Single intracerebroventricular administration of amyloid-beta (25-35) peptide induces impairment in short-term rather than long-term memory in rats

Ample experimental evidence indicates that intracerebral injection or infusion of amyloid-beta peptides (Abeta) to rodents induces learning and memory impairments as well as neurodegeneration in brain areas related to cognitive function. In the present study, we assessed the effects of a single intracerebroventricular (i.c.v.) injection of aggregated Abeta fragment (25-35) at a dose of 15nmol/rat on short-term and long-term memory in rats during the 6-month post-surgery period. The results demonstrate that Abeta(25-35)-induced memory impairments in spontaneous alternation behavior in a Y-maze at 17, 36, and 180 days after the surgery as well as in a social recognition task 110 days post-surgery. Abeta(25-35) also impaired spatial memory in an 8-arm radial maze, but did not influence performance of the step-down passive avoidance task. These results suggest that Abeta(25-35) preferably induces impairments of spatial and non-spatial short-term (working) memory rather than long-term memory in rats.     

Effects of tumor necrosis factor-alpha central administration on hippocampal damage in rat induced by amyloid beta-peptide (25-35)

Male Wistar rats received unilateral intrahippocampal injections of 3 nmol (3.18 microg) aggregated Abeta(25-35), intracerebroventricular bilateral injections of 0.5 microg human recombinant TNFalpha or both (Abeta(25-35) + TNFalpha-treated animals). Seven days after the surgery brain sections were stained with cresyl violet (Nissl), for fragmented DNA (TUNEL), glial fibrillar acidic protein (GFAP) and isolectin B4-reactive microglia. In addition, caspase-3 activity in brain regions was measured fluorometrically. The morphology of the hippocampus after the injection of Abeta(25-35) or both Abeta(25-35) and TNFalpha (but not TNFalpha alone) showed cell loss in the CA1 pyramidal cell layer. The extension of neuronal degeneration measured in the CA1 field was significantly larger in Abeta(25-35)-treated groups compared to the contralateral hemisphere of both vehicle-treated controls and animals injected with TNFalpha alone. TNFalpha augmented the Abeta(25-35)-induced damage, significantly increasing the extension of degenerating area. Administration of Abeta(25-35) caused reactive gliosis in the ipsilateral hemisphere as demonstrated by upregulation of GFAP expression and the presence of hypertrophic astrocytes in the hippocampus. This effect was much more prominent in the hippocampi of rats treated with Abeta(25-35) + TNFalpha but absent after administration of TNFalpha alone. In both Abeta(25-35)-treated groups, the damaged area of the hippocampal CA1 field and lateral band of dentate gyrus displayed many darkly stained round isolectin B4-positive phagocyte-like microglial cells. Sparse TUNEL-positive nuclei were found in the hippocampi of rats treated with Abeta(25-35) alone or together with TNFalpha, but not in the control brain sections or in brain sections of TNFalpha-injected animals. The activity of caspase-3 increased significantly in the ipsilateral hippocampus after the injection of Abeta(25-35). Surprisingly, administration of TNFalpha into the cerebral ventricles prevented this Abeta(25-35)-induced increase in hippocampal caspase-3 activity. The results are discussed from the perspective of dual (neuroprotective and neurodestructive) roles of TNF in the brain.     

Progressive brain dysfunction following intracerebroventricular infusion of beta(1-42)-amyloid peptide

The behavioral, neurochemical and histological changes of rats subjected to 3 days treatment with intracerebroventricular infusion of beta-amyloid peptides(Abeta)(1-42) were investigated 20 days and 80 days after the surgery. Abeta(1-42) produced a dose-dependent and a time-dependent impairment in the spontaneous alternation performance in the Y-maze (spatial working memory), place navigation task in a water maze (spatial reference memory) and passive avoidance retention (non-spatial long-term memory) at doses of 10 and 20 microg/rat. The learning impairments were more severe at 80 days than 20 days after infusion of Abeta(1-42). At 25 days after the infusion, a significant decrease in hemicholinium-3 (HC-3) binding was observed only in the hippocampus, although choline acetyltransferase (ChAT) activity was unchanged in the brain regions tested as compared with the vehicle (Abeta(40-1)) treatment. In contrast, the reduction in ChAT activity 85 days after Abeta(1-42) infusion was significant in hippocampus and striatum. HC-3 binding was also significantly decreased in the posterior cortex, hippocampus and striatum. In the histological analysis, brain atrophy was observed inasmuch as ventricular enlargement and neuronal damage in the CA1 area of the hippocampus were seen 85 days after Abeta(1-42) infusion. These results suggest that the rats subjected to intracerebroventricular infusion of Abeta(1-42) suffered from progressive brain dysfunction, and could be useful as an animal model for evaluating the developmental processes at the early and/or middle stage of Alzheimer's-type dementia.     

S14G-Humanin ameliorates Abeta25-35-induced behavioral deficits by reducing neuroinflammatory responses and apoptosis in mice

Cerebral amyloid-beta protein (Abeta) deposition and associated neuroinflammation and apoptosis are increasingly recognized as an important component leading to cognitive impairment in Alzheimer's disease (AD). Humanin (HN) and its derivative, S14G-HN (HNG), are best known for their ability to suppress neuronal death induced by AD-related insults in vitro. Furthermore, limited in vivo studies show that HNG can ameliorate memory impairment induced by intracerebroventricular injection of anti-cholinergic drugs or Abeta25-35. However, the mechanism underlying the in vivo effect remains unclear. In this study, we sought to determine the effects of HNG on neuroinflammatory responses and apoptosis associated with behavioral deficits induced by Abeta25-35 in vivo. Our results indicate that intracerebroventricular injection of aggregated Abeta25-35 induced impairment of learning and memory, markedly elevated numbers of reactive astrocytes, activated microglia, and apoptotic cells, as well as remarkable increased levels of IL-6 and TNFalpha. Moreover, intraperitoneal HNG treatment ameliorated behavioral deficits, and reduced neuroinflammatory responses and apoptotic cells in the brain. Cumulatively, these finding demonstrate for the first time that HNG may have the potential for attenuating Abeta-induced cognitive deficits by reducing inflammatory responses and apoptosis in vivo, which may add to the novel evidence for anti-inflammatory and antiapoptosis properties of HNG in AD treatment.     

Effects of captopril on locomotor activity, passive avoidance behaviour and spatial memory tasks in the trimethyltin-treated rat

The potential neuroprotective/cognitive enhancing actions of captopril were investigated in the trimethyltin (TMT)-induced neurotoxicity rat model. Acute exposure to TMT produces alterations in locomotor activity, passive avoidance behaviour and spatial memory tasks. Captopril treatment given in combination with the single acute injection of TMT reversed the deficits in spatial memory tasks in 8 out of 25 trials. While post-treatment of TMT-treated rats with captopril brought about a significant improvement in 3 out of 25 trials, pre-treatment of rats for 3 weeks with captopril did not reverse the behavioural deficits produced by TMT in the Morris maze test. Captopril treatment did not block the characteristic hyperactivity or the deficits in passive avoidance behaviour of TMT-treated animals.     

Protection against beta-amyloid peptide-induced memory impairment with long-term administration of extract of Angelica gigas or decursinol in mice

We investigated the effect of long-term oral administration of ethanolic extract of Angelica gigas Nakai (Umbelliferae) (EAG) or decursinol, a coumarin isolated from A. gigas, on beta-amyloid peptide 1-42 (Abeta(1-42))-induced memory impairment in mice. Mice were allowed free access to drinking water (control) or water containing different concentrations of EAG. After 4 weeks, Abeta(1-42) (410 pmol) was administered via intracerebroventricular injection. Pretreatment of mice with EAG (0.1%) for 4 weeks significantly blocked the Abeta(1-42)-induced impairment in passive avoidance performance. Next, mice were fed with chow mixed with various doses of decursinol for 4 weeks before intracerebroventricular injection of Abeta(1-42) (410 pmol). Pretreatment of mice with decursinol (0.001%, 0.002%, and 0.004%) for 4 weeks significantly attenuated the Abeta(1-42)-induced impairment in passive avoidance performance. Decursinol (0.004%) also significantly blunted the Abeta(1-42)-induced decrease in alternation behavior (spatial working memory) in the Y-maze test without change in general locomotor activity. These findings suggest that EAG or decursinol may have preventive effect against memory impairment related with Abeta of Alzheimer's disease.     

Characterizing learning deficits and hippocampal neuron loss following transient global cerebral ischemia in rats

The 2-vessel-occlusion + hypotension (2VO + H) model of transient global cerebral ischemia results in neurodegeneration within the CA1 field of the hippocampus, but previous research has failed to demonstrate robust or reliable learning/memory deficits in rats subjected to this treatment. In the present study, sensitive behavioral protocols were developed in an effort to characterize the cognitive impairments following 2VO + H more precisely. Adult rats were exposed to 10 min of bilateral carotid occlusion with simultaneous hypotension. Following recovery, 2VO + H and control rats were subjected to a series of behavioral tests (locomotor activity, sensorimotor battery, water maze [cued, place, learning set], object recognition, and radial arm maze) over an extended recovery period followed by an assessment of neuronal loss in the dorsal hippocampus. The 2VO + H treatment was associated with long-lasting spatial learning deficits in the absence of other behavioral impairments and with neurodegeneration in dorsal hippocampal CA1. Water maze protocols that placed higher memory demands upon the rats (relatively "hard" vs. "easy") were more sensitive for detecting ischemia-induced deficits. We have shown that the use of appropriate behavioral tests (e.g., a relatively difficult place learning task) allowed for the observation of robust spatial learning deficits in a model previously shown to induce relatively subtle behavioral effects. Thus, the 2VO + H model induces both hippocampal neuronal loss and long-term learning deficits in rats, providing a potentially useful model for evaluating therapeutic efficacy.     

Beta-amyloid (1-42)-induced learning and memory deficits in mice: involvement of oxidative burdens in the hippocampus and cerebral cortex

We have demonstrated that oxidative stress is involved, at least in part, in beta-amyloid protein (Abeta)-induced neurotoxicity in vivo [Eur. J. Neurosci. 1999;11:83-90; Neuroscience 2003;119:399-419]. However, mechanistic links between oxidative stress and memory loss in response to Abeta remain elusive. In the present study, we examined whether oxidative stress contributes to the memory deficits induced by intracerebroventricular injection of Abeta (1-42) in mice. Abeta (1-42)-induced memory impairments were observed, as measured by the water maze and passive avoidance tests, although these impairments were not found in Abeta (40-1)-treated mice. Treatment with antioxidant alpha-tocopherol significantly prevented memory impairment induced by Abeta (1-42). Increased activities of the cytosolic Cu,Zn-superoxide dismutase (Cu,Zn-SOD) and mitochondrial Mn-superoxide dismutase (Mn-SOD) were observed in the hippocampus and cerebral cortex of Abeta (1-42)-treated animals, as compared with Abeta (40-1)-treated mice. The induction of Cu,Zn-SOD was more pronounced than that of Mn-SOD after Abeta (1-42) insult. However, the concomitant induction of glutathione peroxidase (GPX) in response to significant increases in SOD activity was not seen in animals treated with Abeta (1-42). Furthermore, glutathione reductase (GRX) activity was only increased at 2h after Abeta (1-42) injection. Production of malondialdehyde (lipid peroxidation) and protein carbonyl (protein oxidation) remained elevated at 10 days post-Abeta (1-42), but the antioxidant alpha-tocopherol significantly prevented these oxidative stresses. Therefore, our results suggest that the oxidative stress contributes to the Abeta (1-42)-induced learning and memory deficits in mice.     

In vivo administration of corticotropin-releasing hormone at remote intervals following ischemia enhances CA1 neuronal survival and recovery of spatial memory impairments: a role for opioid receptors

The contribution of corticotropin-releasing hormone (CRH) in the modulation of ischemia-induced cell death in vivo remains unclear. We characterized the impact of pre-ischemic administration of CRH (0, 0.1, 1, 5 microg, i.c.v., 15 min prior to vessel occlusion) on neuronal damage following global ischemia in rats. The injection of 5 microg CRH led to a 37% increase in CA1 neuronal survival compared to vehicle-treated ischemic animals, while pre-treatment with alpha-helical CRH (9-41) abolished this neuronal protection. A second objective aimed to determine whether CRH protection is maintained over weeks when the peptide is administered at remote time intervals following ischemia. Compared to vehicle-treated ischemic animals, administration of CRH 8h following global ischemia led to a 61% increase in CA1 neuronal survival observed 30 days post-ischemia. Neuronal protection translated into significant improvement of ischemia-induced spatial memory deficits in the radial maze. Finally, our findings demonstrated that selective blockade of kappa- and delta-opioid receptors (using nor-binaltorphimine and naltrindole, respectively) prior to CRH administration significantly reduced CA1 neuronal protection. These findings represent the first demonstration of enhanced neuronal survival following in vivo CRH administration in a global model of ischemia in rats. They also support the idea that CRH-induced neuroprotection involves opioid receptors activation.     

Memory impairments following basal forebrain lesions

The functional contribution of the nucleus basalis magnocellularis (NBM) and medial septal area (MSA) to memory was evaluated in 4 behavioral tasks. The tasks were postoperative acquisition of a win-stay spatial discrimination in a T-maze, a win-shift spatial discrimination on a radial arm maze, active avoidance in a shuttle box, and passive avoidance in a shuttle box. Bilateral lesions were made by injecting ibotenic acid (IBO) into the NBM or MSA. Control rats received operations in which no neurotoxin was injected. When compared to controls, rats with lesions in either the NBM or MSA had significantly impaired choice accuracy in the T-maze and radial maze tasks, took significantly fewer trials to reach criterion in the acquisition, but not the retention of an active avoidance task, and significantly more trials to reach criterion in the passive avoidance task. The results show that equivalent behavioral changes are obtained from lesions in the NBM and MSA in tasks that vary in their type of motivation, reinforcement, response-reinforcement contingency, and response. These behavioral changes suggest that the NBM and MSA may both be involved in memory.     

Learning and memory effects of neonatal methamphetamine exposure in rats: Role of reactive oxygen species and age at assessment

In utero methamphetamine (MA) exposure leads to a range of adverse effects, such as decreased attention, reduced working‐memory capability, behavioral dysregulation, and spatial memory impairments in exposed children. In the current experiment, preweaning Sprague‐Dawley rats—as a model of third trimester human exposure—were administered the spin trapping agent, N‐tert‐butyl‐α‐phenylnitrone (PBN), daily prior to MA. Rats were given 0 (SAL) or 40 mg/kg PBN prior to each MA dose (10 mg/kg, 4× per day) from postnatal day (P) 6–15. Littermates underwent Cincinnati water maze, Morris water maze, and radial water maze assessment beginning on P30 (males) or P60 (females). Males were also tested for conditioned contextual and cued freezing, while females were trained in passive avoidance. Findings show that, regardless of age/sex, neonatal MA induced deficits in all tests, except passive avoidance. PBN did not ameliorate these effects, but had a few minor effects. Taken together, MA induced learning deficits emerge early and persist, but the mechanism remains unknown.     

Aβ25-35 injection into the temporal cortex induces chronic inflammation that contributes to neurodegeneration and spatial memory impairment in rats

Amyloid-β (Aβ)25-35 is able to cause memory impairment and neurodegenerative events. Recent evidence has shown that the injection of Aβ25-35 into the temporal cortex (TCx) of rats increases the inflammatory response; however, it is unclear how the inflammatory process could be involved in the progression of Aβ25-35 toxicity. In this study we investigated the role of inflammation in the neuronal damage and spatial memory impairment generated by Aβ25-35 in rat TCx using immunohistochemistry, ELISA, and a behavioral test in the radial maze. Our findings show that Aβ25-35 -injection into the TCx induced a reactive gliosis (GFAP and CD11b-reactivity) and an increase of pro-inflammatory cytokines (IL-1β, IL-6, IL-17, and TNF-α) in the TCx and the hippocampus at 5, 15, and 30 days after injection. Thirty days after Aβ25-35 injection, we observed that the inflammatory reaction probably contributed to increase the immunoreactivity of inducible nitric oxide synthase and nitrite levels, as well as to the loss of neurons in TCx and hippocampus. Behavioral performance showed that the neurodegeneration evoked by Aβ25-35 delayed acquisition of learning and impaired spatial memory, because the Aβ25-35-treated animals showed a greater number of errors during the task than the control group. Previous administration of an interleukin receptor antagonist (IL-1ra) (10 and 20 μg/μL, into TCx), an anti-inflammatory agent, suppressed the Aβ25-35-induced inflammatory response and neurodegeneration, as well as memory dysfunction. This study suggests that the chronic inflammatory reaction could contribute to the progression of Aβ25-35 toxicity and cause cognitive impairment.     

Antiamnesic effects of azaindolizinone derivative ZSET845 on impaired learning and decreased ChAT activity induced by amyloid-β 25–35 in the rat

Antiamnesic effects of a newly synthesized azaindolizinone derivative ZSET845 were assessed in rats made learning ability deficient by amyloid-beta (Abeta)25-35 treatment. Intracerebroventricular injection of Abeta25-35 induced a marked decrease in step-through latency in passive avoidance task and reduction in choline acetyltransferase (ChAT) activity in the medial septum and hippocampus, but not in the basal forebrain and cortex. The number of ChAT-immunoreactive cells was decreased in the medial septum. Oral administration of ZSET845 at a dose of 1 or 10 mg/kg ameliorated learning impairment in passive avoidance task and enhanced ChAT activity in the basal forebrain, medial septum and hippocampus, and increased in the number of ChAT-immunoreactive cells in the medial septum in Abeta-treated rats to the levels of vehicle-injected control rats. These results suggest that ZSET845 is worth testing for further preclinical study aimed for the treatment of senile dementia such as Alzheimer's disease.     

Antiamnesic effects of azaindolizinone derivative ZSET845 on impaired learning and decreased ChAT activity induced by amyloid-beta 25-35 in the rat

Antiamnesic effects of a newly synthesized azaindolizinone derivative ZSET845 were assessed in rats made learning ability deficient by amyloid-beta (Abeta)25-35 treatment. Intracerebroventricular injection of Abeta25-35 induced a marked decrease in step-through latency in passive avoidance task and reduction in choline acetyltransferase (ChAT) activity in the medial septum and hippocampus, but not in the basal forebrain and cortex. The number of ChAT-immunoreactive cells was decreased in the medial septum. Oral administration of ZSET845 at a dose of 1 or 10 mg/kg ameliorated learning impairment in passive avoidance task and enhanced ChAT activity in the basal forebrain, medial septum and hippocampus, and increased in the number of ChAT-immunoreactive cells in the medial septum in Abeta-treated rats to the levels of vehicle-injected control rats. These results suggest that ZSET845 is worth testing for further preclinical study aimed for the treatment of senile dementia such as Alzheimer's disease.     

Improvement of passive avoidance task after grafting of fetal striatal cell suspensions in ischemic striatum in the rat

Behavioral recovery and cell survival/growth after grafting of fetal striatal cell suspensions in the ischemic striatum of rats were investigated. Ischemia was induced by one hour intraluminal occlusion of the right middle cerebral artery under halothane anesthesia. During the ischemia rats usually manifested signs of hemiparesis and sometimes rotations. Behavioral function was measured by a passive avoidance task and radial arm maze test at 1-2 weeks and 6-7 weeks after ischemia. The size of the ischemic lesions depended on each animal, but the ischemic animals showed deficits in both passive avoidance task and radial maze test. Two weeks after ischemia, fetal striatal cells, marked with DiI, were transplanted into the ischemic striatum. The transplantation improved the ischemia-induced deficit in the passive avoidance task but not in radial maze test. Although there were variations in the size of the grafts, many DiI-positive cells with dendritic outgrowth were detected under fluorescent microscopy. Immunohistochemical study revealed that many choline acetyltransferase (ChAT) positive cells and GABA-positive cells survived in the grafts. However, striosome-matrix compartments were not evident inside the grafts. Thus, partial recoveries in both cytoarchitectural and behavioral aspects were obtained by striatal cell grafts, suggesting that neural transplantation could be a useful approach in reconstructing ischemic brain function.     

Persistent behavioral impairments and neuroinflammation following global ischemia in the rat

Cognitive deficits associated with cardiac arrest have been well documented; however, the corresponding deficits in animal models of global ischemia have not been comprehensively assessed, particularly after long‐term, clinically relevant survival times. We exposed male Sprague–Dawley rats to 10 min of bilateral carotid artery occlusion + systemic hypotension (40–45 mmHg) or sham surgery, and used histopathological assessments for short‐term survival animals (16 days) and both behavioral and histopathological assessments for long‐term survival animals (270 days). Analyses revealed significant long‐term deficits in ischemic animals’ learning, memory (T‐maze, radial arm maze), working memory (radial arm maze), and reference memory (Morris water maze, radial arm maze) abilities that were not associated with a general cognitive decline. Histological results showed significant increases in glial fibrillary acidic protein, neuron glia 2, OX‐42 and ED‐1 staining, as well as significant decreases in microtubule‐associated protein 2 staining and cornu ammonis area 1 (CA1) cell counts 16 days post‐ischemia. The pattern at 270 days was similar, but notably there was a persistent elevation of ED‐1 staining, suggesting recent cell death as well as significant atrophy of CA1. Whereas previous work has primarily reported transient changes in behavior after global ischemia, this study describes disturbances in several different functional domains following CA1 cell loss at clinically relevant survival times. Moreover, the histopathological outcome is suggestive of a spontaneous repopulation of CA1, but this was not sufficient to offset the behavioral impairments arising from the ischemic insult.     

Cerebral ischemic preconditioning induces lasting effects on CA1 neuronal survival, prevents memory impairments but not ischemia-induced hyperactivity

In ischemic preconditioning, prior exposure to a short 3-min global ischemia provides substantial protection against the deleterious effects of a subsequent prolonged ischemic insult in rats. The objective of the present study was to determine if the neuronal protection induced by ischemic preconditioning influence functional recovery following a 6-min ischemic insult in rats. Animals received either sham-operation, a 3-min ischemia, a preconditioning 3-min global ischemia followed 3 days later by a 6-min global ischemia or a single 6-min global ischemia. Open field habituation, memory performance in the 8-arm radial maze and object recognition were assessed at different intervals following ischemia. Our findings revealed that preconditioning reversed ischemia-induced spatial memory deficits in the 8-arm radial maze, as suggested by significant reduction of working memory errors in preconditioned as compared to ischemic animals. Preconditioning also attenuated ischemia-induced object recognition deficits at short-term intervals. Nonetheless, preconditioning failed to alter ischemia-induced hyperactivity as demonstrated by enhanced behavioral activity in the open field in both preconditioned and ischemic animals compared to 3-min ischemic and sham-operated rats. CA1 cell counts revealed significant neuronal sparing in preconditioned animals that was observed 6-month following reperfusion. Together, these findings suggest that neuronal survival in preconditioned rats is associated with significant improvements of hippocampal-dependent memory functions and, further support that ischemia-induced hyperactivity may not solely depend on selective neuronal damage to hippocampal neurons.     

Red mold rice ameliorates impairment of memory and learning ability in intracerebroventricular amyloid beta-infused rat by repressing amyloid beta accumulation

Amyloid beta (Abeta) peptide related to the onset of Alzheimer's disease (AD) damaged neurons and further resulted in dementia. Monascus-fermented red mold rice (RMR), a traditional Chinese medicine as well as health food, includes monacolins (with the same function as statins) and multifunctional metabolites. In this study, ethanol extract of RMR (RE) was used to evaluate neuroprotection against Abeta40 neurotoxicity in PC12 cells. Furthermore, the effects of dietary administration of RMR on memory and learning abilities are confirmed in an animal model of AD rats infused with Abeta40 into the cerebral ventricle. During continuous Abeta40 infusion for 28 days, the rats of test groups were administered RMR or lovastatin. Memory and learning abilities were evaluated in the water maze and passive avoidance tasks. After sacrifice, cerebral cortex and hippocampus were collected for the examination of AD risk factors. The in vitro results clearly indicate that RE provides stronger neuroprotection in rescuing cell viability as well as repressing inflammatory response and oxidative stress. RMR administration potently reverses the memory deficit in the memory task. Abeta40 infusion increases acetylcholinesterase activity, reactive oxygen species, and lipid peroxidation and decreases total antioxidant status and superoxide dismutase activity in brain, but these damages were potently reversed by RMR administration, and the protection was more significant than that with lovastatin administration. The protection provided by RMR is able to prevent Abeta fibrils from being formed and deposited in hippocampus and further decrease Abeta40 accumulation, even though Abeta40 solution was infused into brain continuously.     

Dynorphin A-(1-13) and (2-13) improve beta-amyloid peptide-induced amnesia in mice

The anti-amnesic effects of dynorphins on beta-amyloid peptide-(25-35)-induced impairment of learning and/or memory in mice were investigated using a Y-maze task and a passive avoidance test. Administration of beta-amyloid peptide-(25-35) (betaAP(25-35); 8.2 nmol, i.c.v.) 7 and 14 days before behavioral tests induced a decrease in both alternation behavior and latency in passive avoidance tests. Dynorphin A-(1-13) and A-(2-13) (0.5 and/or 1.5 nmol, i.c.v.) 30 min before behavioral tests improved the beta-amyloid peptide-(25-35)-induced impairment of alternation performance and shortened the step-down latency. Nor-binaltorphimine (4.9 nmol, i.c.v.) partially blocked the effects of dynorphin A-(1-13), but not A-(2-13). These results indicate that dynorphin A-(1-13) and A-(2-13) improve amnesia induced by betaAP-(25-35) via not only kappa opioid receptors, but also by non-opioid mechanisms.     

Protective effects of idebenone and α-tocopherol on β-amyloid-(1–42)-induced learning and memory deficits in rats: implication of oxidative stress in β-amyloid-induced neurotoxicity in vivo

Amyloid β-peptide (Aβ), the major constituent of the senile plaques in the brains of patients with Alzheimer's disease, is cytotoxic to neurons and has a central role in the pathogenesis of the disease. Previous studies have suggested that oxidative stress is involved in the mechanisms of Aβ-induced neurotoxicity in vitro. In the present study, we examined whether oxidative stress contributes to learning and memory deficits caused by continuous intracerebroventricular infusion of Aβ-(1–42). In the Aβ-(1–42)-infused rats, spontaneous alternation behaviour in a Y-maze and spatial memory in a water maze task were significantly impaired, as compared with Aβ-(40–1)-infused control rats. The retention of passive avoidance learning was also significantly impaired by treatment with Aβ-(1–42). Potent antioxidants idebenone and α-tocopherol prevented the behavioural deficits in Y-maze and water maze, but not passive avoidance, tasks in Aβ-(1–42)-infused rats when they were repeatedly administered by mouth once a day from 3 days before the start of Aβ infusion to the end of behavioural experiments. Lipid peroxide levels in the hippocampus and cerebral cortex of Aβ-(1–42)-infused rats did not differ from those in control animals, and neither idebenone nor α-tocopherol affected the lipid peroxide levels. These results suggest that treatment with antioxidants such as idebenone and α-tocopherol prevents learning and memory deficits caused by Aβ.