured by Western blotting.Results (1) As compared with the normal saline group,the mice in the LPS group (0.6 mg/kg) had significantly slower growth ([2.23±0.22] g vs.[1.18±0.21] g),increased relative liver weight to the body (0.052±0.004 vs.0.072±0.007) and increased TNF-α levels in serum and brain tissues ([62.01±3.32] pg/mL vs.[151.06± 14.51] pg/mL;[186.03±13.24] pg/mL vs.[298.71±41.61] pg/mL,P＜0.05).(2) As compared with the LPS group,Tal treatment group had significantly shortened average escape latency in place navigation test,prolonged active time in spatial probe test,statistically decreased hippocampal TNF-α,IL-1β,TLR4 and NF-κB levels ([73.32±5.18] pg/mL vs.[58.61 ±4.03] pg/mL;[99.15±8.30] pg/mL vs.[75.56±6.13] pg/mL;2.32±0.29 vs.1.71±0.26;1.77±0.24 vs.1.26±0.14) and significantly increased BDNF and NGF levels ([1.33±0.12] pg/mL vs.[1.69±0.25] pg/mL;[41.45±3.47] pg/mL vs.[50.38±5.02] pg/mL,P＜0.05).Conclusion Tal improves learning and memory functions and alleviates neuro-inflammation in postnatal infection of mice,and the underlying mechanism probably involves in inhibiting TLR4/NF-κB signaling pathway activation and increasing neurotrophic factors.