Effects of acute administration of donepezil or memantine on sleep-deprivation-induced spatial memory deficit in young and aged non-human primate grey mouse lemurs (Microcebus murinus).

The development of novel therapeutics to prevent cognitive decline of Alzheimer's disease (AD) is facing paramount difficulties since the translational efficacy of rodent models did not resulted in better clinical results. Currently approved treatments, including the acetylcholinesterase inhibitor donepezil (DON) and the N-methyl-D-aspartate antagonist memantine (MEM) provide marginal therapeutic benefits to AD patients. There is an urgent need to develop a predictive animal model that is phylogenetically proximal to humans to achieve better translation.

Early Development of Symptomatic Drugs in AD: A Systematic Review of the Use of Biomarkers.

Pharmacological therapies currently marketed for Alzheimer's disease (AD) are only symptomatic and show limited effects in terms of clinical benefit. Thus, the development of new symptomatic drugs remains essential. However the dramatic increase in costs associated with drug development together with the poor number of emerging drugs highlights how crucial it is to accelerate the findings aiming to bringing new drugs to market.

Translational Challenge Models in Support of Efficacy Studies: Effect of Cerebral Hypoxia on Cognitive Performances in Rodents.

Empirical evidence currently supports the idea that neurovascular dysfunction is involved in the neurodegenerative process of Alzheimer's disease (AD). In fact, epidemiological studies report that i) vascular risk factors are directly associated with an increased incidence of AD and ii) vascular lesions are frequently co-existent with AD. The neurovascular unit is a key control system for oxygen and nutrients exchange between neurons and microvessels so the integrity of this system is essential for neuronal activity and cell survival.

Brivaracetam: Rationale for discovery and preclinical profile of a selective SV2A ligand for epilepsy treatment.

Despite availability of effective antiepileptic drugs (AEDs), many patients with epilepsy continue to experience refractory seizures and adverse events. Achievement of better seizure control and fewer side effects is key to improving quality of life. This review describes the rationale for the discovery and preclinical profile of brivaracetam (BRV), currently under regulatory review as adjunctive therapy for adults with partial-onset seizures.

Brain catechol-O-methyltransferase (COMT) inhibition by tolcapone counteracts recognition memory deficits in normal and chronic phencyclidine-treated rats and in COMT-Val transgenic mice.

The critical involvement of dopamine in cognitive processes has been well established, suggesting that therapies targeting dopamine metabolism may alleviate cognitive dysfunction. Catechol-O-methyl transferase (COMT) is a catecholamine-degrading enzyme, the substrates of which include dopamine, epinephrine, and norepinephrine. The present work illustrates the potential therapeutic efficacy of COMT inhibition in alleviating cognitive impairment.

On-Going Frontal Alpha Rhythms Are Dominant in Passive State and Desynchronize in Active State in Adult Gray Mouse Lemurs.

The gray mouse lemur (Microcebus murinus) is considered a useful primate model for translational research. In the framework of IMI PharmaCog project (Grant Agreement n°115009, www.pharmacog.

Memantine prevents reference and working memory impairment caused by sleep deprivation in both young and aged Octodon degus.

Memory loss is one of the key features of cognitive impairment in either aging, Mild Cognitive Impairment (MCI) or dementia. Pharmacological treatments for memory loss are today focused on addressing symptomatology. One of these approved compounds is memantine, a partial NMDA receptor antagonist that has proved its beneficial effects in cognition.

Experimental sleep deprivation as a tool to test memory deficits in rodents.

Paradigms of sleep deprivation (SD) and memory testing in rodents (laboratory rats and mice) are here reviewed. The vast majority of these studies have been aimed at understanding the contribution of sleep to cognition, and in particular to memory. Relatively little attention, instead, has been devoted to SD as a challenge to induce a transient memory impairment, and therefore as a tool to test cognitive enhancers in drug discovery.

The prototypical histamine H3 receptor inverse agonist thioperamide improves multiple aspects of memory processing in an inhibitory avoidance task.

Numerous studies have found that histamine plays a major role in memory and that the histamine H3 receptor (H3R) inverse agonist thioperamide improves cognitive performance in various animal models. However, little is known about the stages of memory that are specifically affected by thioperamide. The purpose of the present study was to investigate the effects of thioperamide on acquisition, consolidation and retrieval processes in a one-trial inhibitory avoidance task in female C57BL/6J mice.

Sleep deprivation impairs spatial retrieval but not spatial learning in the non-human primate grey mouse lemur.

A bulk of studies in rodents and humans suggest that sleep facilitates different phases of learning and memory process, while sleep deprivation (SD) impairs these processes. Here we tested the hypothesis that SD could alter spatial learning and memory processing in a non-human primate, the grey mouse lemur (Microcebus murinus), which is an interesting model of aging and Alzheimer's disease (AD). Two sets of experiments were performed.

Lead optimization of thiazolo[5,4-c]piperidines: 3-cyclobutoxy linker as a key spacer for H(3)R inverse agonists.

The simpler, the better: H(3) histamine receptor (H(3)R) are of interest as therapeutic targets in cognitive and somnolence disorders. Here, lead optimization of H(3)R inverse agonists bearing a thiazolo[5,4-c]piperidine group gave rise to a clinical candidate with a much simpler unprecedented benzamide scaffold, displaying decreased hERG activity while maintaining high brain receptor occupancies.

Effects of pharmacological agents, sleep deprivation, hypoxia and transcranial magnetic stimulation on electroencephalographic rhythms in rodents: towards translational challenge models for drug discovery in Alzheimer's disease.

Different kinds of challenge can alter spontaneous ongoing electroencephalographic (EEG) rhythms in animal models, thus providing paradigms to evaluate treatment effects in drug discovery. The effects of challenges represented by pharmacological agents, hypoxia, sleep deprivation and transcranial magnetic stimulation (TMS) on EEG rhythms are here reviewed to build a knowledge platform for innovative translational models for drug discovery in Alzheimer's disease (AD). It has been reported that antagonists of cholinergic neurotransmission cause synchronisation of spontaneous ongoing EEG rhythms in terms of enhanced power of EEG low frequencies and decreased power of EEG high frequencies.

Discovery of a new class of non-imidazole oxazoline-based histamine H(3) receptor (H(3)R) inverse agonists.

H(3)R inverse agonists based on an aminopropoxy-phenyloxazoline framework constitute highly valuable druglike lead compounds that display efficacy in a mouse model of recognition memory.

Behavioural phenotyping reveals anxiety-like features of SV2A deficient mice.

Synaptic vesicle protein 2A (SV2A) is involved in neurotransmitter release and has been identified as the binding site for levetiracetam (Keppra), a novel antiepileptic drug. Homozygous SV2A (-/-) mice are not viable beyond a few weeks. In contrast, heterozygous SV2A (+/-) mice have a normal lifespan.

Levetiracetam reduces anesthetic-induced hyperalgesia in rats.

Background: As part of an increase in excitability, small doses of pentobarbital, propofol, and midazolam induce an increased sensitivity to pain. Specific therapy to prevent or reduce this excitability may offer advantages over current clinical management with analgesics and sedatives. The pharmacological profile of the novel antiepileptic drug, levetiracetam, suggests that it may reduce the intensity of the excitatory stages of anesthesia.

Hydroxyzine prevents isolation-induced vocalization in guinea pig pups: comparison with chlorpheniramine and immepip.

The present pharmacological study was conducted to investigate a possible role of the brain histaminergic system in vocalization induced in guinea pig pups by maternal separation and isolation in an unfamiliar environment. The effects of drugs acting at histamine receptors were determined after intraperitoneal injection, comprising hydroxyzine and chlorpheniramine, both histamine H1 antagonists, and the H3 agonist, immepip. A range of psychoactive drugs known to be active in this paradigm was also tested for comparison.

Histamine H3 antagonist thioperamide dose-dependently enhances memory consolidation and reverses amnesia induced by dizocilpine or scopolamine in a one-trial inhibitory avoidance task in mice.

In the literature, there is some evidence indicating that H3 histamine receptor antagonists, in particular thioperamide, can facilitate learning and memory retrieval in laboratory rodents. The present study aimed at verifying whether this also holds for memory consolidation, a phase of memory for which there is scarcity of convincing data on the effects of H3 receptor antagonists given systemically. To that end, memory consolidation was assessed in C57BL/6J mice using the one-trial step-through inhibitory avoidance task, the compounds being injected immediately after training (foot-shock) and performance measured 24 h later.

Anxiolytic effects of the novel anti-epileptic drug levetiracetam in the elevated plus-maze test in the rat.

There is clinical evidence of anxiolytic action of several anti-epileptic drugs. We evaluated the effects of levetiracetam (Keppra), a new generation anti-epileptic drug, in the plus-maze animal test for anxiolytic activity. Levetiracetam at 17 and 54 mg/kg intraperitoneally (i.