Search

The brain׳s complexity derives not only from the way the intricate network of neurons is wired, but also by protein complexes that recognize and decode chemical information. G protein-coupled receptors (GPCRs) represent the most abundant family of proteins mediating neurotransmission in the brain, and their ability to form homo- and heteromers which amplifies the scope for synaptic communication and fine-tuning. Dopamine receptors are important drug targets and members of both the D 1 /D 5 and D 2 /D 3 /D 4 receptor families form homo- and heteromers. The present article focuses on D 3 receptor homo- and heteromers, in particular, those formed in association with their D 2 counterparts. We highlight the binding profiles and mechanisms of interaction with D 3 –D 3 homomers and D 3 –D 2 heteromers of: first, the PET ligand and potent agonist [ 11 C]-(+)-PHNO; second, the novel, bitopic/allosteric dopamine D 3 receptor antagonist, SB269,652; and third, diverse partial agonists like antipsychotic and aripiprazole. Molecular mechanisms of interplay between the two protomers of heteromeric D 3 –D 2 complexes are likewise discussed: for example, “transactivation”, whereby recruitment of one member of a heteromer harnesses signalling pathways is normally coupled to the other protomer. Finally, D 1 receptor heteromers are also taken into consideration in deciphering the nature of interfaces required to stabilize dimeric assemblies and permit their interaction with G proteins. Improved understanding of D 3 as well as D 2 and D 1 receptor complexes should yield important insights into their physiological roles and pathological significance, and permit the development of novel drug classes with potentially distinctive functional profiles and improved therapeutic windows.

We investigated the effects of continuous artificial light exposure on the mouse substantia nigra (SN). A three month exposure of C57Bl/6J mice to white fluorescent light induced a 30% reduction in dopamine (DA) neurons in SN compared to controls, accompanied by a decrease of DA and its metabolites in the striatum. After six months of exposure, neurodegeneration progressed slightly, but the level of DA returned to the basal level, while the metabolites increased with respect to the control. Three month exposure to near infrared LED light (∼710nm) did not alter DA neurons in SN, nor did it decrease DA and its metabolites in the striatum. Furthermore mesencephalic cell viability, as tested by [3H]DA uptake, did not change. Finally, we observed that 710nm LED light, locally conveyed in the rat SN, could modulate the firing activity of extracellular-recorded DA neurons. These data suggest that light can be detrimental or beneficial to DA neurons in SN, depending on the source and wavelength.

L’ osteopetrosi e una patologia genetica rara, caratterizzata da sclerosi dello scheletro, fratture e gravi deficit ematologici e neuronali, dovuta ad una disfunzione degli osteoclasti e del processo di riassorbimento osseo. In questo articolo descriveremo l’osteopetrosi dal punto di vista sia clinico che genetico, forniremo informazioni sulla sua patogenenesi ed illustreremo le opzioni terapeutiche attuali e future.

The purpose of this study was to investigate the risk of death among elderly outpatients (65 years) with a dementia diagnosis treated with atypical antipsychotics.We conducted a cohort study of 696 patients who entered the Unit of Alzheimer Evaluation (UVA) of Teramo Hospital in Central Italy, during a 3-year period (January 2007-December 2009). Among these patients, 375 were treated with atypical antipsychotics (quetiapine, risperidone and olanzapine). Data were collected from record files sent to the pharmaceutical service of the hospital.Patients taking atypical antipsychotic medication were associated with a significantly higher mortality rate than patients not taking antipsychotics. The relative risk of death in patients treated with antipsychotics compared to control patients was 2.354 (95% CI 1.704-3.279). The greatest increases in mortality rate occurred close to the last drug supply, and declined exponentially as time passed from the last drug supply in patients who stopped drug assumption. Quetiapine was the most commonly prescribed drug and higher doses of this drug were associated with higher mortality rates.These results are in line with the April 2005 warning of the Food and Drug Administration (FDA) that among elderly patients with dementia, the treatment of behavioural disorders with atypical antipsychotics is associated with a higher mortality rate. Given the potential risks of mortality with antipsychotics, and since antipsychotic medications may benefit only a minority of patients, new approaches are clearly needed to manage the neuropsychiatric symptoms of dementia.

We investigated how nitric oxide (NO) synthase inhibitor modulates muscarinic receptor expression in epileptic rats. We found that subchronic treatment (4 days) with Nω-nitro-l-arginine reduced the down-regulation of muscarinic receptors induced by pilocarpine and kainic acid in rat fronto-parietal cortex, notwithstanding the dramatic potentiation of seizures induced by both convulsants. Furthermore, functional experiments in fronto-parietal cortex slices, showed that Nω-nitro-l-arginine reduces the down-regulating effect of pilocarpine on carbachol-induced phosphoinositol hydrolysis. Finally, Nω-nitro-l-arginine greatly potentiated the induction of basic fibroblast growth factor (FGF2) by pilocarpine. These data suggest a potential role of NO in a regulatory feedback loop to control muscarinic receptor signal during seizures. The dramatic potentiation of convulsions by NO synthase inhibitors in some animal models of seizures could derive from preventing this feedback loop.

Recent data indicates that prolonged bright light exposure of rats induces production of neuromelanin and reduction of tyrosine hydroxylase positive neurons in thesubstantia nigra. This effect was the result of direct light reaching thesubstantia nigraand not due to alteration of circadian rhythms. Here, we measured the spectrum of light reaching thesubstantia nigrain rats and analysed the pathway that light may take to reach this deep brain structure in humans. Wavelength range and light intensity, emitted from a fluorescent tube, were measured, using a stereotaxically implanted optical fibre in the rat mesencephalon. The hypothetical path of environmental light from the eye to thesubstantia nigrain humans was investigated by computed tomography and magnetic resonance imaging. Light with wavelengths greater than 600 nm reached the ratsubstantia nigra, with a peak at 709 nm. Eyes appear to be the gateway for light to the mesencephalon since covering the eyes with aluminum foil reduced light intensity by half. Using computed tomography and magnetic resonance imaging of a human head, we identified the eye and the superior orbital fissure as possible gateways for environmental light to reach the mesencephalon.

Autosomal dominant osteopetrosis type II (ADO2) is a heritable osteosclerotic disorder dependent on osteoclast impairment. In most patients it results from heterozygous missense mutations in the chloride channel 7 (CLCN7) gene, encoding for a 2Cl(-)/1H(+) antiporter. By a knock-in strategy inserting a missense mutation in the Clcn7 gene, our two research groups independently generated mouse models of ADO2 on different genetic backgrounds carrying the homolog of the most frequent heterozygous mutation (p.G213R) in the Clcn7 gene found in humans. Our results demonstrate that the heterozygous model holds true presenting with higher bone mass, increased numbers of poorly resorbing osteoclasts and a lethal phenotype in the homozygous state. Considerable variability is observed in the heterozygous mice according with the mouse background, suggesting that modifier genes could influence the penetrance of the disease gene.

This study explores the effect of continuous exposure to bright light on neuromelanin formation and dopamine neuron survival in the substantia nigra. Twenty-one days after birth, Sprague–Dawley albino rats were divided into groups and raised under different conditions of light exposure. At the end of the irradiation period, rats were sacrificed and assayed for neuromelanin formation and number of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra. The rats exposed to bright light for 20 days or 90 days showed a relatively greater number of neuromelanin-positive neurons. Surprisingly, TH-positive neurons decreased progressively in the substantia nigra reaching a significant 29% reduction after 90 days of continuous bright light exposure. This decrease was paralleled by a diminution of dopamine and its metabolite in the striatum. Remarkably, in preliminary analysis that accounted for population density, the age and race adjusted Parkinson's disease prevalence significantly correlated with average satellite-observed sky light pollution.

Interplays between bone and bone marrow are not limited to merely anatomic and histological connections, but include a tight functional correlation. Bone marrow resides within the medullary cavity of the bones and the process of hematopoiesis is regulated, at least in part, by bone cells. Moreover, osteoclasts and osteoblasts derive from precursors of hematopoietic and mesenchymal origin, respectively, both residing within the bone marrow. Alterations in one of these components typically cause impairment in the other, so diseases of the bone marrow compartment often affect the bone and vice versa. All these findings could make us to speculate that bone and bone marrow are not two separate districts, but can be considered as the two elements of the same unique functional unit, the bone-bone marrow organ. Here we will describe histological and functional interplays between bone and bone marrow, and will illustrate some diseases in which this tight correlation is evident.