Effects of beta-casomorphin-5 on passive avoidance response in mice

The effects of intracerebroventricular (i.c.v.) injection of bovine beta-casomorphin-5 (beta-CM-5: Tyr-Pro-Phe-Pro-Gly), a micro-opioid agonist derived from milk beta-casein, on step-down type passive avoidance tasks were investigated in mice. Intracerebroventricular administration of a high dose (10 microg) of beta-CM-5 produced a significant decrease in step-down latency. beta-Funaltrexamine (5 microg, i.c.v.) almost completely reversed the beta-CM-5-induced shortening of step-down latency, although neither naltrindole (5 ng, i.c.v.) nor nor-binaltorphimine (5 microg, i.c.v.) had any significant influence on the effect of beta-CM-5. Meanwhile, a low dose (0.5 microg, i.c.v.) of beta-CM-5 inhibited scopolamine (1 mg/kg)-induced impairment of passive avoidance response. These results indicated that a high dose of beta-CM-5 induces amnesia, whereas a low dose ameliorates scopolamine-induced amnesia.     

ESP-102, a standardized combined extract of Angelica gigas, Saururus chinensis and Schizandra chinensis, significantly improved scopolamine-induced memory impairment in mice

We assessed the effects of oral treatments of ESP-102, a standardized combined extract of Angelica gigas, Saururus chinensis and Schizandra chinensis, on learning and memory deficit. The cognition-enhancing effect of ESP-102 was investigated in scopolamine-induced (1 mg/kg body weight, s.c.) amnesic mice with both passive avoidance and Morris water maze performance tests. Acute oral treatment (single administration prior to scopolamine treatment) of mice with ESP-102 (doses in the range of 10 to 100 mg/kg body weight) significantly reduced scopolamine-induced memory deficits in the passive avoidance performance test. Another noteworthy result included the fact that prolonged oral daily treatments of mice with much lower amounts of ESP-102 (1 and 10 mg/kg body weight) for ten days reversed scopolamine-induced memory deficits. In the Morris water maze performance test, both acute and prolonged oral treatments with ESP-102 (single administration of 100 mg/kg body weight or prolonged daily administration of 1 and 10 mg/kg body weight for ten days, respectively, significantly ameliorated scopolamine-induced memory deficits as indicated by the formation of long-term and/or short-term spatial memory. In addition, we investigated the effects of ESP-102 on neurotoxicity induced by amyloid-beta peptide (Abeta25-35) or glutamate in primary cultured cortical neurons of rats. Pretreatment of cultures with ESP-102 (0.001, 0.01 and 0.1 mug/ml) significantly protected neurons from neurotoxicity induced by either glutamate or Abeta25-35. These results suggest that ESP-102 may have some protective characteristics against neuronal cell death and cognitive impairments often observed in Alzheimer's disease, stroke, ischemic injury and other neurodegenerative diseases.     

Z-Guggulsterone Improves the Scopolamine-Induced Memory Impairments Through Enhancement of the BDNF Signal in <Emphasis Type="Italic">C57BL</Emphasis>/<Emphasis Type="Italic">6J</Emphasis> Mice

Memory impairment is a common symptom in patients with neurodegenerative disorders, and its suppression could be beneficial to improve the quality of life of those patients. Z-guggulsterone, a compound extracted from the resin of plant Commiphora whighitii, exhibits numerous pharmacological effects in clinical practice, such as treatment of inflammation, arthritis, obesity and lipid metabolism disorders. However, the role and possible mechanism of Z-guggulsterone on brain-associated memory impairments are largely unknown. This issue was addressed in the present study in a memory impairment model induced by scopolamine, a muscarinic acetylcholine receptor antagonist, using the passive avoidance, Y-maze and Morris water maze tests. Results showed that scopolamine significantly decreased the step-through latency and spontaneous alternation of C57BL/6J mice in passive avoidance and Y-maze test, whereas increased the mean escape latency and decreased the swimming time in target quadrant in Morris water maze test. Pretreatment of mice with Z-guggulsterone at doses of 30 and 60 mg/kg effectively reversed the scopolamine-induced memory impairments. Mechanistic studies revealed that Z-guggulsterone pretreatment reversed the scopolamine-induced increase in acetylcholinesterase (AchE) activity, as well as decreases in brain-derived neurotrophic factor (BDNF) protein expression and cAMP response element-binding protein (CREB), extracellular regulated kinase 1/2 (ERK1/2) and protein kinase B (Akt) phosphorylation levels in the hippocampus and cortex. Inhibition of the BDNF signal, however, blocked the memory-enhancing effect of Z-guggulsterone. Therefore, these findings demonstrate that Z-guggulsterone attenuates the scopolamine-induced memory impairments mainly through activation of the CREB-BDNF signaling pathway, thereby exhibiting memory-improving effects.     

Prevention of scopolamine-induced memory deficits by schisandrin B, an antioxidant lignan from Schisandra chinensis in mice

The preventive effect of schisandrin B (Sch B), an antioxidant ingredient of Schisandra chinensis, was studied on scopolamine-induced dementia in mouse. Scopolamine developed oxidative stress in the brain with the decreased levels of antioxidant enzymes and increased nitrite level. At the same time, a significant impairment of learning and memory occurred when evaluated by passive avoidance task (PAT) and Morris water maze (MWM) with concomitant increase of acetylcholinesterase (AChE) activity and decreased acetylcholine levels. Pre-treatment by Sch B (10, 25, 50 mg/kg) effectively prevented scopolamine-induced oxidative stress and improved behavioural tasks. Further, the scopolamine-induced increase in AChE activity was significantly suppressed and the level of acetylcholine was maintained as normal by Sch B treatment. These results suggest that Sch B have protective function against cerebral functional defects such as dementia not only by antioxidant prevention but also exerting its potent cognitive-enhancing activity through modulation of acetylcholine level.     

Effects of luteolin on learning acquisition in rats: involvement of the central cholinergic system

The study was conducted to investigate the ameliorating effects of luteolin on memory acquisition in rats. The effects of luteolin on scopolamine-induced impairment of passive avoidance response were evaluated primarily, as well as the role of the central nervous system through the use of central neurotoxins and central nervous antagonists. Luteolin was not reversed by scopolamine N-methylbromide (M-SCOP) but blocked the impairment of learning acquisition induced by cholinergic neurotoxin (ethylcholine aziridinium, AF64A) and muscarinic (scopolamine hydrobromide, SCOP) and nicotinic (mecamylamine, MECA) receptor antagonists. However, it did not block dopaminergic neurotoxin (6-hydroxydopamine, 6-OHDA)-induced and serotonergic neurotoxin (5,7-dihydroxytryptamine, 5,7-DHT)-induced impairments. From these results, we suggest that the attenuating effect of luteolin (10 mg/kg, i.p.) on the deficits of passive avoidance performance induced by SCOP may be related to the increases in the activities of central muscarinic and nicotinic receptors.     

Nodakenin, a coumarin compound, ameliorates scopolamine-induced memory disruption in mice

Nodakenin is a coumarin compound initially isolated from the roots of Angelica gigas. In the present study, we investigated the effects of nodakenin on learning and memory impairments induced by scopolamine (1 mg/kg, i.p.) using the passive avoidance test, the Y-maze test, and the Morris water maze test in mice. Nodakenin (10 mg/kg, p.o.) administration significantly reversed scopolamine-induced cognitive impairments in the passive avoidance test and the Y-maze test (P<0.05), and also reduced escape latency during training in the Morris water maze test (P<0.05). Moreover, swimming times and distances within the target zone of the Morris water maze were greater in the nodakenin-treated group than in the scopolamine-treated group (P<0.05). In an in vitro study, nodakenin was found to inhibit acetylcholinesterase activity in a dose-dependent manner (IC(50)=84.7 microM). In addition, nodakenin was also found to inhibit acetylcholinesterase activity for 6 h in an ex-vivo study. These results suggest that nodakenin may be a useful for the treatment of cognitive impairment, and that its beneficial effects are mediated, in part, via the enhancement of cholinergic signaling.     

Cognitive enhancing effects of alpha asarone in amnesic mice by influencing cholinergic and antioxidant defense mechanisms

The effect of α-asarone on impairment of cognitive performance caused by amnesic drug scopolamine was investigated. Treatment with α-asarone attenuated scopolamine-induced cognitive deficits as evaluated by passive avoidance and Y-maze test. Administration of α-asarone for 15 d improved memory and cognitive function as indicated by an increase in transfer latency time and spontaneous alternation in passive avoidance and the Y-maze test respectively. To understand the action of α-asarone, the levels of acetylcholinesterase (AChE), malondialdehyde (MDA), and superoxide dismutase (SOD) in the hippocampus (Hippo) and cerebral cortex (CC) of scopolamine-induced amnesic mice were evaluated. The mice treated with Scopolamine showed increased activity of AChE, MDA and SOD levels in both the Hippo and the CC area. Treatment with α-asarone attenuated the increased activity of AChE and normalized the MDA and SOD levels in the Hippo and the CC area in the scopolamine treated amnesic mice. These results suggest that α-asarone has a beneficial effect in cognitive impairment induced by dysfunction of cholinergic system in brain through inhibition of AChE activity and by influencing the antioxidant defense mechanism.     

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 (100 mg/kg body weight), aceroside VIII (1 mg/kg body weight) and platyphylloside (1 or 2 mg/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.     

P7C3 Attenuates the Scopolamine-Induced Memory Impairments in C57BL/6J Mice

Memory impairment is the most common symptom in patients with Alzheimer’s disease. The purpose of this study is to evaluate the memory enhancing effects of P7C3, a recently identified compound with robust proneurogenic and neuroprotective effects, on the cognitive impairment induced by scopolamine, a muscarinic acetylcholine receptor antagonist. Different behavior tests including the Y-maze, Morris water maze, and passive avoidance tests were performed to measure cognitive functions. Scopolamine significantly decreased the spontaneous alternation and step-through latency of C57BL/6J mice in Y-maze test and passive avoidance test, whereas increased the time of mice spent to find the hidden platform in Morris water maze test. Importantly, intraperitoneal administration of P7C3 effectively reversed those Scopolamine-induced cognitive impairments in C57BL/6J mice. Furthermore, P7C3 treatment significantly enhanced the level of brain-derived neurotrophic factor (BDNF) signaling pathway in the cortex and hippocampus, and the usage of selective BDNF signaling inhibitor fully blocked the anti-amnesic effects of P7C3. Therefore, these findings suggest that P7C3 could improve the scopolamine-induced learning and memory impairment possibly through activation of BDNF signaling pathway, thereby exhibiting a cognition-enhancing potential.     

Dehydroevodiamine.HCl prevents impairment of learning and memory and neuronal loss in rat models of cognitive disturbance

We previously reported that dehydroevodiamine.HCl (DHED) has anticholinesterase and antiamnesic activities. To verify the effects of DHED on cognitive deficits further, we tested it on the scopolamine-induced amnesia model of the rat using the passive avoidance and eight-arm radial maze tests. A single (20 mg/kg p.o.) and repeated (10 mg/kg p.o.) administrations of DHED could significantly reverse the latency time shortened by scopolamine (1 mg/kg i.p.) to control level. The impaired spatial working memory induced by scopolamine (1 mg/kg i.p.) was also improved significantly by a single injection (6.25 mg/kg i.p.) and repeated administrations of DHED (10 mg/kg p.o.) in the eight-arm radial maze test. In addition, we examined the effects of DHED on the memory impairment and the histological changes of the brain after unilateral electrolytic lesion of the entorhinal cortex (EC) and middle cerebral artery occlusion in rats. The cognitive deficits caused by EC lesion and middle cerebral artery occlusion were improved significantly by repeated administrations of DHED (6.25 mg/kg i.p.) after EC lesion or ischemic insult once a day for 7 days in the passive avoidance test. Histological analysis showed that the neuronal loss in the DHED-treated group was notably reduced in the hippocampal area (CA1) of ischemic rats and in the dentate gyrus and hippocampal area (CA1 and CA3) of EC-lesioned rats compared with the nontreated group. The infarction area was decreased significantly by a single administration of DHED (6.25 mg/kg i.p.) 30 min before ischemic insult for 6 h. These results suggest that DHED might be an effective drug for not only the Alzheimer's disease type, but also the vascular type of dementia.     

Dose-dependent action of corticosteroids on brain serotonin content and passive avoidance behavior.

Corticosterone, 1.0 and 5.0 mg/kg, improved passive avoidance behavior based on fear versus thirst-conflict situation. Corticosterone, 1.0 mg/kg, increased the serotonin (5-HT) content in the hypothalamus and mesencephalon; 5.0 mg/kg of corticosterone had no effect. Plasma corticosterone level increased in a dosedependent manner after corticosterone treatment. dl-Parachlorophenylalanine (PCPA) impaired passive avoidance behavior and decreased the hypothalamic and mesencephalic 5-HT level. After PCPA treatment, the plasma corticosterone level was slightly increased. PCPA pretreatment was able to prevent the action of 1.0 and 5.0 mg/kg of corticosterone on behavior as well as on brain 5-HT level. Corticosterone, 10.0 mg/kg, impaired passive avoidance behavior, decreased the hypothalamic and mesencephalic 5-HT content, and increased the plasma corticosterone level.Monoamine oxidase inhibitor (nialamide) treatment improved the passive avoidance behavior and increased the 5-HT level in the hypothalamus and mesencephalon. The plasma corticosterone level did not change significantly. Nialamide pretreatment abolished the behavioral action of 10.0 mg/kg of corticosterone as well as its action on brain 5-HT level. A large dose of corticosterone (25.0 mg/kg) and 2.5 mg/kg of 6-dehydro-16-methylenhydrocortisone (6DH) had a similar action on passive avoidance behavior and on brain serotonin level as 10.0 mg/kg of corticosterone; however, the plasma corticosterone level was increased only in corticosterone-treated animals and was significantly decreased after 6DH. 11-Deoxycorticosterone (DOC) at a dose of 25.0 mg/kg was ineffective on passive avoidance behavior and on brain serotonin content, whereas it slightly decreased the plasma corticosterone level. Data suggest that the corticosterone has dosedependent dual action on passive avoidance behavior, and its action is, at least partly, mediated via changed brain serotonin metabolism. The action seems to be a glucocorticoid-specific one since mineralocorticoid (DOC) is ineffective on this behavioral pattern.     

Influence of activation and blockade of NMDA receptors on extinction of passive avoidance response in mice with different levels of anxiety

Influence of agonist (D-cycloserine) and antagonist (dizocilpine) N-methyl-D-aspartate receptors on learning and extinction of passive avoidance response in medium-, high-, and low-anxious mice was studied. In medium-anxious mice, D-cycloserine (30 mg/kg) although not changing learning accelerated development of extinction, whereas dizocilpine (0.15 mg/kg), while impairing passive avoidance learning, detained the extinction. In high-anxious mice with good retrieval of memory trace and absence of extinction, D-cycloserine was ineffective, whereas dizocilpine reduced learning and promoted retention of memory trace retrieval at the generated level on extinction. In low-anxious mice, D-cycloserine impaired learning and accelerated extinction, whereas dizocilpine completely blocked learning and retention of passive avoidance response.     

Memory effect of caerulein and its analogs in active and passive avoidance responses in the rat

The memory effects of caerulein (CER) and its analogs ([des-Gln2]-CER and [Leu5,Nle8]-CER) were compared with that of cholecystokinin octapeptide (CCK-8) using active and passive avoidance responses in rats. In the active avoidance test, single subcutaneous (SC) injection of CER and its analogs immediately after the learning trials at doses of 10 and 100 ng/kg prevented extinction of learned task for 10 days, and at a dose of 1000 ng/kg for at least 15 days, but the effect of CCK-8 was somewhat weaker. In the saline control group, the number of responses decreased after 5 days. In the passive avoidance response, electroconvulsive shock (ECS)-induced amnesia was partially prevented by CCK-8 at doses of 100 and 1000 ng/kg SC, while CER and its analogs at doses of more than 100 ng/kg totally prevented the ECS-induced amnesia. Intraperitoneal administration of scopolamine caused complete amnesia which was also partially prevented by CCK-8, while CER could totally prevent the amnesia following SC injection of 2 micrograms/kg. These results indicate that CER and its analogs are more effective than CCK-8 for preventing experimental amnesia.     

Effects of oleamide on choline acetyltransferase and cognitive activities

We screened 50 Korean traditional natural plants to measure the activation effect on choline acetyltransferase and attenuation of scopolamine-induced amnesia. The methanolic extracts from Zizyphus jujuba among the tested 50 plants, showed the highest activatory effect (34.1%) on choline acetyltransferase in vitro. By sequential fractionation of Zizyphus jujuba, the active component was finally identified as cis-9-octadecenoamide (oleamide). After isolation, oleamide showed a 65% activation effect. Administration of oleamide (0.32%) to mice significantly reversed the scopolamine-induced memory and/or cognitive impairment in the passive avoidance test and Y-maze test. Injection of scopolamine to mice impaired performance on the passive avoidance test (31% decrease in step-through latency), and on the Y-maze test (16% decrease in alternation behavior). In contrast, mice treated with oleamide before scopolamine injection were protected from these changes (12-25% decrease in step-through latency; 1-10% decrease in alternation behavior). These results suggest that oleamide should be a useful chemo-preventive agent against Alzheimer's disease.     

5-HT3 receptors in selective animal models of cognition

Role of 5-HT3 receptors in cholinergic hypofunctional models of cognitive impairment in the elevated plus maze model and a passive avoidance model is studied. Cognitive impairment was caused by scopolamine (1 mg/kg, ip) in mice and 5-HT3 ligands mCPBG (1 and 5 mg/kg, ip) and ondansetron (0.5 and 5 mg/kg, ip) were administered before the pre-learning phase to study the effects on acquisition, while post-learning administration was used to determine the effects on consolidation. Ondansetron improved acquisition and retention in cholinergic hypofunctional models while mCPBG potentiated selected impaired cognitive indices. The results indicate the role of 5-HT3 receptors in cognition and that an ideal evaluation of 5-HT3 ligands in cognition should distinguish true cognitive effects from locomotor, motivational and emotional effects.     

Intraseptal injection of scopolamine increases the effect of systemic diazepam on passive avoidance learning and emotionality in rats.

This experiment was designed to assess the role of the septo-hippocampal cholinergic (ACh) system in the deleterious effects produced by systemic benzodiazepine injection on learning processes in rats. Retention of a step through passive avoidance task was analysed after systemic injection of increasing doses of either scopolamine or diazepam applied alone 30 min before the acquisition phase. Results indicated a dose related impairment of retention by each drug: in addition, sub-threshold doses of scopolamine and diazepam applied in combination (diazepam: 2mg/kg plus scopolamine: 0.3mg/kg) produced a decrease of retention latencies, thus showing an additive effect of the combined treatment. Secondly, a sub-threshold dose of scopolamine (15microg/0.5microl) was also administered into the medial septal area, together with an i.p. injection of 2mg/kg of diazepam. This combined treatment produced a severe impairment of retention, in parallel with a large reduction in emotionality (number of faeces). The data are consistent with the hypothesis that peripheral administration of behaviorally effective doses of diazepam on passive avoidance learning might act partially via a septal ACh-GABA/benzodiazepine mechanism. It is also suggested that this mechanism subserves both anxiety and the memorisation of contextual stimuli associated with passive avoidance acquisition, through the modification of the septo-hippocampal activity.     

Protective effect of curcumin against intracerebral streptozotocin induced impairment in memory and cerebral blood flow

AimsThe aim of the present study is to investigate the effect of curcumin on cerebral blood flow (CBF), memory impairment, oxidative stress and cholinergic dysfunction in intracerebral (IC) streptozotocin (STZ) induced memory impairment in mice.Main methodsMemory impairment was induced by STZ (0.5 mg/kg, IC) administered twice with an interval of 48 h in mice. Memory function was assessed by Morris water maze and passive avoidance test. CBF was measured by Laser Doppler Flowmetry (LDF). To study the preventive effect, curcumin (10, 20 and 50 mg/kg, PO) was administered for 21 days starting from the first dose of STZ. In another set of experiment, curcumin was administered for 7 days from 19th day after confirming STZ induced dementia to observe its therapeutic effect. Biochemical parameters of oxidative stress and cholinergic function were estimated in brain on day 21.Key findingsThe major finding of this study is that STZ (IC) caused a significant reduction in CBF along with memory impairment, cholinergic dysfunction and enhanced oxidative stress. Curcumin dose dependently improved CBF in STZ treated mice together with amelioration of memory impairment both in preventive and therapeutic manner.SignificanceThe present study clearly demonstrates the beneficial effects of curcumin, the dietary staple of India, on CBF, memory and oxidative stress which can be exploited for dementia associated with age related vascular and neurodegenerative disorders.     

Possible antioxidant mechanism in melatonin reversal of aging and chronic ethanol-induced amnesia in plus-maze and passive avoidance memory tasks

Cognitive dysfunction is one of the most striking age-related impairments seen in human beings and animals. This impairment probably is due to the vulnerability of the brain cells to increased oxidative stress during aging process. Pineal hormone melatonin is reported to be an endogenous antioxidant, whose peak plasma level declines during aging and in Alzheimer's disease (AD). Present experiments were performed to study the possible effect of exogenously administered melatonin on cognitive performance of young, aged, or ethanol-intoxicated mice (an animal model for AD) using one trial step-down type of passive avoidance and elevated plus-maze task. Aged or chronic ethanol-treated mice showed poor retention of memory in step-down passive avoidance and in elevated plus-maze task. Chronic administration of melatonin (0.1-10 mg/kg, sc) for 30 d or its coadministration with ethanol (15% W/V, 2 g/kg perorally) for 24 d significantly reversed the age-induced or chronic ethanol-induced retention deficits in both the test paradigms. However, in both the memory paradigms chronic administration of melatonin failed to modulate the retention performance of young mice. Chronic administration of melatonin (0.1-10 mg/kg) for 30 d also reversed age-associated decline in forebrain total glutathione (tGSH) level. Chronic ethanol administration to young mice produced decline in forebrain tGSH level and enhanced brain lipid peroxidation, which was significantly reversed by coadministration of melatonin (10 mg/kg). The results of this study showed chronic melatonin treatment reverses cognitive deficits in aged and ethanol-intoxicated mice, which is associated with its antioxidant property.     

In vivo growth inhibitory effect of Withania somnifera (Ashwagandha) on a transplantable mouse tumor, Sarcoma 180.

Withania somnifera is a medicinal plant used in the treatment of a variety of ailments in the Ayurvedic system. Alcoholic extract of the root of the plant was injected(ip) at daily doses of 200 to 1000 mg/kg body wt for 15 days starting from 24 hr after intradermal inoculation of 5 x 10(5) cells of S-180 in BALB/c mice. Solid tumor growth was monitored for 100 days. Doses of 400 mg/kg and above produced complete regression of tumor after an initial growth, the percentage of complete response (CR) increasing with increasing drug dose. A 55% CR was obtained at 1000 mg/kg drug administration, but this dose also produced some mortality among the animals. A significant increase in the volume doubling time and growth delay was seen when the drug dose was increased from 500 to 750 mg/kg body wt, but further increase in drug dose to 1000 mg/kg did not produce any significant increase in these responses. Cumulative doses of 7.5 to 10 g at daily doses of 500 or 750 mg/kg seems to produce a good response in this tumor.     

Fat-1 expression enhance hippocampal memory in scopolamine-induced amnesia

Omega-3 polyunsaturated fatty acids (PUFA) are critical for optimal brain health and are involved in psychiatric and neurological ailments. Here, we report the effects of higher endogenous omega-3 PUFA on memory impairment in the hippocampus by studying mice with transgenic expression of the fat-1 gene that converts omega-6 to omega-3 PUFA. We performed Y-maze and passive avoidance tests to evaluate the memory function of fat-1 mice treated with scopolamine. Fat-1 mice showed induced alternation in the Y-maze test and increased latency in the passive avoidance test. The effects of scopolamine on hippocampal neurogenesis were confirmed by increases in the number of Ki-67- and DCX-positive cells in the fat-1 mice. Western blotting revealed increased brain-derived neurotrophic factor (BDNF) and phosphorylated cAMP response element-binding protein levels, and lower scopolamine-induced apoptosis based on the cleaved-caspase 3 protein level in fat-1 mice. These findings suggest that higher endogenous omega-3 PUFA prevented granular cell loss, increased BDNF signaling, and decreased apoptosis signaling in scopolamine-treated fat-1 mice. These processes may underlie granular cell survival and suggest potential therapeutic targets for memory impairment.