A preclinical screen to evaluate pharmacotherapies for the treatment of agitation in dementia.

Agitation associated with dementia is frequently reported clinically but has received little attention in preclinical models of dementia. The current study used a 7PA2 CM intracerebroventricular injection model of Alzheimer's disease (AD) to assess acute memory impairment, and a bilateral intrahippocampal (IH) injection model of AD (aggregated Aβ1-42 injections) and a bilateral IH injection model of dementia with Lewy bodies (aggregated NAC61-95 injections) to assess chronic memory impairment in the rat. An alternating-lever cyclic-ratio schedule of operant responding was used for data collection, where incorrect lever perseverations measured executive function (memory) and running response rates (RRR) measured behavioral output (agitation).

Lack of support for bexarotene as a treatment for Alzheimer's disease.

Bexarotene has been reported to reduce brain amyloid-β (Aβ) levels and to improve cognitive function in transgenic mouse models of Alzheimer's disease (AD). Four groups failed to fully replicate the primary results but the original authors claimed overall support for the general conclusions. Because of its potential clinical importance, the current work studied the effects of bexarotene using two animal species and highly relevant paradigms.

MRZ-99030 - A novel modulator of Aβ aggregation: II - Reversal of Aβ oligomer-induced deficits in long-term potentiation (LTP) and cognitive performance in rats and mice.

β-amyloid1-42 (Aβ1-42) is a major endogenous pathogen underlying the aetiology of Alzheimer's disease (AD). Recent evidence indicates that soluble Aβ oligomers, rather than plaques, are the major cause of synaptic dysfunction and neurodegeneration. Small molecules that suppress Aβ aggregation, reduce oligomer stability or promote off-pathway non-toxic oligomerization represent a promising alternative strategy for neuroprotection in AD.

Novel 5-aryloxypyrimidine SEN1576 as a candidate for the treatment of Alzheimer's disease.

Prefibrillar assembly of amyloid-β (Aβ) is a major event underlying the development of neuropathology and dementia in Alzheimer's disease (AD). This study determined the neuroprotective properties of an orally bioavailable Aβ synaptotoxicity inhibitor, SEN1576. Binding of SEN1576 to monomeric Aβ 1-42 was measured using surface plasmon resonance.

AβPP-overexpressing transgenic rat model of Alzheimer's disease utilizing the Tg2576 mouse protocol.

The current study examined behavioral and histological effects of amyloid-β (Aβ) protein precursor (AβPP) overexpression in transgenic (Tg) rats created using the same gene, mutation, and promoter as the Tg2576 mouse model of Alzheimer's disease (AD). Male Tg+ rats were bred with female wild-type rats to generate litters of hemizygous Tg+ and Tg- offspring. Tg+ rats and Tg- littermates were tested for memory deficits at 4, 8, and 12 months old using a water-maze procedure.

Orally bioavailable small molecule drug protects memory in Alzheimer's disease models.

Oligomers of beta-amyloid (Aβ) are implicated in the early memory impairment seen in Alzheimer's disease before to the onset of discernable neurodegeneration. Here, the capacity of a novel orally bioavailable, central nervous system-penetrating small molecule 5-aryloxypyrimidine, SEN1500, to prevent cell-derived (7PA2 [conditioned medium] CM) Aβ-induced deficits in synaptic plasticity and learned behavior was assessed. Biochemically, SEN1500 bound to Aβ monomer and oligomers, produced a reduction in thioflavin-T fluorescence, and protected a neuronal cell line and primary cortical neurons exposed to synthetic soluble oligomeric Aβ(1-42).

Novel anti-inflammatory compound SEN1176 alleviates behavioral deficits induced following bilateral intrahippocampal injection of aggregated amyloid-β₁₋₄₂.

Behavioral effects of a novel anti-inflammatory SEN1176 were investigated. This pyrrolo[3,2-e][1,2,4]triazolo[1,5-a]pyrimidine suppresses amyloid-β (Aβ)1-42-induced macrophage production of nitric oxide, TNF-α, IL-1β, and IL-6 in a dose-dependent fashion, an activity profile consistent with SEN1176 being a neuroinflammation inhibitor. Using male Sprague-Dawley rats, SEN1176 was examined relative to detrimental behavioral effects induced following bilateral intrahippocampal (IH) injections of aggregated Aβ1-42.

Quantification of nanoparticle uptake by cells using microscopical and analytical techniques.

Quantification of nanoparticles in biological systems (i.e., cells, tissues and organs) is becoming a vital part of nanotoxicological and nanomedical fields.

RS-0406 arrests amyloid-beta oligomer-induced behavioural deterioration in vivo.

Clinically accessible compounds that arrest or reverse the effects of amyloid-beta (Abeta) on progressively developing behavioural symptomatology and neuropathology in Alzheimer's disease (AD) have yet to become available. However, a viable strategy may be to target and neutralise soluble Abeta oligomers, which have been shown to mediate synaptic dysfunction and to produce cognitive deficits in the intact organism. Inhibiting the aggregation of Abeta is therapeutically attractive, as Abeta aggregation is a pathological event and pharmacological interventions targeting this are likely to have a non-toxic profile.

Behavioural deterioration induced by intrahippocampal NAC61-95 injections and attenuation with ibuprofen.

Pre-aggregated non-amyloid component of alpha-synuclein, NAC(61-95), was injected bilaterally into the CA3 area of rat hippocampus and behaviour was assessed using an alternating-lever cyclic-ratio (ALCR) schedule of operant responding. Four groups of rats were used (n=6 per group), subgroups were treated orally with either ibuprofen (40mg/kg) or vehicle (10% sucrose) twice daily. Intrahippocampal injection of NAC(61-95) increased lever switching errors and numbers of activated astrocytes, and ibuprofen treatment alleviated these effects.

Bilateral intrahippocampal NAC61-95 effects on behavior and moderation with L-NAME treatment.

Residues 61-95 of the non-amyloid component (NAC(61-95)) domain of alpha-synuclein are responsible for the aggregation and neurotoxicity of this protein. This study evaluated the effect of N((omega))-nitro-l-arginine methyl ester (l-NAME), a nitric oxide synthase inhibitor, on the behavior of rats bilaterally injected into the CA3 area of the dorsal hippocampus with aggregated NAC(61-95). Twenty-four male Sprague-Dawley rats were trained to respond under an alternating-lever cyclic-ratio (ALCR) operant schedule.

Feeding association between the nucleus of the solitary tract and the ventral tegmental area.

Male Sprague-Dawley rats were fitted with two cannulae in the VTA and one cannula in the NTS for co-administration of the micro-opioid receptor agonist DAMGO in one site and the opioid antagonist naltrexone in the other. Injection of DAMGO into the VTA or the NTS stimulated feeding. The increase in food intake after DAMGO injection into the VTA was decreased following injection of naltrexone into the NTS.

Roles for the subiculum in spatial information processing, memory, motivation and the temporal control of behaviour.

The subiculum is in a pivotal position governing the output of the hippocampal formation. Despite this, it is a rather under-explored and sometimes ignored structure. Here, we discuss recent data indicating that the subiculum participates in a wide range of neurocognitive functions and processes.

Oligomers of the amyloid-beta protein disrupt working memory: confirmation with two behavioral procedures.

Converging lines of evidence suggest that oligomers of amyloid-beta play a role in the cognitive impairment characteristic of Alzheimer's disease, but only three studies have provided experimental evidence of such impairment. To provide additional information about the effects of these oligomers on memory, the present study examined the memory of groups of rats exposed to ICV injections of the culture media (CM) of Chinese Hamster Ovary cells that were (7PA2) and were not (CHO-) transfected with a human mutation of amyloid precursor protein that appears to cause early-onset Alzheimer's disease. The 7PA2 CM, which contained concentrations of soluble amyloid-beta oligomers physiologically relevant to those found in human brain, significantly disrupted working memory in rats tested in a radial-arm maze.

Thyroxine replacement in an animal model of congenital hypothyroidism.

This study examined the effects of thyroxine (T(4)) treatment on spatial learning and memory in congenitally hypothyroid (CH) rats. Forty CH male offspring of methimazole-treated dams were randomly divided into three groups: no T(4) (vehicle) treatment (n=12), T(4) treatment commencing on postnatal day (P-) 7 (n=14), and T(4) treatment commencing on P-21 (n=14). Normal male rats were used as a control group (n=14).

Orally available compound prevents deficits in memory caused by the Alzheimer amyloid-beta oligomers.

Objective: Despite progress in defining a pathogenic role for amyloid beta protein (Abeta) in Alzheimer's disease, orally bioavailable compounds that prevent its effects on hippocampal synaptic plasticity and cognitive function have not yet emerged. A particularly attractive therapeutic strategy is to selectively neutralize small, soluble Abeta oligomers that have recently been shown to mediate synaptic dysfunction.

Methods: Using electrophysiological, biochemical, and behavioral assays, we studied how scyllo-inositol (AZD-103; molecular weight, 180) neutralizes the acutely toxic effects of Abeta on synaptic function and memory recall.

A bi-directional mu-opioid-opioid connection between the nucleus of the accumbens shell and the central nucleus of the amygdala in the rat.

The central nucleus of the amygdala (CeA) and the nucleus of the accumbens shell (NAc) have been shown to be involved in opioid-mediated feeding behavior. The present study examined whether mu-opioid signalling between the CeA and NAc affected feeding. Male Sprague-Dawley rats were fitted with one cannula placed in the CeA and two cannulae placed in the NAc, which allowed for coadministration of the mu-opioid receptor agonist [D-Ala(2), NMe-Phe(4), Gly-ol(5)]-enkephalin (DAMGO) in one site and the opioid antagonist naltrexone (NTX) in the other site.

Evidence for a mu-opioid-opioid connection between the paraventricular nucleus and ventral tegmental area in the rat.

The paraventricular nucleus (PVN) and the ventral tegmental area (VTA) have been shown to be involved in opioid mediated feeding behavior. The present study examined whether mu-opioid signalling between the PVN and VTA affected feeding behavior. Male Sprague-Dawley rats were cannulated with one cannula placed in the PVN and two cannulae placed in the VTA, which allowed for co-administration of the mu-opioid receptor agonist [D-Ala(2), NMe-Phe(4), Gly-ol(5)]-enkephalin (DAMGO) in one site and the opioid antagonist naltrexone (NTX) in the other site.

Injection of alpha-MSH, but not beta-endorphin, into the PVN decreases POMC gene expression in the ARC.

beta-Endorphin (beta-END) and alpha-melanocyte stimulating hormone (alpha-MSH), neuropeptides derived from proopiomelanocortin (POMC), have opposite effects on eating behavior. We injected rats with alpha-MSH (0.6 nmol) or beta-END (1 nmol) into the PVN (three times in a 26 h period).