Effects of an alpha7 nicotinic receptor agonist and stress on spatial memory in an animal model of Alzheimer's disease.

The aim of the present study was to test the effects of PNU-282987 on spatial learning and memory and hippocampal neurogenesis in both intact and chronically stressed transgenic mice. Transgenic mice with susceptibility to Alzheimer's disease (AD) under immobilization stress and not-stressed animals receiving 0 and 1 mg/kg of PNU-282987 (PNU) were evaluated in a water maze task. The effects of PNU and stress on proliferation of new cells in the hippocampus of these animals were also assessed. The latency to escape the platform was significantly higher in transgenic stressed mice compared to those in the wild stressed group, as well as in transgenic animals without PNU compared to control wild group. On retention of the task, differences emerged on stressed wild animals, PNU wild group, and stressed wild mice receiving PNU. However, no significant differences were detected on new cell proliferation. The results of the present study did not show any impact of stress in acquisition of a spatial task both in wild and transgenic mice. No clear effects of PNU on acquisition of a spatial task in transgenic mice with susceptibility to AD were detected. Although PNU and stress effects were detected on retention of the task in wild animals, no changes were noted in transgenic mice.

Motor and anxiety effects of PNU-282987, an alpha7 nicotinic receptor agonist, and stress in an animal model of Alzheimer's disease.

Behavioral and Psychological Symptoms in Dementia (BPSD) are also seen in Alzheimer's disease (AD), being agitation and anxiety common symptoms. Since cholinergic agonists used to be the first pharmacological intervention in AD and this neurotransmission system have been related to cognitive and behavioral symptoms in this serious disease, we here address the question of a possible therapeutic role of PNU-282987 (PNU), an alpha7 nicotinic agonist, in motor activity and anxiety-like behaviors in an animal model of AD. On the other hand, since stress is an unavoidable condition in our daily activities, which activates physiological systems and deregulates body's homeostasis, we also evaluated the possible precipitating effects of stress in the onset of behavioral deficits in animals with susceptibility to AD. A dose of 0 or 1 mg/kg of PNU was administered to transgenic mice under restrained stress or not, resulting in 4 experimental groups: SAL, PNU, SAL-STR, PNU-STR. The main goal of this study was to evaluate the possible therapeutic role of PNU- 282987 alpha7 nicotinic agonist in motor activity and anxiety-like behaviors, as well as the possible effects of stress in precipitating the onset of behavioral deficits in animals with susceptibility to AD. The present results suggest a differential effect of stress (p=0.011) and PNU (p= 0.009) on anxiety evaluated in an open field depending on genetic vulnerability. Moreover, PNU seems to reverse stress effects in the same apparatus. This was also observed when a more sensitive task such as the zero maze was used.

Recognition memory and ß-amyloid plaques in adult Tg2576 mice are not modified after oral exposure to aluminum.

The role of aluminum (Al) in Alzheimer disease is highly controversial. However, this element has been detected in neuritic plaques and neurofibrillary tangles in patients with Alzheimer disease. Its presence in neuritic plaques in hippocampus is especially relevant, as this is an area closely related to spatial learning and memory. In this study, the diet of wild-type and Tg2576 mice (animals overexpressing the human amyloid precursor protein) was supplemented with Al lactate (1 mg/g). General neurotoxic Al effects were evaluated using a functional observational battery and a novel object recognition task. Four experimental groups were used: Control-wild, Al-wild, Control-Tg, and Al-Tg mice. The results show a decreased home-cage activity and an increase in piloerection in all Al-exposed animals, and an increased sensorimotor reactivity in Tg2576 mice given Al. Neither Al treatment nor genotype had any noticeable effect on corticosterone levels and Al concentrations in frontal cortex and cerebellum of the mice. Recognition memory was impaired in Tg2576 mice, whereas ß-amyloid plaque depositions were observed in all these animals. However, Al did not alter the recognition memory and ß-amyloid plaque loads of Tg2576 mice.

Amyloid ß peptide levels increase in brain of AßPP Swedish mice after exposure to chlorpyrifos.

Chlorpyrifos (CPF) is an organophosphate pesticide widely used in intensive agriculture. Various studies have demonstrated delayed neurotoxic effects in adult mammals after acute CPF exposure. This pesticide induces oxidative stress and neuronal damage, which suggests a possible relationship between CPF exposure and Alzheimer's disease (AD). In the present study, we examined in a mice model of AD, long-term changes in the behavior and brain levels of amyloid ß after acute CPF exposure. Fifty mg/kg of CPF were subcutaneously injected to Tg2576 (Tg) mice carrying the Swedish amyloid-ß protein precursor (AßPP) mutation for AD. General status, body weight, acetyl cholinesterase (AChE) inhibition, and behavioral changes were assessed. Amyloid ß fragment (1-40 and 1-42) levels were also measured in the cortical and hippocampal brain regions. A significant and transient decrease in body weight was observed 72 hr after treatment, while no autonomic effects were noted. Motor activity was decreased in Tg mice seven months after CPF treatment. Acquisition learning in a water maze task was not affected, but retention was ameliorated in CPF-exposed Tg mice. Amyloid ß levels increased in the brains of treated Tg mice eight months after CPF exposure. The results of this study show that some behavioral changes persisted or emerged months after acute CPF exposure, while amyloid ß levels increased. These findings raise concern about the risk of developing neurodegenerative diseases following moderate exposure to CPF in vulnerable subjects.

Behavioral effects of PNU-282987, an alpha7 nicotinic receptor agonist, in mice.

The cholinergic system is closely related to learning and memory processes, and its neurodegeneration seems to be involved in neurodegenerative and neuropsychiatric cognitive disorders in the elderly. Alpha7 nicotinic acetylcholine receptors (nAChRs) have recently been shown to mediate neuroprotection and enhance cognitive performance in a variety of tasks, suggesting that there may be a new target for the pharmacotherapy of cognitive deficiencies. In this study, we investigated the behavioral effects of the acute and sub-chronic administration of 0, 1, 3, and 5 mg/kg of PNU-282987 (PNU) on motor activity, anxiety and learning in open-field and Morris water maze tasks in mice. Our results showed that the highest dose of PNU (5 mg/kg) diminished motor activity in the open-field following 5 and 12 days of administration (acute and sub-chronic, respectively). No effects on the acquisition of the Morris water maze were observed. However, only 1 mg/kg of PNU administered just before training trials over a period of 5 days showed beneficial effects on the retention of the water maze when evaluated 4 h after water maze acquisition. Further studies are needed to clarify the effects on the cognitive performance and potential neuroprotection of these agents in an elderly population with slight or severe deficiency in learning and memory processes, and/or in animal models vulnerable to neurodegenerative disorders.

Combined effects of perfluorooctane sulfonate (PFOS) and maternal restraint stress on hypothalamus adrenal axis (HPA) function in the offspring of mice.

Although it is known that prenatal exposure to perfluorooctane sulfonate (PFOS) can cause developmental adverse effects in mammals, the disruptive effects of this compound on hormonal systems are still controversial. Information concerning the effects of PFOS on hypothalamus adrenal (HPA) axis response to stress and corticosterone levels is not currently available. On the other hand, it is well established that stress can enhance the developmental toxicity of some chemicals. In the present study, we assessed the combined effects of maternal restraint stress and PFOS on HPA axis function in the offspring of mice. Twenty plug-positive female mice were divided in two groups. Animals were given by gavage 0 and 6 mg PFOS/kg/day on gestation days 12-18. One half of the animals in each group were also subjected to restraint stress (30 min/session, 3 sessions/day) during the same period. Five plug-positive females were also included as non-manipulated controls. At 3 months of age, activity in an open-field and the stress response were evaluated in male and female mice by exposing them to 30 min of restraint stress. Male and female offspring were subsequently sacrificed and blood samples were collected to measure changes in corticosterone levels at four different moments related to stress exposure conditions: before stress exposure, immediately after 30 min of stress exposure, and recuperation levels at 60 and 90 min after stress exposure. Results indicate corticosterone levels were lower in mice prenatally exposed to restraint. In general terms, PFOS exposure decreased corticosterone levels, although this effect was only significant in females. The recuperation pattern of corticosterone was mainly affected by prenatal stress. Interactive effects between PFOS and maternal stress were sex dependent. The current results suggest that prenatal PFOS exposure induced long-lasting effects in mice.

Evaluation of the protective role of melatonin on the behavioral effects of aluminum in a mouse model of Alzheimer's disease.

In this study, five months old female transgenic (Tg2576) and wild-type mice were exposed for 6 months to aluminum (1mg Al/g diet), melatonin (10mg/kg/day), Al plus melatonin, or vehicle only (control group). General motor activity was evaluated using an open-field, whereas spatial learning and memory were assessed in a water maze. Aluminum levels in hippocampus, cortex and cerebellum were determined. Aluminum-treated Tg2576 mice showed higher Al levels in hippocampus than non-Al treated animals. No Al effects on general motor activity were found, while the open-field test showed an increased number of rearings in Tg2576 mice. A lower habituation pattern was observed in melatonin-treated animals. Differences in learning were noted in the water maze acquisition test, in which Al-treated Tg2576 mice showed more difficulties in learning the task than Al-exposed wild mice. No significant effects of melatonin in the acquisition task were observed. The present results indicate that Tg2576 mice are sensitive to high dietary Al levels. A significant protector role of melatonin on Al-induced behavioral effects was not observed.