Biomedical subjects

David M Pache

Publications and source records attributed to David M Pache.

5 recordsLinked to original sources

PubMed2006

An antibody to the beta-secretase cleavage site on amyloid-beta-protein precursor inhibits amyloid-beta production.

Proteolytic cleavage of amyloid-beta-protein precursor (AbetaPP) by beta- and gamma-secretases results in production of the amyloid-beta peptide (Abeta) that accumulates in the brains of sufferers of Alzheimer's disease (AD). We have developed a monoclonal antibody, 2B12, which binds in the vicinity of the beta-secretase cleavage site on AbetaPP but does not bind within the Abeta region. We hypothesised that this antibody, directed against the substrate rather than the enzyme, could inhibit cleavage of AbetaPP by beta-secretase via steric hindrance and thus reduce downstream production of Abeta. The antibody would enter cells by binding to AbetaPP when it is at the cell surface and then be internalised with the protein. We subsequently demonstrated that, after addition of 2B12 to standard growth media, this antibody was indeed capable of inhibiting Abeta40 production in neuroblastoma and astrocytoma cells expressing native AbetaPP, as measured by an ELISA. This inhibition was both concentration- and time-dependent and was specific to 2B12. We were only able to inhibit approximately 50% of Abeta40 production suggesting that not all AbetaPP is trafficked to the cell surface. We propose that this antibody could be used as a novel, putative therapy for the treatment of AD.

Amyloid Precursor Protein Secretases↗

PubMed2005

Co-administration of fluoxetine and WAY100635 improves short-term memory function.

The aim of this study was to determine whether the action of the antidepressant fluoxetine or the anxiolytic buspirone could be modified by specific 5-hydroxytriptamine (5-HT(1A)) receptor blockade in a short-term memory paradigm. Male Wistar rats were trained to perform the putative short-term memory task, delayed non-matching to position. WAY100635, a selective 5-HT(1A) receptor antagonist (0.15 mg/kg), was administered 15 min before either the selective serotonin reuptake inhibitor fluoxetine (3 mg/kg), or the partial 5-HT(1A) receptor agonist and dopamine D2 receptor antagonist, buspirone (0.3 mg/kg). 8-Hydroxy-di-n-propylamino tetralin (8-OH-DPAT), a full 5-HT(1A) receptor agonist (0.3 mg/kg), was also included in the study as a positive control. WAY100635 alone had no effect on any behavioural parameter measured (response accuracy, delay lever press activity and trial completion). 8-OH-DPAT impaired response accuracy in a delay-dependent manner, an effect reversed by WAY100635. Fluoxetine also impaired response accuracy delay-dependently. WAY100635 pretreatment not only reversed this deficit but improved response accuracy, in the presence of a significant deficit in trial completion. At the dose used, buspirone showed no significant differences compared to the control group. The data suggest that fluoxetine impairs short-term memory function by the indirect activation of 5-HT(1A) receptors, but that its co-administration with WAY100635 improves short-term memory function.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed2005

Does the human leukaemia differentiation factor fragment HLDF6 improve memory via brain DNA and protein synthesis?

The novel human differentiating factor peptide fragment HLDF6 (Thr-Gly-Glu-Asn-His-Arg) was synthesized and purified. HLDF6 (0.1mg/kg i.p. but not 1mg/kg i.p.) improved not only long-term (24h) memory in adult rats in the water maze behavioural paradigm but also performance in the delayed matching-to-position (DMTP) task (0.3 and 1.0 but not 0.1mg/kg i.p). Hence, HLDF6 not only enhanced allocentric spatial learning and reference memory (water maze) but also improved temporal, spatial and working memory processes in the DMTP behavioural paradigm. Immunoreactivity blotting analysis of HLDF (the protein precursor of HLDF6) was performed and the following rank order of visual intensities from brain structures was noted: hippocampus cerebral cortex cerebellum hypothalamus striatum. Subsequently, we found that the highest absolute levels of HLDF were expressed in the hippocampus and cerebral cortex as detected by ELISA. We also demonstrated that HLDF6 enhanced [(3)H]-thymidine and [(14)C]-leucine incorporation into whole brain and hippocampal homogenates (maxima occurring within the range 10 (-12)-10 (-6) M) suggesting that this hexapeptide promoted de novo DNA and protein biosynthesis. We discuss this data in terms of their implications for links with other integrative metabolic pathways involving immediate early gene activation which may underpin a potential application for HLDF6 in limiting memory impairments associated with neurodegenerative diseases.

Animals↗

PubMed2003

Buspirone differentially modifies short-term memory function in a combined delayed matching/non-matching to position task.

This study investigated the action of 5-hydroxytryptamine (5-HT) mimetics on short-term memory function. The objective was to determine whether two closely related tasks could differentiate between partial 5-HT(1A) receptor activation, full 5-HT(1A) receptor activation and generalised enhanced serotonin (5-HT) activity. Male hooded Lister rats were trained to perform an operant-based combined delayed matching/non-matching to position task. Drugs used were: fluoxetine (3 mg/kg, i.p.), a selective 5-HT reuptake inhibitor; the full 5-HT(1A) receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 0.3 mg/kg, s.c.); and the partial 5-HT(1A) receptor agonist, buspirone (1 mg/kg, i.p.). Buspirone differentially disrupted response accuracy depending on the style of trial. There was no such difference in the case of 8-OH-DPAT, which impaired accuracy in both delayed matching/non-matching to position task, while fluoxetine affected neither. Thus, the findings suggest that partial 5-HT(1A) receptor activation compromises cognitive function to a greater extent than full 5-HT(1A) receptor activation, although a dopaminergic component cannot be excluded since buspirone possesses some dopamine D2 receptor antagonist activity. Furthermore, it suggests that there is a differential role for 5-HT in these two closely related behavioural tasks.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed2002

Morphine, cocaine and antidepressant induced motivational activity and midbrain dopaminergic neurotransmission.

Positive motivational properties of opioids, stimulants and serotonin selective reuptake inhibitors have been reported following place preference conditioning. The possibility that these effects are associated with changes in dopamine concentration in the nucleus accumbens or striatum was investigated. Male Wistar rats were place conditioned in a three compartment model to vehicle or drug (morphine 2.5 mg/kg, cocaine 5 mg/kg, sertraline 5 mg/kg or paroxetine 15 mg/kg) alternately for 8 days using a 30 min pre-treatment time. Control animals received saline only. Nucleus accumbens and striatal tissue were dissected 72 h after final drug dose, and the concentration of dopamine and its metabolites determined using high performance liquid chromatography (HPLC). Striatal dopamine D1-like receptor density was also determined through radioligand binding. Significant place preference (P<0.05) was observed with morphine, cocaine and sertraline. Morphine treated subjects showed a significant decrease (P<0.05) in striatal dopamine concentration, whilst cocaine and sertraline treatment resulted in a significant increase in striatal dopamine levels. Nucleus accumbens concentrations of dopamine, and striatal dopamine D1-like receptor density remained unchanged. The changes in striatal dopamine concentrations are consistent with withdrawal from opioid and stimulant compounds, and suggest that place preference conditioning may, in part, result from negative motivational or aversive effects.

3,4-Dihydroxyphenylacetic Acid↗