Similar deficits of central histaminergic system in patients with Down syndrome and Alzheimer disease

Schneider, Christoph; Risser, Daniele; Kirchner, Lieselotte; Kitzmüller, Erwin; Cairns, Nigel J.; Prast, H.; Singewald, Nicolas; Lubec, Gert

doi:10.1016/s0304-3940(97)13379-1

Cited by 69 publications

(34 citation statements)

References 29 publications

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“…This is in contrast to our previous data in human postmortem tissues [21], and may be seen as contradictory to previous reports showing reductions in dopamine and its acidic metabolites DOPAC and HVA, in DS fetal and adult brains [35,40,66]. Our study suggests that, even if dopamine levels are reduced, the D 1 -coupled postreceptor mechanisms may not be affected in the hippocampus of trisomic mice, contrary to the effects observed at the cortical or cerebellar levels [21,28].…”

Section: Discussioncontrasting

confidence: 99%

G-Protein-Associated Signal Transduction Processes Are Restored after Postweaning Environmental Enrichment in Ts65Dn, a Down Syndrome Mouse Model

et al. 2011

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Individuals with Down syndrome (DS) present cognitive deficits that can be improved by early implementation of special care programs. However, they showed limited and temporary cognitive effects. We previously demonstrated that postnatal environmental enrichment (EE) improved clearly, though temporarily, the execution of visuospatial memory tasks in Ts65Dn mice, a DS model bearing a partial trisomy of murine chromosome 16; but in contrast to wild-type littermates, there was a lack of structural plasticity in pyramidal cell structure in the trisomic cerebral cortex. In the present study, we have investigated the impact of EE on the function of adenylyl cyclase and phospholipase C as a possible mechanism underlying the time-limited improvements observed. Basal production of cyclic adenosine monophosphate (cAMP) was not affected, but responses to GTPγS, isoprenaline, noradrenaline, SKF 38393 and forskolin were depressed in the Ts65Dn hippocampus. In EE conditions, cAMP accumulation was not significantly modified in control animals with respect to nonenriched controls. However, EE had a marked effect in Ts65Dn mice, in which cAMP production was significantly increased. Similarly, EE increased phospholipase C activity in Ts65Dn mice, in response to carbachol and calcium. We conclude that EE restores the G-protein-associated signal transduction systems that are altered in Ts65Dn mice.

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Section: Discussioncontrasting

confidence: 99%

G-Protein-Associated Signal Transduction Processes Are Restored after Postweaning Environmental Enrichment in Ts65Dn, a Down Syndrome Mouse Model

et al. 2011

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“…Increasing brain histamine release is another potential mechanism to improve cognition in AD, because reports suggest that histaminergic neuronal activity is compromised in AD. Schneider et al (1997) reported that the level of histidine decarboxylase, the enzyme responsible for converting histidine to histamine, was decreased approximately 50% in the frontal cortex of patients with AD. Airaksinen et al (1991) reported that, in patients with AD, large numbers of large globular neurofibrillary tangles were found in the tuberomammillary neurons of the hypothalamus.…”

Section: Introductionmentioning

confidence: 99%

The 5-Hydroxytryptamine₄ Receptor Agonists Prucalopride and PRX-03140 Increase Acetylcholine and Histamine Levels in the Rat Prefrontal Cortex and the Power of Stimulated Hippocampal θ Oscillations

Johnson

Drummond²,

Grimwood³

et al. 2012

J Pharmacol Exp Ther

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5-Hydroxytryptamine (5-HT) 4 receptor agonists reportedly stimulate brain acetylcholine (ACh) release, a property that might provide a new pharmacological approach for treating cognitive deficits associated with Alzheimer's disease. The purpose of this study was to compare the binding affinities, functional activities, and effects on neuropharmacological responses associated with cognition of two highly selective 5-HT 4 receptor agonists, prucalopride and 6,7-dihydro-4-hydroxy-7-isopropyl-6-oxo-N-[3-(piperidin-1-yl)propyl]thieno[2,3-b]pyridine-5-carboxamide (PRX-03140). In vitro, prucalopride and PRX-03140 bound to native rat brain 5-HT 4 receptors with K i values of 30 nM and 110 nM, respectively, and increased cAMP production in human embryonic kidney-293 cells expressing recombinant rat 5-HT 4 receptors. In vivo receptor occupancy studies established that prucalopride and PRX-03140 were able to penetrate the brain and bound to 5-HT 4 receptors in rat brain, achieving 50% receptor occupancy at free brain exposures of 330 nM and 130 nM, respectively. Rat microdialysis studies revealed that prucalopride maximally increased ACh and histamine levels in the prefrontal cortex at 5 and 10 mg/kg, whereas PRX-03140 significantly increased cortical histamine levels at 50 mg/kg, failing to affect ACh release at doses lower than 150 mg/kg. In combination studies, donepezil-induced increases in cortical ACh levels were potentiated by prucalopride and PRX-03140. Electrophysiological studies in rats demonstrated that both compounds increased the power of brainstem-stimulated hippocampal oscillations at 5.6 mg/kg. These findings show for the first time that the 5-HT 4 receptor agonists prucalopride and PRX-03140 can increase cortical ACh and histamine levels, augment donepezil-induced ACh increases, and increase stimulated-hippocampal power, all neuropharmacological parameters consistent with potential positive effects on cognitive processes.

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“…Defects in the histaminergic system have been linked with cognitive deficiencies in neurodegenerative diseases, including Alzheimer's disease and Down syndrome (8)(9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

The Histamine N-Methyltransferase T105I Polymorphism Affects Active Site Structure and Dynamics

2007

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Histamine N-methyltransferase (HNMT) is the sole enzyme responsible for inactivating histamine in the mammalian brain. The human HNMT gene contains a common threonine-isoleucine polymorphism at residue 105, distal from the active site. The 105I variant has decreased activity and lower protein levels relative to the 105T protein. Crystal structures of both variants have been solved, but reveal little regarding how the T105I polymorphism affects activity. We performed molecular dynamics simulations of both 105T and 105I at 37°C to explore the structural and dynamic consequences of the polymorphism. The simulations indicate that replacing Thr with the larger Ile residue leads to greater burial of residue 105 and heightened packing interactions between residue105 and residues within helix α3 and strand β3. This altered packing is directly translated to the active site resulting in the reorientation of several co-substrate-binding residues. The simulations also show that the hydrophobic histamine-binding domain in both proteins undergoes a large-scale breathing motion that exposes key catalytic residues and lessens the hydrophobicity of the substrate-binding site.

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Similar deficits of central histaminergic system in patients with Down syndrome and Alzheimer disease

Cited by 69 publications

References 29 publications

G-Protein-Associated Signal Transduction Processes Are Restored after Postweaning Environmental Enrichment in Ts65Dn, a Down Syndrome Mouse Model

G-Protein-Associated Signal Transduction Processes Are Restored after Postweaning Environmental Enrichment in Ts65Dn, a Down Syndrome Mouse Model

The 5-Hydroxytryptamine₄ Receptor Agonists Prucalopride and PRX-03140 Increase Acetylcholine and Histamine Levels in the Rat Prefrontal Cortex and the Power of Stimulated Hippocampal θ Oscillations

The Histamine N-Methyltransferase T105I Polymorphism Affects Active Site Structure and Dynamics

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Similar deficits of central histaminergic system in patients with Down syndrome and Alzheimer disease

Cited by 69 publications

References 29 publications

G-Protein-Associated Signal Transduction Processes Are Restored after Postweaning Environmental Enrichment in Ts65Dn, a Down Syndrome Mouse Model

G-Protein-Associated Signal Transduction Processes Are Restored after Postweaning Environmental Enrichment in Ts65Dn, a Down Syndrome Mouse Model

The 5-Hydroxytryptamine4 Receptor Agonists Prucalopride and PRX-03140 Increase Acetylcholine and Histamine Levels in the Rat Prefrontal Cortex and the Power of Stimulated Hippocampal θ Oscillations

The Histamine N-Methyltransferase T105I Polymorphism Affects Active Site Structure and Dynamics

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The 5-Hydroxytryptamine₄ Receptor Agonists Prucalopride and PRX-03140 Increase Acetylcholine and Histamine Levels in the Rat Prefrontal Cortex and the Power of Stimulated Hippocampal θ Oscillations