3,4-Methylenedioxymethamphetamine (MDMA) is an amphetamine derivative, which is neurotoxic to both serotonin (5HT) and dopamine (DA) nerve terminals. Previous reports, carried out in rodents and ...non-human primates, demonstrated neurotoxicity to monoamine axon terminals, although no study has analyzed nigral and striatal cell bodies at the sub-cellular level.
In this study, we examined intrinsic nigral and striatal cells, and PC12 cell cultures to evaluate whether, in mice, MDMA might affect nigral and striatal cell bodies.
After administering MDMA, we analyzed effects induced in vivo and in vitro using high-performance liquid chromatography (HPLC) analysis, light- and electron microscopy with immunocytochemistry, and DNA comet assay.
We found that MDMA (5 mg/kg x4, 2 h apart), besides a decrease of nigrostriatal DA innervation and 5HT loss, produces neuronal inclusions within nigral and intrinsic striatal neurons consisting of multi-layer ubiquitin-positive whorls extending to the nucleus of the cell. These fine morphological changes are associated with clustering of heat shock protein (HSP)-70 in the nucleus, very close to chromatin filaments. In the same experimental conditions, we could detect oxidation of DNA bases followed by DNA damage. The nature of inclusions was further investigated using PC12 cell cultures.
The present findings lead to re-consideration of the neurotoxic consequences of MDMA administration. In fact, occurrence of ubiquitin-positive neuronal inclusions and DNA damage both in nigral and striatal cells sheds new light into the fine alterations induced by MDMA, also suggesting the involvement of nuclear and cytoplasmic components of the ubiquitin-proteasome pathway in MDMA toxicity.
In animals, sporadic injections of the mitochondrial toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) selectively damage dopaminergic neurons but do not fully reproduce the features of human ...Parkinson's disease. We have now developed a mouse Parkinson's disease model that is based on continuous MPTP administration with an osmotic minipump and mimics many features of the human disease. Although both sporadic and continuous MPTP administration led to severe striatal dopamine depletion and nigral cell loss, we find that only continuous administration of MPTP produced progressive behavioral changes and triggered formation of nigral inclusions immunoreactive for ubiquitin and α-synuclein. Moreover, only continuous MPTP infusions caused long-lasting activation of glucose uptake and inhibition of the ubiquitin-proteasome system. In mice lacking α-synuclein, continuous MPTP delivery still induced metabolic activation, but induction of behavioral symptoms and neuronal cell death were almost completely alleviated. Furthermore, the inhibition of the ubiquitin-proteasome system and the production of inclusion bodies were reduced. These data suggest that continuous low-level exposure of mice to MPTP causes a Parkinson-like syndrome in an α-synucleindependent manner.
Oral hygiene among children in Italy Troiano, G; Pozzi, T; Simi, R ...
European journal of public health,
11/2018, Letnik:
28, Številka:
suppl_4
Journal Article
The latest increase in childhood obesity focused attention on the important consequences that this phenomenon may have on public health in relationship to the increasing risk that an obese child may ...become an obese adult. To deal with this problem, there is necessary to assess systematically the distribution of childhood nutritional status at different levels: international, regional and local. In this paper are presented data on underweight, overweight and obesity prevalence in third grade primary school children, aged 8/9 years in Tuscany (2008) and its distribution in relationship to the demographic breadth of their place of residence.
Data from statistic sample of 2109 (1.091 males, 1.018 females), 8/9 years school-children were collected; weight and height were measured using standardised personnel and instruments. Exact month age was calculated between the data of measurement and that of birth. Body Mass Index (BMI) classes were calculated using Cole et al.'s epidemiologic cut-off for children and adolescents. Residence areas were divided into four classes based on the number of inhabitants (< 10.000; 10.000-50.000; > 50.000; > 50.000 metropolitan).
The prevalence of underweight was 0.88% (0.76% in males and 1.01% in females), the prevalence of overweight was 23.43% (22.33% in males and 24.65% in females), the prevalence of obese was 7.95% (9.08% in males, 6.70% in females). The lowest prevalence of obese (6.46%) was found in towns with over 50.000 residents (metropolitan).
The obesity prevalence in Tuscany children is still lower than that of the Italian National Survey, while the overweight prevalence it's the same. Obesity prevalence (10.71%) is higher in municipalities with low residents number (< 10.000).
Seizures represent the most common neurological emergency in ecstasy abusers; however, no study addressed whether (±) 3,4-methylenedioxymethamphetamine (“ecstasy”) per se might produce long-lasting ...alterations in brain excitability related to a pro-convulsant effect.
C57Black mice were treated with three regimens of (±) 3,4-methylenedioxymethamphetamine (5mg/kg×2 for 1, 2 or three consecutive days). Following the last dose of (±) 3,4-methylenedioxymethamphetamine, during a time interval of 8 weeks, the following procedures were carried out: 1) cortical electroencephalographic recordings, including power-spectrum analysis; 2) administration of sub-threshold doses of kainate; 3) measurement of regional
14C2-deoxyglucose uptake; 4) monoamine assay. We demonstrate that all mice pre-treated with (±) 3,4-methylenedioxymethamphetamine showed long-lasting encephalographic changes with frequencies peaking at 3–4.5Hz at the power-spectrum analysis. This is concomitant with latent brain hyperexcitability within selected limbic brain regions, as shown by seizure facilitation and long-lasting latent metabolic hyperactivity which can be unraveled by phasic glutamate stimulation. This study sheds new light into the brain targets of (±) 3,4-methylenedioxymethamphetamine and discloses the occurrence of (±) 3,4-methylenedioxymethamphetamine-induced latent hyperexcitability within limbic areas, while it might provide a model to study in controlled experimental conditions limbic seizures and status epilepticus in C57Black mice. Persistent changes produced by (±) 3,4-methylenedioxymethamphetamine in limbic brain excitability might be responsible for seizures and limbic-related disorders in chronic (±) 3,4-methylenedioxymethamphetamine abusers.
Protein clearing pathways named autophagy (ATG) and ubiquitin proteasome (UP) control homeostasis within eukaryotic cells, while their dysfunction produces neurodegeneration. These pathways are ...viewed as distinct biochemical cascades occurring within specific cytosolic compartments owing pathway-specific enzymatic activity. Recent data strongly challenged the concept of two morphologically distinct and functionally segregated compartments. In fact, preliminary evidence suggests the convergence of these pathways to form a novel organelle named autophagoproteasome. This is characterized in the present study by using a cell line where, mTOR activity is upregulated and autophagy is suppressed. This was reversed dose-dependently by administering the mTOR inhibitor rapamycin. Thus, we could study autophagoproteasomes when autophagy was either suppressed or stimulated. The occurrence of autophagoproteasome was shown also in non-human cell lines. Ultrastructural morphometry, based on the stochiometric binding of immunogold particles allowed the quantitative evaluation of ATG and UP component within autophagoproteasomes. The number of autophagoproteasomes increases following mTOR inhibition. Similarly, mTOR inhibition produces overexpression of both LC3 and P20S particles. This is confirmed by the fact that the ratio of free vs. autophagosome-bound LC3 is similar to that measured for P20S, both in baseline conditions and following mTOR inhibition. Remarkably, within autophagoproteasomes there is a slight prevalence of ATG compared with UP components for low rapamycin doses, whereas for higher rapamycin doses UP increases more than ATG. While LC3 is widely present within cytosol, UP is strongly polarized within autophagoproteasomes. These fine details were evident at electron microscopy but could not be deciphered by using confocal microscopy. Despite its morphological novelty autophagoproteasomes appear in the natural site where clearing pathways (once believed to be anatomically segregated) co-exist and they are likely to interact at molecular level. In fact, LC3 and P20S co-immunoprecipitate, suggesting a specific binding and functional interplay, which may be altered by inhibiting mTOR. In summary, ATG and UP often represent two facets of a single organelle, in which unexpected amount of enzymatic activity should be available. Thus, autophagoproteasome may represent a sophisticated ultimate clearing apparatus.
Abstract Methamphetamine produces locomotor activation and typical stereotyped motor patterns, which are commonly related with increased catecholamine activity within the basal ganglia, including the ...dorsal and ventral striatum. Since the cerebellum is critical for movement control, and for learning of motor patterns, we hypothesized that cerebellar catecholamines might be a target of methamphetamine. To test this experimental hypothesis we injected methamphetamine into C57 Black mice at the doses of 5 mg/kg two or three times, 2 h apart. This dosing regimen is known to be toxic for striatal dopamine terminals. However, we found that in the cerebellum, methamphetamine increased the expression of the primary transcript of the tyrosine hydroxylase (TH) gene, followed by an increased expression of the TH protein. Increased TH was localized within Purkinje cells, where methamphetamine increased the number of TH-immunogold particles, and produced a change in the distribution of the enzyme by increasing the cytoplasmic percentage. Increased TH expression was accompanied by a slight increase in noradrenaline content. This effect was highly site-specific for the cortex of posterior vermal lobules, while only slight effects were detectable in the hemispheres. The present data indicate that the cerebellum does represent a target of methamphetamine, which produces specific and fine alterations of the catecholamine system involving synthesis, amount, and compartmentalization of TH as well as increased noradrenaline levels. This may be relevant for motor alterations induced by methamphetamine. In line with this, inherited cerebellar movement disorders in various animal species including humans are associated with increased TH immunoreactivity within intrinsic neurons of the same lobules of the cerebellar cortex.
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