Locus Coeruleus (LC) is the main noradrenergic nucleus of the brain, which is involved in many physiological functions including cognition; its impairment may be crucial in the neurobiology of a ...variety of brain diseases. Locus Coeruleus-Magnetic Resonance Imaging (LC-MRI) allows to identify
in vivo
LC in humans. Thus, a variety of research teams have been using LC-MRI to estimate LC integrity in normal aging and in patients affected by neurodegenerative disorders, where LC integrity my work as a biomarker. A number of variations between LC-MRI studies exist, concerning post-acquisition analysis and whether this had been performed within MRI native space or in
ad hoc
-built MRI template space. Moreover, the reproducibility and reliability of this tool is still to be explored. Therefore, in the present study, we analyzed a group of neurologically healthy, cognitively intact elderly subjects, using both a native space- and a template space-based LC-MRI analysis. We found a good inter-method agreement, particularly considering the LC Contrast Ratio. The template space-based approach provided a higher spatial resolution, lower operator-dependency, and allowed the analysis of LC topography. Our
ad hoc
-developed LC template showed LC morphological data that were in line with templates published very recently. Remarkably, present data significantly overlapped with a recently published LC “metaMask”, that had been obtained by averaging the results of a variety of previous LC-MRI studies. Thus, such a template space-based approach may pave the way to a standardized LC-MRI analysis and to be used in future clinic–anatomical correlations.
Background Neurodegenerative diseases may extend outside the central nervous system (CNS) and involve the gastrointestinal (GI) tract. The gut would appear to be a pathological marker for ...neurodegeneration, as well as a site for studying the pathophysiology of neurodegeneration. In fact, both in the ENS and CNS, misfolded proteins are likely to initiate a process of neurodegeneration. For example, the very same protein aggregates can be detected both in the ENS and CNS. In both systems, misfolded proteins are likely to share common cell‐to‐cell diffusion mechanisms, which may occur through a parallel prion‐like diffusion process. Independently from the enteric or central origin, misfolded proteins may proceed along the following steps, they: (i) form aggregates; (ii) are expressed on plasma membrane; (iii) are secreted extracellularly; (iv) are glycated to form advanced glycation end‐products (AGEs); (v) are internalized through specific receptors placed on neighboring cells (RAGEs); (vi) are cleared by autophagy; and (vii) are neurotoxic. These features are common for a‐synuclein (in Parkinson's disease and other synucleinopathies), β‐amyloid and tau (in degenerative dementia), SOD‐1 and TDP43 (in amyotrophic lateral sclerosis), and PrPsc (in prion diseases). While in some diseases these features are common to both ENS and CNS, in others this remains a working hypothesis.
Purpose This review analyzes GI alterations from a pathological perspective to assess whether the enteric nervous system (ENS) mirrors the neuropathology described in the CNS. We discuss the potential mechanisms that lead to the onset and spread of neurodegeneration within the gut, from the gut to the brain, and vice versa.
Increasing findings indicate that a dysfunction in the autophagy machinery is common during retinal degeneration. The present article provides evidence showing that an autophagy defect in the outer ...retinal layers is commonly described at the onset of retinal degeneration. These findings involve a number of structures placed at the border between the inner choroid and the outer retina encompassing the choriocapillaris, the Bruch's membrane, photoreceptors and Mueller cells. At the center of these anatomical substrates are placed cells forming the retinal pigment epithelium (RPE), where autophagy seems to play most of its effects. In fact, a failure of the autophagy flux is mostly severe at the level of RPE. Among various retinal degenerative disorders, age-related macular degeneration (AMD) is mostly affected by a damage to RPE, which can be reproduced by inhibiting the autophagy machinery and it can be counteracted by the activation of the autophagy pathway. In the present manuscript evidence is provided that such a severe impairment of retinal autophagy may be counteracted by administration of a number of phytochemicals, which possess a strong stimulatory activity on autophagy. Likewise, natural light stimulation administered in the form of pulsatile specific wavelengths is capable of inducing autophagy within the retina. This dual approach to stimulate autophagy is further strengthened by the interaction of light with phytochemicals which is shown to activate the chemical properties of these natural molecules in sustaining retinal integrity. The beneficial effects of photo-biomodulation combined with phytochemicals is based on the removal of toxic lipid, sugar and protein species along with the stimulation of mitochondrial turn-over. Additional effects of autophagy stimulation under the combined effects of nutraceuticals and light pulses are discussed concerning stimulation of retinal stem cells which partly correspond to a subpopulation of RPE cells.
Interkingdom communication between bacteria and host organisms is one of the most interesting research topics in biology. Quorum sensing molecules produced by Gram-negative bacteria, such as acylated ...homoserine lactones and quinolones, have been shown to interact with host cell receptors, stimulating innate immunity and bacterial clearance. To our knowledge, there is no evidence that these molecules influence CNS function. Here, we have found that low micromolar concentrations of the Pseudomonas aeruginosa quorum sensing autoinducer, 2-heptyl-3-hydroxy-4-quinolone (PQS), inhibited polyphosphoinositide hydrolysis in mouse brain slices, whereas four selected acylated homoserine lactones were inactive. PQS also inhibited forskolin-stimulated cAMP formation in brain slices. We therefore focused on PQS in our study. Biochemical effects of PQS were not mediated by the bitter taste receptors, T2R4 and T2R16. Interestingly, submicromolar concentrations of PQS could be detected in the serum and brain tissue of adult mice under normal conditions. Levels increased in five selected brain regions after single i.p. injection of PQS (10 mg/kg), peaked after 15 min, and returned back to normal between 1 and 4 h. Systemically administered PQS reduced spontaneous locomotor activity, increased the immobility time in the forced swim test, and largely attenuated motor response to the psychostimulant, methamphetamine. These findings offer the first demonstration that a quorum sensing molecule specifically produced by Pseudomonas aeruginosa is centrally active and influences cell signaling and behavior. Quorum sensing autoinducers might represent new interkingdom signaling molecules between ecological communities of commensal, symbiotic, and pathogenic microorganisms and the host CNS.
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Parkinson’s disease (PD) is a neurodegenerative disorder which leads to severe movement impairment; however, Parkinsonian patients frequently suffer from gastrointestinal (GI) problems which at ...present are poorly understood, scarcely investigated, and lack an effective cure. Traditionally, PD is attributed to the loss of mesencephalic dopamine‐containing neurons; nonetheless, additional nuclei, such as the dorsal motor nucleus of the vagus nerve and specific central noradrenergic nuclei, are now identified as targets of PD. While the effects of PD on the somatic motor systems are well characterized, the influence on the digestive system still needs to be clarified. Recent findings demonstrate the occurrence of pathological alterations within peripheral neuronal networks in the GI tract of Parkinsonian patients. However, it remains unclear whether a real cell loss occurs, and whether this happens specifically for a subclass of autonomic neurons or if it reflects the sole loss of autonomic nerves. This review summarizes the neurochemical and morphological changes which might be responsible for impaired GI motility. Moreover, we focus on the experimental models to reproduce the altered digestive system of Parkinsonian patients since an experimental model able to mimic such features of PD is required. In the last part of the manuscript, we suggest potential therapeutic targets.
The cellular prion protein (PrPc) is physiologically expressed within selective brain areas of mammals. Alterations in the secondary structure of this protein lead to scrapie-like prion protein ...(PrPsc), which precipitates in the cell. PrPsc has been detected in infectious, inherited or sporadic neurodegenerative disorders. Prion protein metabolism is dependent on autophagy and ubiquitin proteasome. Despite not being fully elucidated, the physiological role of prion protein relates to chaperones which rescue cells under stressful conditions.Methamphetamine (METH) is a widely abused drug which produces oxidative stress in various brain areas causing mitochondrial alterations and protein misfolding. These effects produce a compensatory increase of chaperones while clogging cell clearing pathways. In the present study, we explored whether METH administration modifies the amount of PrPc. Since high levels of PrPc when the clearing systems are clogged may lead to its misfolding into PrPsc, we further tested whether METH exposure triggers the appearance of PrPsc. We analysed the effects of METH and dopamine administration in PC12 and striatal cells by using SDS-PAGE Coomassie blue, immune- histochemistry and immune-gold electron microscopy. To analyze whether METH administration produces PrPsc aggregates we used antibodies directed against PrP following exposure to proteinase K or sarkosyl which digest folded PrPc but misfolded PrPsc. We fond that METH triggers PrPsc aggregates in DA-containing cells while METH is not effective in primary striatal neurons which do not produce DA. In the latter cells exogenous DA is needed to trigger PrPsc accumulation similarly to what happens in DA containing cells under the effects of METH. The present findings, while fostering novel molecular mechanisms involving prion proteins, indicate that, cell pathology similar to prion disorders can be mimicked via a DA-dependent mechanism by a drug of abuse.
▶ In the present study we detect the anatomical distribution and the sub-cellular localization of α-synuclein in the C57BL/6J mouse's central nervous system. ▶ Using two new monoclonal antibodies, ...specifically recognizing two different epitopes on the α-synuclein sequence, we show that the sub-cellular localization of this protein changes in the different brain and spinal cord areas. ▶ Our results indicate that α-synuclein might absolve to more than one function in the neurons and that either pathological, or physiological behavior of this protein, could be due to a specific sub-cellular localization.
Alpha-synuclein is a 140 amino acids’ protein, widely expressed in the nervous system of different vertebrates and closely related with several neurodegenerative disorders. Although its pathological involvement is reported from long time, its physiological function and its role in neurodegeneration is not yet clear. Disposing of two new monoclonal antibodies, able to detect alpha-synuclein in different compartments of the neurons, the aim of this study is to create an anatomical map of the protein's distribution in the central nervous system of C57 BL\6J mouse, the mouse strain most sensitive to 1-methyl 4-phenyl 1,2,3,6-tetrahydro pyridine neurotoxicity and widely used to apply toxic models of Parkinson disease. The two monoclonal antibodies confirm their ability in visualizing the protein in distinct compartments of the neurons, since 2E3 detects alpha-synuclein in the nerve cells’ fibers, whereas 3D5 preferentially in the neuronal nuclei. Both antibodies, instead, are able to show alpha-synuclein at the synaptic terminals. The protein is ubiquitary distributed in the brain, as well as in the spinal cord, but its sub-cellular localization differs markedly in the various regions of the central nervous system. Among alpha-synuclein immunoreactive territories, we describe a particular organization in habenular nuclei, dorsal hippocampus, olfactory bulbs, brain stem nuclei and cerebellar cortex. This preliminary immunohistochemical study, provides the first anatomical map of the alpha-synuclein distribution in the C57 BL\6J mouse CNS and suggests that alpha-synuclein is differentially localized, at sub-cellular level, in different types of neurons and that, therefore, it can plays a specific role for each neuronal subtype. Our study in healthy C57 BL/6J mice represents a starting point to analyze the variations in the overall distribution of alpha-synuclein in mouse models of Parkinson disease.
Background and Purpose
It is thought that the mechanism of action of anticancer chemotherapeutic agents is mainly due to a direct inhibition of tumour cell proliferation. In tumour specimens, the ...endothelial cell proliferation rate increases, suggesting that the therapeutic effects of anticancer agents could also be attributed to inhibition of tumour angiogenesis. Hence, we investigated the potential effects of Pt(O,O′‐acac)(γ‐acac)(DMS) (Pt(DMS)), a new platinum drug for non‐genomic targets, on human renal carcinoma and compared them with those of the well‐established anticancer drug, cisplatin.
Experimental Approach
Tumour growth, tumour cell proliferation and microvessel density were investigated in a xenograft model of renal cell carcinoma, developed by injecting Caki‐1 cells into BALB/c nude mice. The antiangiogenic potential of compounds was also investigated using HUVECs.
Key Results
Treatment of the Caki‐1 cells with cisplatin or Pt(DMS) resulted in a dose‐dependent inhibition of cell survival, but the cytotoxicity of Pt(DMS) was approximately fivefold greater than that of cisplatin.
Pt(DMS) was much more effective than cisplatin at inhibiting tumour growth, proliferation and angiogenesis in vivo, as well as migration, tube formation and MMP1, MMP2 and MMP9 secretion of endothelial cells in vitro. Whereas, cisplatin exerted a greater cytotoxic effect on HUVECs, but did not affect tube formation or the migration of endothelial cells. In addition, treatment of the xenograft mice with Pt(DMS) decreased VEGF, MMP1 and MMP2 expressions in tumours.
Conclusions and Implications
The antiangiogenic and antitumour activities of Pt(DMS) provide a solid starting point for its validation as a suitable candidate for further pharmacological testing.
This work represents a detailed methodological description of automated stereology dedicated to all brainstem catecholamine nuclei. Each tyrosine-hydroxylase-containing nucleus was analyzed to count ...the following features: i) nuclear volume; ii) neuron number per nucleus; iii) neuron area per each nucleus.A number of reports described catecholamine-containing neurons within brainstem of a variety of animal species. In a recently published work, we reported a simultaneous quantitative analysis of tyrosine hydroxylase-positive neurons in the whole brainstem. Here we report the detailed step by step stereological procedure which allowed to perform a morphometric assessment of each catecholamine nucleus. This protocol provides the method chance to analyze simultaneously various morphological features in the same experimental setting to avoid variability when single nuclei are analyzed in different experiments. This improves the reliability of comparisons between brainstem catecholamine nuclei within the reticular formation to increase our insight about the key functional roles played by these cells in the mammalian brain. In fact, despite being a discrete number of neurons scattered in a small brain area, these cells provide remarkable axonal collateralization which allows the modulation of neuronal activity in the entire CNS. The step by step description of brainstem stereology provided here is reported in order to share these methods and enhance quantitative studies about these fascinating nuclei. At the same time we aim to provide a tool to be used routinely when analyzing the morphology and physiology of brainstem catecholamine cells.
Clinical trials for neuroprotection in ALS Siciliano, G; Carlesi, C; Pasquali, L ...
CNS & neurological disorders drug targets,
07/2010, Letnik:
9, Številka:
3
Journal Article
Recenzirano
Owing to uncertainty on the pathogenic mechanisms underlying motor neuron degeneration in amyotrophic lateral sclerosis (ALS) riluzole remains the only available therapy, with only marginal effects ...on disease survival. Here we review some of the recent advances in the search for disease-modifying drugs for ALS based on their putative neuroprotective effetcs. A number of more or less established agents have recently been investigated also in ALS for their potential role in neuroprotection and relying on antiglutamatergic, antioxidant or antiapoptotic strategies. Among them Talampanel, beta-lactam antibiotics, Coenzyme Q10, and minocycline have been investigated. Progress has also been made in exploiting growth factors for the treatment of ALS, partly due to advances in developing effective delivery systems to the central nervous system. A number of new therapies have also been identified, including a novel class of compounds, such as heat-shock protein co-inducers, which upregulate cell stress responses, and agents promoting autophagy and mitochondriogenesis, such as lithium and rapamycin. More recently, alterations of mRNA processing were described as a pathogenic mechanism in genetically defined forms of ALS, as those related to TDP-43 and FUS-TLS gene mutations. This knowledge is expected to improve our understanding of the pathogenetic mechanism in ALS and developing more effective therapies.
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