Cajanus cajan (L) Millsp. seed extract ameliorates scopolamine-induced amnesia through increase in antioxidant defense mechanisms and cholinergic neurotransmission.

Decline in cholinergic function and oxidative/nitrosative stress play a central role in Alzheimer's disease (AD). Previous quantitative HPLC profiling analysis has revealed the presence of Pinostrobin, formononetin, vitexin and other neuroprotective flavonoids in Cajanus cajan seed extract. This study was designed to investigate the protective action of Cajanus cajan ethanol seed extract (CC) on learning and memory functions using scopolamine mouse model of amnesia. Materials and methods: Adult mice were pretreated with CC (50, 100, or 200mg/kg, p.o) or vehicle (10ml/kg, p.o) for 16 days consecutively. Scopolamine, a competitive muscarinic cholinergic receptor antagonist (1mg/kg, i.p.) was given an hour after CC pretreatment from days 3 to 16.  The mice were subjected to behavioural tests from day 11 (open field test (OFT)/ Y-maze test (YMT) and Morris water maze task (MWM) from days 12-16. Animals were euthanized 1h after behavioral test on day 16 and discrete brain regions isolated for markers of oxidative stress and cholinergic signaling. Molecular docking analysis was undertaken to predict the possible mechanism(s) of CC-induced anti-amnesic action.  pre-administration of CC significantly reversed working memory and learning deficits caused by scopolamine in YMT and MWM tests, respectively. Moreover, CC prevented scopolamine-induced oxidative and nitrosative stress radicals in the hippocampus evidenced in significant increase in glutathione (GSH) level, superoxide dismutase (SOD) and catalase (CAT) activities with a marked decrease in malondialdehyde (MDA) production, as well as significant inhibition of hippocampal scopolamine-induced increase in acetylcholinesterase activity by CC. The molecular docking analysis showed that out of the 19 compounds, the following had the highest binding affinity; Pinostrobin (-8.7 Kcal/mol), friedeline (-7.5kCal/mol), and lupeol (-8.2 Kcal/mol), respectively, to neuronal muscarinic M1 acetylcholine receptor, α7 nicotinic acetylcholine receptor and amyloid beta peptide binding pockets, which further supports the ability of CC to enhance neuronal cholinergic signaling and possible inhibition of amyloid beta aggregation. This study showed that Cajanus cajan seeds extract improved working memory and learning through enhancement of cholinergic signaling, antioxidant capacity and reduction in amyloidogenesis.

Potential ameliorative effect of Cynodon dactylon (L.) pers on scopolamine-induced amnesia in rats: Restoration of cholinergic and antioxidant pathways.

AIM: The present study explored Cynodon dactylon hydro-ethanolic extract (CDE) effect on scopolamine-induced amnesic rats. MATERIALS AND METHODS: C. dactylon extract was subjected to antioxidant (DPPH and H2O2) and acetylcholinesterase enzyme tests by in vitro methods. Scopolamine (1 mg/kg, i.p) was administered to rats except for normal control. Donepezil (3 mg/kg, p.o), CDE (100, 200, and 400 mg/kg p.o) were administered to treatment groups. Behavioral paradigm: Morris water maze (MWM), elevated plus maze (EPM), and passive avoidance test (PAT) were conducted. Later, rats were sacrificed and brain homogenate was tested for levels of acetylcholinesterase, glutathione, and lipid peroxidase. Histopathology examination of cortex and hippocampus of all the groups was done. STATISTICAL METHOD: The statistical methods used were ANOVA and Tukey's post hoc test. RESULTS: CDE antioxidant activity was demonstrated by decreasing DPPH and H2O2 levels confirmed through in vitro analysis. Treatment group rats reversed scopolamine induced amnesia by improvement in spatial memory, decreased transfer latency and increased step through latency significantly (P<0.001) in behavior models such as morris water maze, elevated plus maze and passive avoidance task respectively. CDE modulated acetylcholine transmission by decreased acetylcholinesterase enzyme level (P < 0.001) and scavenging scopolamine-induced oxidative stress by increased reduced glutathione levels and decreased lipid peroxidation levels in the rat brain. CDE and donepezil-treated rats showed mild neurodegeneration in comparison to scopolamine-induced severe neuronal damage on histopathology examination. CONCLUSION: C. dactylon extract provides evidence of anti-amnesic activity by the mechanism of decreased acetylcholinesterase enzyme level and increased antioxidant levels in scopolamine-induced amnesia in rats.

Amelioration of Scopolamine-Induced Amnesic, Anxiolytic and Antidepressant Effects of Ficus Benghalensis in Behavioral Experimental Models.

Background and Objectives: Ficus benghalensis (FB) is a commonly found tree in Pakistan and its various parts have folkloric importance in managing neurological ailments. In the present study, methanolic extract of its bark has been tested on an experimental animal model to evaluate memory-enhancing, anxiolytic and antidepressant activities to validate the claimed therapeutic potential. Materials and Methods: Methanolic extract of freshly isolated bark was prepared and subjected to preliminary phytochemical studies and gas chromatography-mass spectrometry (GC-MS) analysis for the presence of phytocomponents. To evaluate its effect on spatial learning, passive-avoidance test-step through (PAT-ST), Y-maze and Morris water maze (MWM) tests were carried out. Open-field (OFT) and elevated plus maze (EPM) tests were employed to explore the anti-anxiety potential of FB while a forced swimming test (FST) was utilized to assess its anti-depressant prospective. FB doses of 100, 200 and 300 mg/kg with positive and negative controls given to Sprague Dawley (SD) rats. Results: phytochemical studies showed the presence of various phytoconstituents including alkaloids, flavonoids, terpenes, phenolics and anthraquinones. The presence of synephrine, aspargine, glucose, fructose and fatty acids was revealed by GC-MS analysis. FB administration led to significant improved memory retention when evaluated through passive avoidance (p < 0.05), Y-maze (p < 0.05) and Morris water maze (p < 0.05) tests in a scopolamine model of amnesic rats. When tested by open field and elevated plus maze tests, FB demonstrated anxiety-resolving characteristics (p < 0.05) as animals dared to stay in open areas more than a control group. Mobility time was increased and immobility time was reduced (p < 0.05-0.01) in rats treated with FB, unveiling the anti-depressant importance of F. benghalensis. Conclusion: methanolic extract of F. benghalensis bark furnished scientific proof behind folkloric claims of the memory improving, anxiety-reducing and depression-resolving characteristics of the plant. These activities might be possible due to interaction of its phytoconstituents with serotonergic, glutamatergic, cholinergic and GABAergic systems in the brain.

Effect of Gmelina arborea on learning and memory in amnesia-induced and non-amnesia groups of albino Wistar rats.

Background The brain is the centre of the nervous system in all vertebrates. The central cholinergic pathways play a prominent role in learning and memory processes. Dementia is a mental disorder characterized by the loss of intellectual ability, which invariably involves the impairment of memory. The crude extracts of the Gmelina arborea plant are reported to possess wound-healing, anti-diarrheal, anti-oxidant, anti-diabetic, and anti-ulcer property. The present study was designed to evaluate the effects of G. arborea on learning and memory in albino Wistar rats. Methods A total of 36 healthy rats were selected for the study, which were divided in to six groups. Standard screening tests such as the elevated plus maze (EPM), Morris water maze (MWM), and step-down passive avoidance (SDA) tests were used for testing the learning and memory processes. Results Gmelina arborea at higher doses (1000 mg/kg) showed statistically significant activity in EPM, MWM, and SDA tests for assessing the learning and memory paradigms when compared to the control group in amnesia-induced and non-amnesia groups of rats. Conclusions This is the first ever study to report the effects of G. arborea on learning and memory in both amnesia-induced and non-amnesia groups of rats. Our results show that G. arborea potentiates the processes of learning and memory. The observed pharmacological activities should be further evaluated by detailed experimental studies and revalidated by clinical trials.

Terminalia chebula extract prevents scopolamine-induced amnesia via cholinergic modulation and anti-oxidative effects in mice.

BACKGROUND: Terminalia chebula Retz. (Combretaceae) is a traditional herbal medicine that is widely used in the treatment of diabetes, immunodeficiency diseases, and stomach ulcer in Asia. However, the anti-amnesic effect of T. chebula has not yet been investigated. The present study was designed to determine whether T. chebula extract (TCE) alleviates amnesia induced by scopolamine in mice. We also investigated possible mechanisms associated with cholinergic system and anti-oxidant effects. METHODS: TCE (100 or 200 mg/kg) was orally administered to mice for fourteen days (days 1-14), and scopolamine was intraperitoneally injected to induce memory impairment for seven days (days 8-14). Learning and memory status were evaluated using the Morris water maze. Hippocampal levels of acetylcholine (ACh), acetylcholinesterase (AChE) and choline acetyltransferase (ChAT) were measured ex vivo. Levels of reactive oxygen species (ROS), nitric oxide (NO), and malondialdehyde (MDA) in the hippocampus were also examined. RESULTS: In the Morris water maze task, TCE treatment reversed scopolamine-induced learning and memory deficits in acquisition and retention. TCE reduced hippocampal AChE activities and increased ChAT and ACh levels in the scopolamine-induced model. Moreover, TCE treatment suppressed scopolamine-induced oxidative damage by ameliorating the increased levels of ROS, NO, and MDA. CONCLUSION: These findings suggest that TCE exerts potent anti-amnesic effects via cholinergic modulation and anti-oxidant activity, thus providing evidence for its potential as a cognitive enhancer for amnesia.

The ethanolic extract of the Eclipta prostrata L. ameliorates the cognitive impairment in mice induced by scopolamine.

ETHNOPHARMACOLOGICAL RELEVANCE: Eclipta prostrata L. (Asteraceae) has been prescribed for whole body nourishment and nervine tonic in Asia. However, the effects of E. prostrata in learning and memory have not been fully explored. AIM OF THE STUDY: To scientifically elucidate the effects of E. prostrata on cognitive functions, we examined whether E. prostrata could ameliorate a cholinergic blockade-induced memory impairment, and we also investigated the effects of E. prostrata on the synaptic plasticity in the hippocampus. MATERIALS AND METHODS: Memory impairment was induced by scopolamine, a cholinergic muscarinic receptor antagonist. The anti-amnesic effects of the ethanolic extract of Eclipta prostrata L. (EEEP) were measured in mice by the passive avoidance, Y-maze and Morris water maze tasks. To test the effects of EEEP on synaptic plasticity, we measured long-term potentiation (LTP) in the hippocampus. We also studied several signaling molecules related to learning and memory, such as phosphorylated protein kinase B (Akt) or phosphorylated glycogen synthase kinase-3ß (GSK-3ß). RESULTS: In the passive avoidance task, EEEP (50 or 100mg/kg, p.o.) significantly ameliorated the shortened step-through latency induced by scopolamine. EEEP (100mg/kg, p.o.) also showed significant increase in alternation behavior during the Y-maze task. In the Morris water maze task, scopolamine-induced a decrease in both the swimming time within the target zone and the number of crossings where the platform had been placed were significantly reversed by EEEP (50 or 100mg/kg, p.o.). Moreover, EEEP (100µg/ml) significantly enhanced hippocampal LTP without affecting basal synaptic transmission. The administration of EEEP (100mg/kg) increased the phosphorylation levels of Akt and GSK-3ß in the hippocampal region. CONCLUSION: These results suggest that EEEP has memory-ameliorating activity against scopolamine-induced cognitive impairment and facilitates LTP in the hippocampus. This could be, at least in part, mediated by the activation of the Akt-GSK-3ß signaling pathway.

Attenuating effect of bioactive coumarins from Convolvulus pluricaulis on scopolamine-induced amnesia in mice.

Convolvulus pluricaulis Chois. (Convolvulaceae) has been used in Ayurveda as Medhya Rasyana (nervine tonic) to treat various mental disorders. This study was designed to isolate the bioactive compound(s) of this plant and to evaluate their effect against scopolamine-induced amnesia. Column chromatography of the chloroform and ethyl-acetate fractions led to the isolation of three coumarins identified as scopoletin, ayapanin and scopolin. All the three compounds at 2.5, 5, 10 and 15 mg/kg, p.o. were evaluated for memory-enhancing activity against scopolamine-induced amnesia using elevated plus maze and step down paradigms. Effect on acetylcholinesterase activity in mice brain was also evaluated. Scopoletin and scopolin, in both the paradigms, significantly and dose dependently attenuated the scopolamine-induced amnesic effect. Furthermore, these compounds at 10 and 15 mg/kg exhibited activity comparable to that of standard drug, donepezil. The compounds also exhibited significant acetylcholinesterase inhibitory activity.

Antiamnesic and Antioxidants Effects of Ferulago angulata Essential Oil Against Scopolamine-Induced Memory Impairment in Laboratory Rats.

Ferulago angulata (Apiaceae) is a shrub indigenous to western Iran, Turkey and Iraq. In traditional medicine, F. angulata is recommended for treating digestive pains, hemorrhoids, snake bite, ulcers and as sedative. In the present study, the effects of inhaled F. angulata essential oil (1 and 3%, daily, for 21 days) on spatial memory performance were assessed in scopolamine-treated rats. Scopolamine-induced memory impairments were observed, as measured by the Y-maze and radial arm-maze tasks. Decreased activities of superoxide dismutase, glutathione peroxidase and catalase along with increase of acetylcholinesterase activity and decrease of total content of reduced glutathione were observed in the rat hippocampal homogenates of scopolamine-treated animals as compared with control. Production of protein carbonyl and malondialdehyde significantly increased in the rat hippocampal homogenates of scopolamine-treated animals as compared with control, as a consequence of impaired antioxidant enzymes activities. Additionally, in scopolamine-treated rats exposure to F. angulata essential oil significantly improved memory formation and decreased oxidative stress, suggesting memory-enhancing and antioxidant effects. Therefore, our results suggest that multiple exposures to F. angulata essential oil ameliorate scopolamine-induced spatial memory impairment by attenuation of the oxidative stress in the rat hippocampus.

Evaluation of potential antiamnesic activities of aqueous extract of Vitex trifolia leaves against scopolamine induced amnesia and in normal rats.

BACKGROUND: The goal of this study was to evaluate the cerebroprotective and cognition-enhancing activities of the aqueous Vitex trifolia (Vt) L. (Verbenaceae) leaf extract against scopolamine-induced amnesia and in normal rats. METHODS: Reference or working memory and long-term memory in rodents were tested by experimental paradigms like passive avoidance (PA) and T-maze (TM), respectively. TM and Morris water maze (MWM) were used to screen putative spatial or localization task and the navigation memory-enhancing activities of Vt extract, respectively. In both the PA and TM models, scopolamine (0.5 mg/kg, intraperitoneal, 30 min prior to the trial) was used to induce amnesia, and donepezil (3 mg/kg/day for 15 days) was used as a standard antiamnesic drug. In MWM, two doses of Vt extract were tested against normal control rats. The aqueous Vt extract was prepared as a suspension in 0.5% carboxymethyl cellulose and administered orally at two doses (10 and 20 mg/kg/day) for 15 days to the respective group of rats. RESULTS: The higher dose (20 mg/kg) of plant extract exhibited significant (p<0.01) antiamnesic activity in the PA and TM models vs. the control. In the MWM test, at probe trial, Vt extract 20 mg/kg showed the least escape latency time, which was statistically significant (p<0.01) and exhibited maximum percentage of time spent in the probe quadrant by 60.75%. CONCLUSIONS: These results partly substantiate the traditional use of Vt leaves for improvement of cognition, indicating that daily administration of Vt leaves differentially could modulate short- and long-term learning and memory in rats probably through its battery of anticholinesterase, procholinergic, anti-inflammatory, antioxidant, and neuroprotective activities.

Total isoflavones from soybean and tempeh reversed scopolamine-induced amnesia, improved cholinergic activities and reduced neuroinflammation in brain.

The present study was undertaken to compare the neuroprotective effects between total isoflavones from soybean and tempeh against scopolamine-induced cognitive dysfunction. Total isoflavones (10, 20 and 40mg/kg) from soybean (SI) and tempeh (TI) were administered orally to different groups of rats (n=6) for 15days. Piracetam (400mg/kg, p.o.) was used as a standard drug while scopolamine (1mg/kg, i.p.) was used to induce amnesia in the animals. Radial arm and elevated plus mazes served as exteroceptive behavioural models to measure memory. Brain cholinergic activities (acetylcholine and acetylcholinesterase) and neuroinflammatory activities (COX-1, COX-2, IL-1ß and IL10) were also assessed. Treatment with SI and TI significantly reversed the scopolamine effect and improved memory with TI group at 40mg/kg, p.o. exhibiting the best improvement (p<0.001) in rats. The TI (10, 20 and 40mg/kg, p.o.) significantly increased (p<0.001) acetylcholine and reduced acetylcholinesterase levels. Meanwhile, only a high dose (40mg/kg, p.o.) of SI showed significant improvement (p<0.05) in the cholinergic activities. Neuroinflammation study also showed that TI (40mg/kg, p.o.) was able to reduce inflammation better than SI. The TI ameliorates scopolamine-induced memory in rats through the cholinergic neuronal pathway and by prevention of neuroinflammation.

Prepulse inhibition (PPI) disrupting effects of Glycyrrhiza glabra extract in mice: a possible role of monoamines.

Liquorice extract was reported to have nootropic and/or antiamnestic effects. Prepulse inhibition (PPI) of startle response is a multimodal, cross-species phenomenon used as a measure of sensorimotor gating. Previous studies indicated that liquorice/its constituents augmented mouse brain monoamine levels. Increased brain monoamines' transmission was suggested to underlie PPI disruption. However, the effect of antiamnestic dose(s) of the extract on PPI has not been investigated despite the coexistence of impaired memory and PPI deficit in some neurological disorders. The effect of administration of the antiamnestic dose of the extract (150 mg/kg for 7 days) was tested on PPI of acoustic startle response in mice. It resulted in PPI disruption and therefore its effect on monoamines' levels was investigated in a number of mouse brain areas involved in PPI response mediation. Results demonstrated that the extract antiamnestic dose augmented cortical, hippocampal and striatal monoamine levels. It was therefore concluded that liquorice extract (150 mg/kg)-induced PPI deficit was mediated through augmenting monoaminergic transmission in the cortex, hippocampus and striatum. These findings can be further investigated in experimental models for autism, psychosis and Huntington's disease to decide the safety of using liquorice extract in ameliorating memory disturbance in disorders manifesting PPI deficit.

Quercetin protects against the Aß(25-35)-induced amnesic injury: involvement of inactivation of rage-mediated pathway and conservation of the NVU.

Quercetin has demonstrated protective effects against Aß-induced toxicity on both neurons and endothelial cells. However, whether or not quercetin has an effect on the neurovascular coupling is unclear. In the present study, we aim to investigate the anti-amnesic effects of quercetin and to explore the underlying mechanisms. Aß(25-35) (10 nmol) was administrated to mice i.c.v. Quercetin was administrated orally for 8 days after injection. Learning and memory behaviors were evaluated by measuring spontaneous alternation in Morris Water Maze test and the step-through positive avoidance test. The regional cerebral blood flow was monitored before the Aß(25-35) injection and on seven consecutive days after injection. Mice were sacrificed and cerebral cortices were isolated on the last day. The effects of quercetin on the neurovascular unit (NVU) integrity, microvascular function and cholinergic neuronal changes, and the modification of signaling pathways were tested. Our results demonstrate that quercetin treatment for Aß(25-35)-induced amnesic mice improved the learning and memory capabilities and conferred robust neurovascular coupling protection, involving maintenance of the NVU integrity, reduction of neurovascular oxidation, modulation of microvascular function, improvement of cholinergic system, and regulation of neurovascular RAGE signaling pathway and ERK/CREB/BDNF pathway. In conclusion, in Aß(25-35)-induced amnesic mice, optimal doses of quercetin administration were beneficial. Quercetin protected the NVU likely through reduction of oxidative damage, inactivation of RAGE-mediated pathway and preservation of cholinergic neurons, offering an alternative medication for Alzheimer's disease.

Cognition-enhancing and neuroprotective activities of the standardized extract of Betula platyphylla bark and its major diarylheptanoids.

Diarylheptanoids have been the center of the intensive research efforts for Alzheimer's disease and other neurodegenerative diseases. The present study aimed to determine the effect of the standardized extract of B. platyphylla bark and its major diarylheptanoids in scopolamine-induced amnesic mice through cyclic AMP response element-binding protein (CREB) activation. Oral administration of the standardized extract of B. platyphylla bark (100mg/kg body weight), aceroside VIII (1mg/kg body weight) and platyphylloside (1 or 2mg/kg body weight) significantly ameliorated scopolamine-induced amnesia in passive avoidance test. CREB phosphorylation and brain-derived neurotrophic factor (BDNF) expression in the cortex and hippocampus of the scopolamine-treated mice were markedly increased by the treatment of the standardized extract of B. platyphylla bark and platyphylloside. The standardized extract of B. platyphylla bark and its major diarylheptanoids also significantly protected HT22 cells against neurotoxicity induced by glutamate insult. The standardized extract of B. platyphylla bark and platyphylloside may ameliorate memory deficits by activating the CREB-BDNF pathway and prevent a neurodegeneration by inhibiting neuronal cell death.

[2-Methyl-3-phenylaminomethylquinolin-4-one as potential antidepressant with nootropic properties].

The new compound, 2-methyl-3-phenylaminomethylquinolin-4-on, belongs to V class of toxicity and exhibits antidepressant and antiamnesic properties. It is established that this compound reduces the duration of immobilization in the test of behavioral despair, prevents from the scopolamine induced amnesia, and exhibits antagonism with reserpine in mice. In a dose of 100 mg/kg, the synthesized compound influences the levels of cerebral catecholamines similarly to imipramine, but with a more pronounced decrease in the level of 5-hydroxytryptamine.

Influence of N-methyl D-aspartate receptor mechanism on WIN55,212-2-induced amnesia in rat dorsal hippocampus.

In this study, we investigated the effects of both N-methyl D-aspartate (NMDA) and MK-801 on WIN55,212-2(WIN)-induced amnesia in rats. Step-through inhibitory avoidance of memory was used to examine the retrieval of memory, 24 h after training. All drugs were injected bilaterally into the dorsal hippocampus (intra-CA1) of rats. Pretraining and posttraining or pretesting administration of the nonselective CB1/CB2 receptor agonist, WIN (0.5 µg/rat), decreased the step-through latency. However, amnesia induced by pretraining or posttraining injections of WIN was reversed by a pretest administration of WIN (0.25 and 0.5 µg/rat). Pretest microinjections of different doses of NMDA (0.1, 0.5, and 1 µg/rat) elicited no response, but NMDA (0.5 and 1 µg/rat) did induce full recovery from amnesia induced by WIN (0.5 µg/rat). The posttraining and pretest injection of a higher dose of the NMDA receptor antagonist, MK801 (MK; 4 µg/rat), caused an impairment in the memory retrieval. However, amnesia induced by posttraining injections of MK (4 µg/rat) was reversed by a pretest administration of MK (4 µg/rat). In addition, pretest administration of different doses of the antagonist (2 and 4 µg/rat) induced full recovery of WIN-induced amnesia, but did not influence memory recovery in the subjects, which had received posttraining (0.5 µg/rat) and pretest WIN (0.25 and 0.5 µg/rat). Pretesting coadministration of ineffective doses of WIN (0.1 µg/rat) with NMDA (0.1 µg/rat), but not with MK (1 µg/rat), restored WIN-induced (0.5 µg/rat) amnesia. It can be concluded that the NMDA receptor mechanism located in the dorsal hippocampus may be involved in WIN-induced amnesia.

Asparagus recemosus enhances memory and protects against amnesia in rodent models.

Asparagus Racemosus (AR) is an Ayurvedic rasayana possessing multiple neuropharmacological activities. The adpatogenic and antidepressant activity of AR is well documented. The present study was undertaken to assess nootropic and anti-amnesic activities of MAR in rats. The Morris water maze (MWM) and elevated plus maze (EPM) models were employed to evaluate learning and memory activity. Subsequently, the anti-amnestic activity was evaluated in scopolamine and sodium nitrite (NaNO(2))-induced amnestic models in rats. Rats pre-treated with MAR (50, 100 and 200mg/kg, p.o) for 7 days showed significant decrease in escape latency in the MWM test indicating nootropic activity. MAR also significantly reversed scopolamine and sodium nitrite-induced increase in transfer latency on EPM indicating anti-amnesic activity. Further, MAR dose-dependently inhibited acetylcholinesterase enzyme in specific brain regions (prefrontal cortex, hippocampus and hypothalamus). Thus, MAR showed nootropic and anti-amnesic activities in the models tested and these effects may probably be mediated through augmentation of cholinergic system due to its anti-cholinesterase activity.

n-3 phosphatidylserine attenuated scopolamine-induced amnesia in middle-aged rats.

Phosphatidylserine (PS) extracted from bovine brain differs from transphosphatidylated soybean lecithin PS (SB-PS) in its n-3 long-chain polyunsaturated fatty acid (LC-PUFA) content. Both, however, were suggested to affect cognitive performance. We compared the effect of chronic administration of a novel n-3 LC-PUFA PS conjugates (n-3 PS) versus SB-PS, fish oil (FO), SB-PS+FO, or control oil in middle-aged rats, on brain fatty acids composition and performance in behavioral tasks. Our hypothesis was that the n-3 LC-PUFA vehicles will affect these outcomes better than the other diets. Brain phospholipid docosahexaenoic acid levels increased significantly (p=0.0434) with n-3 PS only. None of the treatments affected the animals' task performance in compare with the control, although reversal from the non-match-to-sample to match-to-sample rule in the T-maze differed (p=0.0434) between the experimental diets. Conversely, the acquisition of the Morris water maze task was impaired by scopolamine (SCO) in all but the n-3 PS group (p=0.0019). In the probe, when pretreated with SCO, the SB-PS+FO group and to a lesser degree the n-3 PS group, spent longer latency times (p=0.0390) in the non-peripheral zones of the water maze compared to the control; this may be interpreted as anxiolytic-like behavior. These results suggest that the n-3 LC-PUFA carrier may play a role in these fatty acids bioavailability and their impact on specific cognitive processes.

Proapoptotic and prepulse inhibition (PPI) disrupting effects of Hypericum perforatum in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: St. John's wort extract is commonly used as a wound healing, anti-inflammatory, anxiolytic, diuretic, antibiotic, antiviral and cancer chemoprotective agent. It also has nootropic and/or antiamnestic effects. AIM OF THE STUDY: Prepulse inhibition (PPI) of startle response is a valuable paradigm for sensorimotor gating processes. A previous study indicated that single administration of St. John's wort extract (500 mg/kg) caused PPI disruption in rats. The effect of antiamnestic doses of the extract on PPI has not been investigated despite the coexistence of impaired memory and PPI deficit in some neurological disorders. MATERIALS AND METHODS: The effects of acute (500 mg/kg) and chronic (200mg/kg for 3 days) administration of St. John's wort extract were investigated for its antiamnestic activity. The effects of administration of the antiamnestic dose of the extract and hyperforin, its main active component, were tested on PPI of an acoustic startle response in rats. This study also investigated the proapoptotic effect of hyperforin in animals, demonstrating PPI deficit, by electrophoresis of DNA isolated from selected brain areas. RESULTS: Disruption of PPI resulted after treatment of rats with an antiamnestic dose of the extract (200mg/kg for 3 days) and with hyperforin. Gel electrophoresis showed DNA fragmentation of the cortices of hyperforin-treated animals exhibiting PPI deficit. CONCLUSIONS: The exacerbating effect of St. John's wort extract on PPI deficit may provide a limitation for using the extract to manage cognitive disturbance in psychotic and Huntington's disease patients manifesting PPI deficit.

Long-term treatment with fish oil prevents memory impairments but not hippocampal damage in rats subjected to transient, global cerebral ischemia.

Cerebral ischemia leads to neurodegeneration and cognitive impairment. Fish oil (FO) constitutes a rich dietary source of omega-3 polyunsaturated fatty acids especially docosahexaenoic acid (DHA). The objective of the present study was to investigate whether long-term treatment with commercial, high concentration DHA-containing FO could be effective in alleviating both the cognitive and neurodegenerative deficits caused by transient, global cerebral ischemia (TGCI) in rats. Naive rats were trained for 10 days in an 8-arm radial maze task and then subjected to TGCI for 15 minutes (4-VO model) 3 days later (day 13). Retention of the previously acquired cognition (ie, memory) was assessed weekly on days 20, 27, 34, 41, 48, and 55 and measured by 3 behavioral parameters as follows: (i) latency to find the goal box, (ii) number of reference memory errors, and (iii) number of working memory errors. The extent of pyramidal cell death in the hippocampus was examined at the end of the behavioral analysis on day 43. Fish oil (300 mg/kg DHA, gavage) administration occurred once daily beginning 3 days before TGCI (the last day of training) and continued until day 41. Transient, global cerebral ischemia markedly disrupted memory performance measured by all 3 parameters (P < .0001 vs sham). This amnesic effect of ischemia persisted until the end of the behavioral analysis. Treatment with FO progressively reversed the TGCI-induced retention deficit until rats achieved control levels. This protective effect of FO on learning/memory function was clearly observed after both daily and cumulative data analysis (P < .001-0.01 vs vehicle). Such memory improvements remained statistically significant, even after cessation of FO treatment, indicating a sustained effect of FO. In contrast, FO failed to prevent ischemia-induced hippocampal damage in areas CA1, CA2, or CA4. Therefore, the present findings suggest that long-term FO treatment is able to facilitate functional recovery after ischemic brain damage, an effect that was distinct from hippocampal damage.

Alzheimer's disease, amnestic mild cognitive impairment, and age-associated memory impairment: current understanding and progress toward integrative prevention.

Alzheimer's disease, AD, is the most common form of dementia. AD initially targets memory and progressively destroys the mind. The brain atrophies as the neocortex suffers neuronal, synaptic, and dendritic losses, and the hallmark amyloid plaques and neurofibrillary tangles proliferate. Pharmacological management, at best, is palliative and transiently effective, with marked adverse effects. Certain nutrients intrinsic to human biochemistry (orthomolecules) match or exceed pharmacological drug benefits in double-blind, randomized, controlled trials, with superior safety. Early intervention is feasible because its heritability is typically minimal and pathological deterioration is detectable years prior to diagnosis. The syndrome amnestic mild cognitive impairment exhibits AD pathology and to date has frustrated attempts at intervention. The condition age-associated memory impairment is a nonpathological extreme of normal brain aging, but with less severe cognitive impairment than amnestic mild cognitive impairment. Age-associated memory impairment is a feasible target for early intervention against AD, beginning with the modifiable AD risk factors - smoking, hypertension, homocysteine, type 2 diabetes, insulin resistance, and obesity. Stress reduction, avoidance of toxins, and mental and physical exercise are important aspects of prevention. The diet should emphasize omega-3 fatty acids docosahexaenoic acid and eicosapentaenoic acid; flavonoids and other antioxidant nutrients; and B vitamins, especially folate, B6 and B12. Dietary supplementation is best focused on those proven from randomized, controlled trials: the phospholipids phosphatidylserine and glycerophosphocholine, the energy nutrient acetyl-L-carnitine, vitamins C and E, and other antioxidants. A comprehensive integrative strategy initiated early in cognitive decline is the most pragmatic approach to controlling progression to Alzheimer's disease.