Houttuynia cordata Improves Cognitive Deficits in Cholinergic Dysfunction Alzheimer’s Disease-Like Models

Cognitive impairment is a result of dementia of diverse causes, such as cholinergic dysfunction and Alzheimer’s disease (AD). Houttuynia cordata Thunb. (Saururaceae) has long been used as a traditional herbal medicine. It has biological activities including protective effects against amyloid beta (Aβ) toxicity, via regulation of calcium homeostasis, in rat hippocampal cells. To extend previous reports, we investigated the effects of water extracts of H. cordata herb (HCW) on tauopathies, also involving calcium influx. We then confirmed the effects of HCW in improving memory impairment and neuronal damage in mice with Aβ-induced neurotoxicity. We also investigated the effects of HCW against scopolamine-induced cholinergic dysfunction in mice. In primary neuronal cells, HCW inhibited the phosphorylation of tau by regulating p25/p35 expression in Aβ-induced neurotoxicity. In mice with Aβ-induced neurotoxicity, HCW improved cognitive impairment, as assessed with behavioral tasks, such as novel object recognition, Y-maze, and passive avoidance tasks. HCW also inhibited the degeneration of neurons in the CA3 region of the hippocampus in Aβ-induced neurotoxicity. Moreover, HCW, which had an IC₅₀ value of 79.7 μg/ml for acetylcholinesterase inhibition, ameliorated scopolamine-induced cognitive impairment significantly in Y-maze and passive avoidance tasks. These results indicate that HCW improved cognitive impairment, due to cholinergic dysfunction, with inhibitory effects against tauopathies and cholinergic antagonists, suggesting that HCW may be an interesting candidate to investigate for the treatment of AD.     

Cerebral protective and cognition-improving effects of sinapic acid in rodents

We previously demonstrated that tenuifoliside B and 3,6'-disinapoylsucrose in Polygalae Radix, the root of Polygala tenuifolia WILLDENOW, inhibited potassium cyanide (KCN)-induced hypoxia and scopolamine-induced memory impairment in mice. Because both ingredients have a common sinapoyl moiety in their structure, we inferred that the sinapoyl moiety could inhibit hypoxia and memory impairment. In the present study to clarify the hypothesis, sinapic acid inhibited KCN-induced hypoxia and scopolamine-induced memory impairment as well as tenuifoliside B and 3,6'-disinapoylsucrose did. In addition, sinapic acid inhibited decompression- or bilateral carotid artery ligation-induced hypoxia (or mortality) and CO2-induced impairment in mice, and basal forebrain lesion-induced cerebral cholinergic dysfunction (decreases in acetylcholine concentration and choline acetyltransferase activity) in rats. These results, taken together, suggest the possibilities that sinapic acid is not only a very important moiety in the pharmacological activities of tenuifoliside B and 3,6'-disinapoylsucrose but also a candidate for a cerebral protective and cognition-improving medicine.     

Ethanolic Extract of the Seed of Zizyphus jujuba var. spinosa Ameliorates Cognitive Impairment Induced by Cholinergic Blockade in Mice

In the present study, we investigated the effect of ethanolic extract of the seed of Zizyphus jujuba var. spinosa (EEZS) on cholinergic blockade-induced memory impairment in mice. Male ICR mice were treated with EEZS. The behavioral tests were conducted using the passive avoidance, the Y-maze, and the Morris water maze tasks. EEZS (100 or 200 mg/kg, p.o.) significantly ameliorated the scopolamine-induced cognitive impairment in our present behavioral tasks without changes of locomotor activity. The ameliorating effect of EEZS on scopolamine-induced memory impairment was significantly reversed by a sub-effective dose of MK-801 (0.0125 mg/kg, s.c.). In addition, single administration of EEZS in normal naïve mouse enhanced latency time in the passive avoidance task. Western blot analysis was employed to confirm the mechanism of memory-ameliorating effect of EEZS. Administration of EEZS (200 mg/kg) increased the level of memory-related signaling molecules, including phosphorylation of extracellular signal-regulated kinase or cAMP response element-binding protein in the hippocampal region. Also, the time-dependent expression level of brain-derived neurotrophic factor by the administration of EEZS was markedly increased from 3 to 9 h. These results suggest that EEZS has memory-ameliorating effect on scopolamine-induced cognitive impairment, which is mediated by the enhancement of the cholinergic neurotransmitter system, in part, via NMDA receptor signaling, and that EEZS would be useful agent against cognitive dysfunction such as Alzheimer’s disease.     

Improvement by low doses of nociceptin on scopolamine-induced impairment of learning and/or memory

The effects of fmol doses of nociceptin/orphanin FQ on scopolamine-induced impairment of learning and/or memory were examined using spontaneous alternation of Y-maze and step-down type passive avoidance tasks. While fmol doses of nociceptin alone had no effect on spontaneous alternation or passive avoidance behavior in normal mice, administration of nociceptin (10 and/or 100 fmol/mouse) 30 min before spontaneous alternation performance or the training session of the passive avoidance task, significantly improved the scopolamine-induced impairment of spontaneous alternation and passive avoidance behavior. This ameliorating effect was not antagonized by nocistatin (0.5 and 5.0 nmol/mouse, i.c.v.), naloxone benzoylhydrazone (2.3, 11.2, and 56.1 micromol/kg, s.c.) or nor-binaltorphimine (4.9 nmol/mouse, i.c.v.). These results indicated that very low doses of nociceptin ameliorate impairments of spontaneous alternation and passive avoidance induced by scopolamine, and suggested that this peptide has bidirectional modulatory effects on learning and memory; impairment at high doses and amelioration at low doses.     

Effects of systemic administration of beta-casomorphin-5 on learning and memory in mice

The effects of systemic administration of bovine beta-casomorphin-5 (Tyr-Pro-Phe-Pro-Gly), a mu-opioid receptor agonist derived from milk beta-casein, on spontaneous alternation behavior in the Y-maze (spatial short-term memory) and step-down-type passive avoidance response (non-spatial long-term memory) were investigated in mice. Intraperitoneal (i.p.) administration of beta-casomorphin-5 (0.1-20 mg/kg) did not have a significant effect on either spontaneous alternation behavior or passive avoidance response. However, a low dose (1 mg/kg, i.p.) of beta-casomorphin-5 improved scopolamine (1 mg/kg, s.c.)-induced impairment of spontaneous alternation behavior and passive avoidance response. Pretreatment with intracerebroventricular injections of beta-funaltrexamine (a mu-opioid receptor antagonist, 0.1 microg/mouse) and naloxonazine (a mu(1)-opioid antagonist, 5 microg/mouse), which did not improve scopolamine-induced impairment, prevented the ameliorating effect of beta-casomorphin-5 on scopolamine-induced impairment of passive avoidance response. These results indicated that systemic administration of a low dose (1 mg/kg, i.p.) of beta-casomorphin-5 improves the disturbance of learning and memory resulting from cholinergic dysfunction through central mediation involving mu(1)-opioid receptors.     

Role of central angiotensin receptors in scopolamine-induced impairment in memory, cerebral blood flow, and cholinergic function

Rational

Inhibition of renin?Cangiotensin system (RAS) improves cognitive functions in hypertensive patients. However, role of AT1 and AT2 receptors in memory impairment due to cholinergic hypofunction is unexplored.

Objective

This study investigated the role of AT1 and AT2 receptors in cerebral blood flow (CBF), cholinergic neurotransmission, and cerebral energy metabolism in scopolamine-induced amnesic mice.

Methods

Scopolamine was given to male Swiss albino mice to induce memory impairment tested in passive avoidance and Morris water maze tests after a weeklong administration of blocker of AT1 receptor, candesartan, and AT2 receptor, PD123, 319. CBF was measured by laser Doppler flowmetry. Biochemical and molecular studies were done in cortex and hippocampus of mice brain.

Results

Scopolamine caused memory impairment, reduced CBF, acetylcholine (ACh) level, elevated acetylcholinesterase (AChE) activity, and malondialdehyde (MDA). Administration of vehicle had no significant effect on any parameter in comparison to control. Candesartan prevented scopolamine-induced amnesia, restored CBF and ACh level, and decreased AChE activity and MDA level. In contrast, PD123, 319 was not effective. However, the effect of AT1 receptor blocker on memory, CBF, ACh level, and oxidative stress was blunted by concomitant blockade of AT2 receptor. Angiotensin-converting enzyme (ACE) activity, ATP level, and mRNA expression of AT1, AT2, and ACE remained unaltered.

Conclusion

The study suggests that activation of AT1 receptors appears to be involved in the scopolamine-induced amnesia and that AT2 receptors contribute to the beneficial effects of candesartan. Theses finding corroborated the number of clinical studies that RAS inhibition in hypertensive patients could be neuroprotective.     

Suppression of nitric oxide synthesis by L-NAME reverses the beneficial effects of pioglitazone on scopolamine-induced memory impairment in mice

Pioglitazone, an agonist of peroxisome proliferator-activated receptor gamma (PPARγ), which is widely used in treatment of type 2 diabetes, has shown some therapeutic effect in Alzheimer's disease. In this study, effects of acute pioglitazone on acquisition, consolidation and retrieval of memory, and also the involvement of nitric oxide (NO) in the effects of pioglitazone on spatial recognition memory has been investigated in a two-trial recognition Y-maze test and passive avoidance in mice. Memory impairment was induced by scopolamine (1 mg/kg, i.p.). Pioglitazone (10 and 20 mg/kg, p.o.) was administrated prior to either acquisition, consolidation or retention trials, while L-NAME (N-nitro-l-arginine methyl ester), a non-specific NO synthase inhibitor, was administered (10 mg/kg, i.p.) 30 min before each trial. Results: 1) pioglitazone improved the acquisition of recognition spatial memory-impaired by scopolamine; L-NAME dramatically reversed improving effects of pioglitazone on memory acquisition; 2) pioglitazone did not change the consolidation of spatial memory, impaired by scopolamine; 3) pioglitazone improved the retrieval of spatial memory and L-NAME did not alter the beneficial effect of pioglitazone; 4) pioglitazone did not affect scopolamine-induced cognitive impairments in the passive avoidance test.The present study demonstrates the beneficial effect of acute pioglitazone administration on acquisition and retrieval of scopolamine-induced cognitive deficits. This effect was reversed only in acquisition phase by nitric oxide synthase inhibitor, L-NAME, therefore, it could be concluded that NO might be involved in the pioglitazone beneficial effect of spatial memory acquisition.     

Effects of four non-cholinergic cognitive enhancers in comparison with tacrine and galanthamine on scopolamine-induced amnesia in rats

Amnesia can be induced in rats in the passive avoidance paradigm by administration of scopolamine, a central muscarinic receptor antagonist. Tacrine or galanthamine, inhibitors of acetylcholinesterase, given in conjunction with scopolamine partially reversed the scopolamine-induced deficit in passive avoidance performance. Four so-called cognitive enhancers, all widely used for the treatment of the symptoms associated with mental aging, cerebral insufficiency and senile memory disorder, were investigated in this paradigm. Piracetam, an extract of Ginkgo biloba, dihydroergocristine and a combination of raubasine with dihydroergocristine, all attenuated the amnesia induced by scopolamine. In contrast, nicergoline had no significant effect. Raubasine alone also failed to significantly attenuate scopolamine-induced amnesia, although some doses of raubasine had a non-significant tendency (P<0.10) to reduce the amnesia.     

Acteoside of Callicarpa dichotoma attenuates scopolamine-induced memory impairments

We previously reported that ten phenylethanoid glycosides including acteoside isolated from the leaves and twigs of Callicarpa dichotoma significantly attenuated glutamate-induced neurotoxicity. In the present study, we examined anti-amnesic activity of acteoside using scopolamine-induced (1 mg/kg body weight, s.c.) amnesic mice with both passive avoidance and Morris water maze tests. Acute oral treatment (single administration prior to scopolamine treatment) of mice with acteoside (1.0, 2.5 mg/kg body weight) significantly mitigated scopolamine-induced memory deficits in the passive avoidance test. It is interesting to note that prolonged oral daily treatment of mice with much lower amount (0.1 mg/kg body weight) of acteoside for 10 d reversed the scopolamine-induced memory deficits. In the Morris water maze, prolonged oral treatment with acteoside (prolonged daily administration of 1.0 mg/kg body weight for 10 d) significantly ameliorated scopolamine-induced memory deficits showing the formation of long-term and/or short-term spatial memory. We suggest, therefore, that acteoside has anti-amnesic activity that may ultimately hold significant therapeutic value in alleviating certain memory impairment observed in Alzheimer's disease.     

Improvement in long term and visuo-spatial memory following chronic pioglitazone in mouse model of Alzheimer's disease

Peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonists (thiazolidinediones) are widely prescribed for the treatment of type-II diabetes mellitus. Recently, PPAR-γ agonists have shown neuroprotective effects in neurodegenerative disorders. The current study was carried out to investigate the effects of chronic administration of pioglitazone, a PPAR-γ agonist, on cognitive impairment in a mouse model of Alzheimer's disease induced by scopolamine. Scopolamine was administered in a dose of 1 mg/kg intraperitoneally (i.p.). Cognitive functions were assessed using step-down latency (SDL) on a passive avoidance apparatus and escape latency in Morris water maze test. Pioglitazone was also investigated for its effects on parameters of oxidative stress by measuring malondialdehyde (MDA) and reduced glutathione (GSH) levels in the brain. Scopolamine produced significant reduction in SDL and prolongation of escape latency indicating cognitive impairment in mice. Pioglitazone (20 and 40 mg/kg, i.p.), administered for 21 days, showed significant dose-dependent improvement in scopolamine-induced dysfunctions in long-term and visuo-spatial memory in passive avoidance and Morris water maze tests, respectively. Furthermore, pioglitazone significantly prevented the fall in GSH levels and elevation in brain MDA levels induced by scopolamine. These results demonstrate that pioglitazone offers protection against scopolamine-induced dysfunctions in long-term and visuo-spatial memory, possibly due to its antioxidant action, and therefore, could have a therapeutic potential in Alzheimer's disease.     

国产与加拿大产西洋参茎叶总皂苷促智作用的比较

目的对国产和加拿大产西洋参茎叶总皂苷在促进学习记忆、保护急性脑缺血作用方面进行比较研究。方法采用小鼠一次性训练被动回避式条件反射的方法(跳台法、避暗法)和空间辨别学习记忆实验(水迷宫法)等方法进行研究。结果国产西洋参茎叶总皂苷(20 mg.kg-1)和加拿大产西洋参茎叶总皂苷(20 mg.kg-1)可显著减少东莨菪碱致记忆获得障碍小鼠在跳台实验中的错误次数,并可不同程度地延长脑缺血再灌注小鼠在跳台及避暗中的潜伏期,显著缩短水迷宫实验中小鼠找到安全台的时间,还可显著延长双侧颈总动脉结扎小鼠存活时间。结论国产西洋参茎叶总皂苷在促智作用方面表现出与加拿大产西洋参茎叶总皂苷相似的药效。     

Tachykinin NK₁ receptor antagonist co-administration attenuates opioid withdrawal-mediated spinal microglia and astrocyte activation

Stigmasterol, a kind of phytosterol, is present in small amounts in various foods. In the present study, we investigated the effects of stigmasterol on scopolamine-induced memory impairments using the passive avoidance and the Morris water maze tasks in mice. In addition, changes in memory-related molecules, including extracellular signal-regulated kinase (ERK) and cAMP response element-binding protein (CREB), were examined following the administration of stigmasterol. Scopolamine-induced memory impairments were significantly attenuated by the administration of stigmasterol (10mg/kg) in the passive avoidance task. In the Morris water maze task, the escape latencies were significantly decreased in the stigmasterol-treated group compared to the scopolamine-treated group during the training phase. The swimming times within the target zone during the probe trial were significantly increased as compared to scopolamine-treated mice. Furthermore, the ameliorating effect of stigmasterol on scopolamine-induced memory dysfunction was blocked by a sub-effective dose of dizocilpine (MK-801), an NMDA receptor antagonist, and tamoxifen, an estrogen receptor antagonist, in the passive avoidance task. In addition, the expression levels of phosphorylated ERK and CREB in the hippocampus were significantly increased by stigmasterol, which was blocked by tamoxifen or MK-801 with scopolamine. These results suggest that stigmasterol-induced cognitive ameliorative effects are mediated by the enhancement of cholinergic neurotransmission system via the activation of estrogen or NMDA receptors.     

Vinpocetine: nootropic effects on scopolamine-induced and hypoxia-induced retrieval deficits of a step-through passive avoidance response in rats

Vinpocetine, vincamine, aniracetam, and Hydergine, compounds with purported cognition activating activity, were evaluated for their ability to prevent scopolamine-induced and hypoxia-induced impairment of passive avoidance retention (24 hr) in rats. Vinpocetine (peak effect dose [PED]= 200 mg/kg PO), aniracetam (PED = 100 mg/kg PO), vincamine (PED = 30 mg/kg PO), and Hydergine (PED = 1 mg/kg PO) prevented memory disruption by scopolamine. Vinpocetine (PED = 3 mg/kg PO) and aniracetam (PED = 30 mg/kg PO) were also effective in preventing disruption of passive avoidance retention impaired by 7% oxygen hypoxia. In contrast, Hydergine (0.05 to 3 mg/kg PO) and vincamine (0.3 to 100 mg/kg PO) were not effective against hypoxia-induced impairment. Hydergine at doses greater than 10 mg/kg PO markedly impaired motor function. In both tests the protection was dose-related for all test substances in an inverted U-shaped manner. Mecamylamine (1, 3, 10 mg/kg SC), (-)-nicotine (0.1 to 0.4 mg/kg SC), apovincaminic acid (1-400 mg/kg PO) and pemoline (1-100 mg/kg PO) did not protect against memory impairment induced by either procedure. These data support the view that vinpocetine, a compound chemically distinct from the pyrrolidinones, has a cognitive activating ability as defined in models of both scopolamine-induced and hypoxia-induced memory impairment in rats.     

Protective effect of Cnestis ferruginea and its active constituent on scopolamine-induced memory impairment in mice: A behavioral and biochemical study

Abstract

Context: Cnestis ferruginea Vahl ex DC (Connaraceae) (CF) is used in traditional African medicine in the management of CNS disorders. The degeneration and dysfunction of cholinergic neurons is closely associated with the cognitive deficits of Alzheimer’s disease (AD) and oxidative stress has been implicated in its pathogenesis. However, the influence of C. ferruginea on the cholinergic system and oxidative stress parameters has not been explored.

Objective: The present study investigates the effect of methanol root extract of C. ferruginea and its active constituent amentoflavone (CF-2) on memory, oxidative stress and acetylcholinesterase (AChE) activity in scopolamine-induced amnesia.

Materials and methods: Mice were orally treated with CF (25–200?mg/kg), CF-2 (6.25–25?mg/kg) for three days and memory impairment was induced by intraperitoneal injection of scopolamine (3?mg/kg). Memory function was evaluated by passive avoidance and Morris water maze tests. Biochemical parameters of oxidative stress and cholinergic function were estimated in brain after the completion of behavioral studies.

Results: Scopolamine caused memory impairment along with increased AChE activity and oxidative stress in mice brain. Oral administration of CF and CF-2 significantly prevented scopolamine-induced memory impairment, inhibited AChE and enhanced antioxidant enzyme activity in the brain following scopolamine injection as compared to vehicle administration in scopolamine (i.p.)-treated mice that were comparable to the effect of tacrine.

Discussion and conclusion: The study demonstrated that C. ferruginea and its constituent have significant protective effect against scopolamine-induced memory deficits in mice that can be attributed to their antioxidant and antiAChE activity.     

Tanshinone congeners improve memory impairments induced by scopolamine on passive avoidance tasks in mice

Tanshinones are a group of diterpenoids found in the roots of Salvia miltiorrhiza Bunge which has been used to treat cardiac disease. In the present study, we investigated the effect of the tanshinone congeners, tanshinone I, tanshinone IIA, cryptotanshinone, and 15, 16-dihydrotanshinone I, on learning and memory impairments induced by scopolamine (1 mg/kg, i.p.), a muscarinic antagonist, using passive avoidance tasks in mice. Tacrine was used as a positive control. Tanshinone I (2 or 4 mg/kg, p.o.), tanshinone IIA (10 or 20 mg/kg, p.o.), cryptotanshinone (10 mg/kg, p.o.), and 15, 16-dihydrotanshinone I (2 or 4 mg/kg, p.o.) significantly reversed scopolamine-induced cognitive impairments (P<0.05). Tanshinone I (2 mg/kg, p.o.) and tanshinone IIA (10 or 20 mg/kg, p.o.) were also reversed diazepam-induced cognitive dysfunctions (P<0.05). In addition, cryptotanshinone and 15, 16-dihydrotanshinone I were found to have an inhibitory effect on acetylcholinesterase in vitro with IC(50) values 82 and 25 microM, respectively. Furthermore, cryptotanshinone inhibited acetylcholinesterase activity for 3 h and 15, 16-dihydrotanshinone I for 6 h in an ex-vivo study. These results suggest that tanshinone congeners may be useful for the treatment of cognitive impairment and that their beneficial effects are mediated, in part, by cholinergic signaling enhancement.     

Cognitive-enhancing and antioxidant activities of iridoid glycosides from Scrophularia buergeriana in scopolamine-treated mice

The cognitive-enhancing activities of E-harpagoside and 8-O-E-p-methoxycinnamoylharpagide (MCA-Hg) isolated from Scrophularia buergeriana were evaluated in scopolamine-induced amnesic mice by the Morris water maze and by passive avoidance tests. E-harpagoside and MCA-Hg significantly improved the impairment of reference memory induced by scopolamine in the Morris water maze test. The mean escape latency, the mean path length and swimming movement were also improved by both compounds. In passive avoidance test, E-harpagoside and MCA-Hg (2 mg/kg body weight, p.o.) significantly ameliorated scopolamine-induced amnesia by as much as 70% of the level found in normal control mice. Donepezil, an acetylcholinesterase inhibitor and the most widely used drug for AD treatment was employed as a positive control. The activity of acetylcholinesterase was inhibited significantly by E-harpagoside or MCA-Hg within the cortex and hippocampus to a level similar to that observed in mice treated with donepezil (2 mg/kg body weight, p.o.). Moreover, treatment with E-harpagoside or MCA-Hg to scopolamine-induced amnesic mice significantly decreased TBARS level which was accompanied by an increase in the activities or contents of glutathione reductase, SOD and reduced GSH. We believe these data demonstrate that E-harpagoside or MCA-Hg exerted potent cognitive-enhancing activity through both anti-acetylcholinesterase and antioxidant mechanisms.     

Modulatory effect of sildenafil in diabetes and electroconvulsive shock-induced cognitive dysfunction in rats

The nitric oxide/guanylyl cyclase, cyclic guanosine monophosphate/phosphodiesterase 5 (NO/cGMP/PDE5) pathways play a key role in physiological and pathological situations, such as synaptic plasticity, learning and memory formation, diabetic gastropathy and neuropathy, long-term potentiation (LTP), epilepsy, cerebral ischemia, and neurodegenerative diseases. Several studies have demonstrated the alteration of NO-cGMP pathway in cognitive impairment. The present study was aimed to study the effect of sildenafil, a PDE5 inhibitor on diabetes and electroconvulsive shock (ECS)-induced cognitive dysfunction in rat using one-trial step-through type of passive avoidance and elevated plus-maze task. Diabetic and ECS-treated rats showed poor learning performance in step-through passive avoidance and plus-maze task. Acute administration of sildenafil significantly reversed the diabetes and ECS-induced retention deficits in both the test paradigms. Sildenafil also significantly improved the cognitive performance in young rats in both the paradigms. Furthermore, L-NAME, a non-selective NOS inhibitor and methylene blue, a guanylate cyclase inhibitor blocked the effect of sildenafil. The results thus suggest that cognitive impairment might be due to the modulatory effect of nNOS or PDE5 enzyme on cGMP levels. Moreover, sildenafil-induced reversal of cognitive impairment suggests the protective role of PDE5 inhibitors in neurodegenerative disorders.     

The ameliorating effect of the extract of the flower of Prunella vulgaris var.lilacina on drug-induced memory impairments in mice

Prunella vulgaris var. lilacina is widely distributed in Korea, Japan, China, and Europe, and its flowers are used to treat inflammation in traditional Chinese medicine. In the present study, we studied the effects of the ethanolic extract of the flower of P. vulgaris var. lilacina (EEPV) on drug-induced learning and memory impairment using the passive avoidance, the Y-maze, and the Morris water maze tasks in mice. EEPV (25 or 50 mg/kg, p.o.) significantly ameliorated scopolamine-induced cognitive impairments in the passive avoidance and Y-maze tasks (P < 0.05). In the Morris water maze task, EEPV (25 mg/kg, p.o.) significantly shortened escape latencies in training-trials. Furthermore, swimming times within the target zone during the probe-trial were significantly increased as compared with scopolamine-treated mice (P < 0.05). In addition, the reduced latency induced by MK-801 treatment in the passive avoidance task was ameliorated by EEPV (25 mg/kg, p.o.) (P < 0.05). Additionally, the ameliorating effect of EEPV on scopolamine-induced memory dysfunction was antagonized by a sub-effective dose of MK-801. These results suggest that EEPV would be useful for treating cognitive impairments induced by cholinergic dysfunction, and that it exerts its effects via NMDA receptor signaling.     

Effect of nicergoline on learning and memory

The anti-amnestic action of nicergoline was studied using the following experimental methods for learning and memory impairment, based on passive avoidance response: amnesia induced by maximal electroshock in mice, scopolamine-induced amnesia in mice and amnesia by paradoxical sleep deprivation in rats. Piracetam, meclofenoxate, pyritinol, deanol and phenazepam were used as reference drugs. The results show that nicergoline demonstrates well-expressed anti-amnestic effect manifested by reducing the amnestic effect of maximal electroshock, scopolamine or paradoxical sleep deprivation, its effect being equal to or more pronounced than piracetam, meclofenoxate, pyritinol, deanol and phenazepam.     

Cognition-enhancing and neuroprotective effects of hederacolchiside-E from Pulsatilla koreana

The root extract of Pulsatilla koreana (Ranunculaceae) has been found to have prominent abilities to reverse scopolamine-induced cognitive impairment in rats, and to increase the viability of human neuroblastoma SK-N-SH cells incubated with amyloid-beta peptide (1 - 42) [A beta (1 - 42)]. In vivo and in vitro activity-guided fractionation studies using solvent-partitioning and subsequent chromatographic separations led to the isolation of hederacolchiside-E, an oleanolic glycoside, as an active ingredient. Administration of hederacolchiside-E (30 and 60 mg/kg body weight, P. O.) increased the step-through latency time in the passive avoidance test as efficiently as tacrine (30 mg/kg, P. O.). The neuroprotective effect of hederacolchiside-E on SK-N-SH cells against the toxicity of A beta (1 - 42) was comparable to that of catechin. These data suggest that hederacolchiside-E might be a good therapeutic candidate for the treatment of Alzheimer's disease.