Dehydroevodiamine·HCl enhances cognitive function in memory-impaired rat models

Progressive memory impairment such as that associated with depression, stroke, and Alzheimer's disease (AD) can interfere with daily life. In particular, AD, which is a progressive neurodegenerative disorder, prominently features a memory and learning impairment that is related to changes in acetylcholine and abnormal β-amyloid (Aβ) deposition in the brain. In the present study, we investigated the effects of dehydroevodiamine·HCl (DHED) on cognitive improvement and the related mechanism in memory-impaired rat models, namely, a scopolamine-induced amnesia model and a Aβ₁₋₄₂-infused model. The cognitive effects of DHED were measured using a water maze test and a passive avoidance test in the memory-impaired rat models. The results demonstrate that DHED (10 mg/kg, p.o.) and Donepezil (1 mg/kg, p.o.) ameliorated the spatial memory impairment in the scopolamine-induced amnestic rats. Moreover, DHED significantly improved learning and memory in the Aβ₁₋₄₂-infused rat model. Furthermore, the mechanism of these behavioral effects of DHED was investigated using a cell viability assay, reactive oxygen species (ROS) measurement, and intracellular calcium measurement in primary cortical neurons. DHED reduced neurotoxicity and the production of Aβ-induced ROS in primary cortical neurons. In addition, similar to the effect of MK801, DHED decreased intracellular calcium levels in primary cortical neurons. Our results suggest that DHED has strong protective effects against cognitive impairments through its antioxidant activity and inhibition of neurotoxicity and intracellular calcium. Thus, DHED may be an important therapeutic agent for memory-impaired symptoms.

Dehydroevodiamine.HCl Improves Stress-Induced Memory Impairments and Depression Like Behavior in Rats

Dehydroevodiamine.HCl (DHED) has been reported to prevent memory impairment and neuronal cell loss in a rat model with cognitive disturbance. We investigated the effect of DHED on memory impairment and behavioral abnormality caused by stress. We demonstrated that DHED can improve stress-induced memory impairments and depression-like behaviors by using open-field test, Y-maze test and forced swimming test. DHED treatment significantly recovered the decreases in the levels of neural cell adhesion molecule (NCAM) proteins caused by stress and the decreases in cell viability. Our results suggested that DHED is a potential drug candidate for neuronal death, memory impairment and depression induced by stress.

Amyloid Precursor Protein Binding Protein-1 Is Up-regulated in Brains of Tg2576 Mice

Amyloid precursor protein binding protein-1 (APP-BP1) binds to the carboxyl terminus of amyloid precursor protein and serves as a bipartite activation enzyme for the ubiquitin-like protein, NEDD8. Previously, it has been reported that APP-BP1 rescues the cell cycle S-M checkpoint defect in Ts41 hamster cells, that this rescue is dependent on the interaction of APP-BP1 with hUba3. The exogenous expression of APP-BP1 in neurons has been reported to cause DNA synthesis and apoptosis via a signaling pathway that is dependent on APP-BP1 binding to APP. These results suggest that APP-BP1 overexpression contributes to neurodegeneration. In the present study, we explored whether APP-BP1 expression was altered in the brains of Tg2576 mice, which is an animal model of Alzheimer's disease. APP-BP1 was found to be up-regulated in the hippocampus and cortex of 12 month-old Tg2576 mice compared to age-matched wild-type mice. In addition, APP-BP1 knockdown by siRNA treatment reduced cullin-1 neddylation in fetal neural stem cells, suggesting that APP-BP1 plays a role in cell cycle progression in the cells. Collectively, these results suggest that increased expression of APP-BP1, which has a role in cell cycle progression in neuronal cells, contributes to the pathogenesis of Alzheimer's disease.

Pathogenesis of Alzheimer's Dementia

Alzhelmer's disease (AD) is the most common cause of dementia that arises on a neuropathological background of amyloid plaques containing betaamylold (Abeta) derived from amyloid precursor protein (APP) and tau-rich neurofibrillary tangles. To date, the cause and progression of familial or sporadic AD have not been fully elucidated. About 10% of all cases of AD occur as autosomal dominant inherited forms of early-onset AD, which are caused by mutations in the genes encoding APP, presenilin-1 and presenilin-2. Proteolytic processing of APP by beta-gamma-secretase and caspase generates Abetaand carboxyl-terminal fragments of APP (APP-CTFs), which have been implicated in the pathogenesis of AD. The presenilins function as one of the gamma-secretases. Abetawhich is the main component of the amyloid plaques found, is known to exert neurotoxicity by accumulating free radicals, disturbing calcium homeostasis, evoking inflammatory response and activating signaling pathways. The CTFs have been found in AD patients' brain and reported to exhibit much greater neurotoxicity than Abeta. Furthermore CTFs are known to impair calcium homeostasis and learning and memory, triggering a strong inflammatory reaction through MAPKs- and NF-kappaB-dependent astrocytosis and iNOS induction. Recently, it was reported that CTF translocated into the nucleus and in turn, affected transcription of genes including glycogen synthase kinase-3beta which results in the induction of tau-rich neurofibrillary tangles and subsequently cell death. One of the hallmarks of AD, neurofibrillary tangles (NFT), is formed by insoluble intracellular polymers of hyperphosphorylated tau that is believed to cause apoptosis by disrupting cytoskeletal and axonal transport. This review covers the processing of APP, toxic mechanisms of Abetaand CTFs of APP, presenilin and also tau in relation to the pathogenesis of AD.

Caspase is Regulated by ROS in CT Induced Neuronal Cell Death / 대한해부학회지

Carboxy-terminal fragment of amyloid precusor protein (CT) is a candidate of causal molecule in the pathogenesis of Alzheimer's disease. Although it has been identified that CT shows cytotoxicity in various types of cells, little is known about the molecular mechanism of the cytotoxic on neuronal cells by CT. In the present study, we investigated the relevance of reactive oxygen species (ROS) generation to CT induced cell death in SK-N-SH cells. We showed CT induced ROS production and antioxidant GSH inhibited the increase of ROS production, thereby preventing neuronal cell death. These results indicate that CT induce neuronal cell death through mediation of ROS. Furthermore, increase of caspase activity resulted from CT reduced by GSH. It is implicate that caspase-3 may act downstream of ROS in the pathway neuronal cell death induced by CT.

Increased Labelling of Perivascular Phagocytes by Blood Borne HRP in the SAM P10 Brain / 대한해부학회지

The present study examined the uptake of blood borne horseradish peroxidase (HRP) by perivascular cells in the senescence -accelerated mouse prone -10 (SAMP10) and the senescence -accelerated mouse resistant -1 (SAMR1) brains. SAMP10 and SAMR1 brains were studied from mice of each of the following ages: 3 months old SAMP10, 12 ~14 months old SAMP10, 3 months old SAMR1, and 12 ~14 months old SAMR1. Animals were injected via a tail vein with HRP (type VI) solution. Two hours later animals were transcardially perfused with 4% paraformaldehyde and 1% glutaraldehyde mixture. After sectioning with a vibrating microtome, brain sections were stained using a DAB solution. Products of the HRP -DAB reaction were frequently and intensely labelled in the perivascular cells along the microvasculature, especially in the young SAMP10 brain. Electron microscopy revealed that the reaction products were evident in the endothelium of the microvasculature, as well as the perivascular phagocytes of arterioles or venules. In the aged SAMP10, the number of perivascular cells showing HRP -reaction products was lower than in the young SAMP10. Under the electron microscope, the perivascular cells of the aged SAMP10 brain showed very weak intensity of HRP staining, and these cells contained abundant foamy vacuoles or lipid droplets. In both young and aged SAMR1 brains, labelled perivascular phagocytes were very occasionally found. In summary, the present results showed increased uptake of blood -borne HRP by perivascular phagocytes in the young SAMP10 brain, and the age related decrease of this labelling, which suggests altered microvascular barrier function with aging in the SAMP10 brain.

Antidepressant Effect of Ethaverine / 대한정신약물학회지

The effects of a L-type calcium channel blocker, ethaverine were investigated in the rat forced swimming test, after single and repeated administration. Ethaverine in doses of 20 mg/kg, 40 mg/kg after single and repeated administration reduced significantly the duration of immobility in the forced swimming test. Fluoxetine administered in a single dose of 40 mg/kg did not influence the duration of immobility, but fluoxetine in a dose of 40 mg/kg administered repeatedly reduced significantly the duration of immobility. Ethaverine in a dose of 10 mg/kg did not affect the immobility after single and repeated administration. Imipramine and fluoxetine in doses which were not effective by themselves, increased the immobilityreducing effect when administered concormitantly with ethaverine in a dose of 10 mg/kg. Imipramine in a dose of 20 mg/kg and fluoxetine in a dose of 80 mg/kg, administered alone reduced the immobility time. The reduction of immobility after the concormitant administration of ethaverine in a dose of 10 mg/kg and imipramine in a dose of 20 mg/kg, fluoxetine in a dose of 80 mg/kg was significantly greater than after imipramine or fluoxetine, administered alone. The anti-immobility effect of the ethaverine was significantly counteracted by haloperidol in a dose of 0.5 mg/kg. The effects of ethaverine on the levels of monoamines and their metabolites were also investigated in rat striatum, cerebral cortex, cerebellum, medulla oblongata, hypothalamus, midbrain, hippocampus. Treatment with ethaverine caused alterations on the levels of dopamine and its metabolite in rat striatum, cerebral cortex, hypothalamus, medulla oblongata, cerebellum, but not on the levels of norepinephrine and serotonin and its metabolite. The observed effects of ethaverine indicate that ethaverine may have an antidepressant activity and may interact with the brain dopaminergic system. The present results suggest that the concormitant administration of ethaverine and antidepressants may have a more potent therapeutic antidepressant effect and/or may permit reduction of the dose of antidepressant and thus diminish its side effects.

Alzheimer's Disease and Apoptosis

Apoptosis is a form of cell death in which the cells shrink and exhibit nuclear chromatin condensation and DNA fragmentation, and yet maintain membrane integrity. Many lines of evidence have shown that brain neurons are vulnerable to degeneration by apoptosis. Also it has been suggested that apoptosis is one of the mechanism contributing neuronal loss in Alzheimer's disease(AD), since the conditions in the disease(A beta peptide, oxidative stress, low energy metabolism) are the inducers that activate apoptosis. Indeed some neurons in vulnerable regions of the AD brain show DNA damage, chromatin condensation, and apoptic bodies. Consistently, mutations in AD causative genes(Amyloid precursor protein, Presenilin-1 and Presenilin-2) increase A beta peptide1-42(Abeta1-42) and sensitize neuronal cell to apoposis. However, several lines of evidence have shown that the location of neuronal loss and A beta peptide deposition is not correlated in AD brain and transgenic mice brain over-expressing Abeta1-42. Taken together, these data may indicated that A beta peptide(and other causative factors of AD) can interact with other cellular insults or risk factors to exacerbate pathological mechansim of AD through apoptosis. Thus, this review discusses possible role and mechanism of apoptosis in AD.

The Change of Expression in Amyloid Precursor Protein mRNA and Amyloid Precursor Protein by Transient Ischemia

Although the mechanism has not been clearly understood, it has been reported that various altered gene expressions are induced by cerebral ischemia. In order to investigate the effects of transient cerebral ischemia on the amyloid precursor protein(APP) metabolism, the 3 isoforms of APP mRNA and the APP were examined. Rats were given ischemic insult through middle cerebral artery occlusion and reperfusions using blunted 4-0 nylon thread after exposure of cervical region. Groups were assigned with each being 1 hour occlusion and 1hr, 3hrs, 8hrs, 1day, 3days, 7days after reperfusion. The rats were then sacrificed and cerebral cortex of each animal was dissected. The mRNA level of APP770, 751, 695 was investigated by reverse transcription coupled polymerase chain reaction (RT-PCR) and the protein amount of APP was investigated by Western blotting method. The results showed that transient ischemia induced the change of APP mRNA. The APP mRNA which encodes the KPI(Kunitz-type protease inhibitor) domain began to increase after 1 day, reaching a maximun at 3 days, and then decreased to control level in the 7 days. The protein level of APP was same until 7 days. We conclude that transient cerebral ischemia alters the gene expression of APP isoforms. Therefore, we speculate that some factors regulating the splicing of APP gene transcript may also undergo ischemia-induced changes and the increase in levels of KPI-APP following ischemia might be associated with pathological changes during the ischemic process.

Effect of Immobilization Stress on the Expression of Amyloid Precursor Protein in the Mouse Brain

BACKGROUND: The Central nervous system(CNS) plays a essential role in mediating~stress responses. However, the enact mechanism of the CNS in mediating stress responses has not been clarified sufficiently as yet. Stress may cause brain dysfunction including cognitive dysfunction which was most commonly found in Alzheimer's dementia. Amyloid precursor protein(APP) is a large, ubiquitously distributed and evolutionarily conserved molecule whose function remains unknown. Although the precise function of APP following injury to the CNS such as stab and kainic acid lesion. However, there have not been reports on the effects of stress on the expression of amyloid precursor protein in the brain. This study was undertaken to elucidate the effects of stress on the expression of APP in the mouse brain. METHODS: The several brain region was isolated from the mouse that was in the immoblization stress for 30 min, 1 hour, and 2 hours. The mouse brain was divided into 5 regions, cerebral cortex, cerebellum hippocampus, midbrain and thalamus, corpus striatum and brain stem. The change of mRNA was examined in the several brain regions using Northern blot hybridization. RESULTS: The amounts of APP mRNA in the cerebral cortex, hippocampus and brain stem were found to be significantly increased after stress for 30 minutes and to 1.each a maximum after stress for 1 hour and to normal range at stress for 2 hours. On the contray, the contents of APP mRNA in midbrain and thalamus were decreased after stress for 30 minutes and sustained after stress for 2 hours. CONCLUSION: These findings suggest that APP may not be static but functional protein reactive to stress and stress may increase the levels of APP mRNA especially in Alzheimer disease associated sites such as cerebral cortex and hippocampus, which may contriute to the pathogenesis of Alzheimer disease.

Amyloid Deposits in Supratentorial Meningiomas: Clinicopathological and Immunohistochemical Study

Amyloidosis is the definition for a group of diseases that have, in common, the infiltration of one or more tissues by an abnormal protein material-the amyloid substance, which is detected histologically by their green polarization color after Congo red staining. Despite increased interest on basic nature of amyloidosis by recent immunohistochemical or experimental study, the knowledge about the incidence and neurotoxic effect of cerebral amyloid or concomitant occurrence with brain tumor is still inchoate. We examined the incidence and clinico-pathologic characteristics of the patients with amyloid deposits in supratentorial meningiomas. Particularly about their neurotoxic effect to adjacent brain is considered one of the possible cause of seizure in 33 patients who underwent resection surgery for meningioma at the Keimyung University during the past three years. The pathological review and subgrouping by histologic type were done in all 33 specimens with sufficient size of paraffin block, defined by their morphology and polarization color after Congo red staining for diagnosis of amyloid deposits localized in the tumor. Immunohistochemical studies using monoclonal antibodies for amyloid-A protein(AA) and beta-amyloid(A beta) were evaluated to identify subtypes of amyloidosis. The rate of incidence of amyloid deposit in meningioma was 21%, i.e. seven out of thirty three cases. All laboratory findings and clinical studies did not suggest a systemic form. Seizure occurrence was one out of seven cases(14%), which was of no statistical significance. Immunohistochemical study for AA subtype was all negative, but showed all positive for A beta protein around the vessels. Recent reports has also demonstrated that Amyloid precusor protein(APP) and A beta is related in Alzheimer's disease, hereditary cerebral hemorrhage with amyloidosis-Dutch type(HCHWA-D) and amyloid angiopathy. Our research data indicates that the incidence of amyloid deposit is as high as 21% in supratentorial meningiomas. It seems that it is one of the possible cause of seizure. Nonsystemic microdeposits of amyloid and their subtype and it's relationship to neurotoxic effect in meningiomas remain to be confirmed by immunoelectron microscopic examination or immunohistochemical methods.

Studies on the effect of aging to the hypothalamo-neurohypophyseal endocrine cells and catecholaminergic neurons / 대한해부학회지

No abstract available.

Effects of aluminum on choline uptake and activities of choline acetyltransferase and acetylcholinesterase in rat brain / 신경정신의학

No abstract available.

A Study on Osteoarthrosis in Korean Young Women Volley Ball Players / 대한정형외과학회잡지

Degenerative joint disease is a non-inflammatory disorder of movable joints characterized by deterioration and abrasion of articular cartilage, and also by formation of new bone at the joint surfaces. It is by far the most common form of arthritis in persons over the age of fifty, but manifestation of this disease do not appear as a rule until the fourth or fifth decade. Despite the frequent occurrence of osteoarthrosis in the adult population, many parameters of its pathogenesis have not yet been established. It is generally accepted that many types of injury, and prolonged strenous sporting activity are capable of producing the initial cartilage lesion that leads to the development of degenerative joint disease. But little information is available on its frequency in young athletes. The present study was designed to obtain more precise information about the effect of prolonged strenuous athletic activities on the development of osteoarthrosis in young women athletes. After a detailed clinical examination of the joints of 50 Korean young women volley ball players between 19 and 24 years of age, routine roentgenography was taken of hips, knees, ankles, shoulders, elbows, wrists and hands. The following results were obtained: 1. 23(46%) of 50 young women volley ball players had radiological evidence of osteoarthrosis in one or other of the joint X-rays, but there was no instance of apparent narrowing of the joint space. Nine(18%) of 50 young players had osteoarthrosis in more than 2 joints. Among 50 young volley ball players, 19(38%) athletes had symptomatic osteoarthrosis. 2. The knee joints were most commonly affected(34%). Less frequent sites were ankles(16%), elbow(8%), shoulders(8%) and hips(2%). But there was no involvement of the distal interphalangeal joints of the hand which are most frequently affected in the elderly. 3. 8(16%) of 50 athletes were found to have osteoarthrosis at the site of an injury. The knee joints showed this association most frequently. 4. It was found that body weight and occupation did not affect the incidence of the osteoarthrosis significantly.

A Study on the Acrylamide Gel Electrophoretic Analysis of Joint Fluid Proteins / 대한정형외과학회잡지

Analysis of synovial fluid is a most helpful aid in diagnosis and differentiating the varlous types of arthritis. But little information is available on joint fluid proteins and immunoglobullns. The present study was designed to obtain more precise information about each component of joint fluid proteins, using Acrylamide Gel Microzone system with a Densitometer. The following results were obtained: 1. The amount of total protein in both types of arthritis was approximately twice as high as that in the normal group (Normal;2.12± 0.50g%, R.A.;4.51± 1.18g%, Tbc;4.10± 1.02g%). 2. The albumin fraction was decreased in both types of arthrltis (R.A.;42.15± 5.21g%, Tbc; 44.24± 5.61g%) in comparison with 65.25± 4.40g% in the normal group. 3. The percentages of Alpha 1 and Beta globulin in both types of arthritis were similar to that in the normal group. (Normal:Alpha 1;6.01± 1.10, beta; 12.40± 1.90) 4. The percentages of Alpha 2 globulin and gamma globulin in both types of arthritis were approximately twice as high as that in the normal group. (Normal:Alpha 2;5.31± 1.62, Gamrna; 11.03± 1.51).