Paola Soldani

The role of the locus coeruleus in the development of Parkinson's disease.

In Parkinsons disease, together with the classic loss of dopamine neurons of the substantia nigra pars compacta, neuropathological studies and biochemical findings documented the occurrence of a concomitant significant cell death in the locus coeruleus. This review analyzes the latest data obtained from experimental parkinsonism indicating that, the loss of norepinephrine in Parkinsons disease might worsen the dopamine nigrostriatal damage. Within this latter context, basic research provided a new provocative hypothesis on the significance of locus coeruleus in conditioning the natural history of Parkinsons disease. In particular, the loss of a trophic influence of these neurons might be crucial in increasing the sensitivity of nigrostriatal dopamine axons to various neurotoxic insults. In line with this, recently, it has been shown that locus coeruleus activity plays a pivotal role in the expression of various immediate early genes and in inducing the phosphorilation of cyclic adenosine monophosphate response element-binding proteins, suggesting a role of the nucleus in sustaining a protective effect.

Methamphetamine produces neuronal inclusions in the nigrostriatal system and in PC12 cells

Mice treated with the psychostimulant methamphetamine (MA) showed the appearance of intracellular inclusions in the nucleus of medium sized striatal neurones and cytoplasm of neurones of the substantia nigra pars compacta but not in the frontal cortex. All inclusions contained ubiquitin, the ubiquitin activating enzyme (E1), the ubiquitin protein ligase (E3‐like, parkin), low and high molecular weight heat shock proteins (HSP 40 and HSP 70). Inclusions found in nigral neurones stained for α‐synuclein, a proteic hallmark of Lewy bodies that are frequently observed in Parkinsons disease and other degenerative disorders. However, differing from classic Lewy bodies, MA‐induced neuronal inclusions appeared as multilamellar bodies resembling autophagic granules. Methamphetamine reproduced this effect in cultured PC12 cells, which offered the advantage of a simple cellular model for the study of the molecular determinants of neuronal inclusions. PC12 inclusions, similar to those observed in nigral neurones, were exclusively localized in the cytoplasm and stained for α‐synuclein. Time‐dependent experiments showed that inclusions underwent a progressive fusion of the external membranes and developed an electrodense core. Inhibition of dopamine synthesis by α‐methyl‐p‐tyrosine (αMpT), or administering the antioxidant S‐apomorphine largely attenuated the formation of inclusions in PC12 cells exposed to MA. Inclusions were again observed when αMpT‐treated cells were loaded with l‐DOPA, which restored intracellular dopamine levels.

Protein clearing pathways in ALS

In the present review a large amount of experimental and clinical studies on ALS are discussed in an effort to dissect common pathogenic mechanisms which may provide novel information and potential therapeutic strategies for motor neuron degeneration.Protein clearing systems play a critical role in motor neuron survival during excitotoxic stress, aging and neurodegenerative disorders. Among various mechanisms which clear proteins from the cell recent studies indicate autophagy as the most prominent pathway to promote survival of motor neurons.Autophagy regulates the clearance of damaged mitochondria, endoplasmic reticulum and misfolded proteins in eukaryotic cells. Upon recruitment of the autophagy pathway, an autophagosome is produced and directed towards lysosomal degradation.Here we provide evidence that in both genetic and sporadic amyotrophic lateral sclerosis (ALS, the most common motor neuron disorder) a defect in the autophagy machinery is common. In fact, swollen, disrupted mitochondria and intracellular protein aggregates accumulate within affected motor neurons. These structures localize within double membrane vacuoles, autophagosomes, which typically cluster in perinuclear position. In keeping with this, when using autophagy inhibitors or suppressing autophagy promoting genes, motor symptoms and motor neuron death are accelerated. Conversely stimulation of autophagy alleviates motor neuron degeneration.Therefore, autophagy represents an important target when developing novel treatments in ALS.

Ultrastructural and ultracytochemical study of the human nasal respiratory epithelium in vasomotor rhinitis

Objectives—Several pieces of evidence have suggested that nitric oxide (NO) fulfills important functions in the respiratory mucosa, under both normal and pathological conditions. This study was performed to investigate the role of NO in the nasal respiratory epithelium of patients affected by vasomotor rhinitis. The structure and ultrastructure of the epithelium were also examined. Material and Methods—The localization of NO synthase activity was determined by means of reduced nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase ultracytochemistry. Nasal mucosa was obtained from patients who had undergone surgical therapy for reduction of the inferior turbinate. Results—Examination of hematoxylin–eosin-stained sections revealed that most of the nasal mucosa covering the surgical samples was characterized by severe epithelial damage. The ultrastructural study confirmed the light microscopic observations. Ciliary loss, absence of the intercellular junctions and distension of the intercellular spaces were found in the damaged epithelium. The basement membrane was frequently interrupted. Some epithelial cells were identified as basal cells. Other cells of the damaged epithelium were probably involuted ciliated and goblet cells. The ultracytochemical study showed that the basal cells were NADPH-diaphorase-negative in healthy subjects and strongly NADPH-diaphorase-positive in subjects with vasomotor rhinitis. Conclusions—It is suggested that NO has cytotoxic effects and causes inhibition of mitotic activity in the basal cells, leading to epithelial disruption and breakdown of the protective functions of the epithelium.

Effects of subacute exposure to noise on the noradrenergic innervation of the cardiovascular system in young and aged rats: a morphofunctional study

The effects of subacute noise stress on the noradrenergic pattern and receptor-mediated responses were examined in aorta and atria of young and aged rats. Noise exposure increased the density of noradrenergic fibres and responses to the β-adrenergic agonist isoprenaline in the cardiac tissue of young animals. In aged rats, the stressing stimulus markedly increased the maximal response to the α-agonist on the aortic musculature; on the contrary, a reduced responsiveness to the β-agonist was observed at the cardiac level, without any noteworthy changes in the noradrenergic pattern in comparison to aged controls. The present results indicate that subacute noise stress induces both morphological and functional modifications of the noradrenergic nervous system and also that after subacute noise stress, morphological changes do not necessarily correspond exactly to functional data; the latter show responses that are more widely differentiated than the morphological ones.

Effects of loud noise exposure on DNA integrity in rat adrenal gland

Loud noise is generally considered an environmental stressor causing negative effects on acoustic, cardiovascular, nervous, and endocrine systems. In this study, we investigated the effects of noise exposure on DNA integrity in rat adrenal gland evaluated by the comet assay. The exposure to loud noise (100 dBA) for 12 hr caused a significant increase of DNA damage in the adrenal gland. Genetic alterations did not decrease 24 hr after the cessation of the stimulus. We hypothesize that an imbalance of redox cell status is responsible for the induction and persistence of noise-induced cellular damage.

Morphofunctional Changes in the Noradrenergic Innervation of the Rat Cardiovascular System After Varying Duration of Noise Stress

One, six and twelve hs of exposure to acoustic stress showed different influences on the noradrenergic pattern and receptor function of the rat atria and aorta. Moreover, the lipid content of the adrenal cortex and hepatic glycogen were histochemically evaluated in the same animals to correlate these observations with the previous results. The increase in exposure time induced a corresponding increase in sympathetic innervation, which was more evident at cardiac level. The functional results showed that the potency of the agonists on the alpha- and beta-adrenoceptors does not vary, with the exception of 6-h treatment, which affected beta-receptors. By contrast, the M.R.R. of beta-receptors proved to be modified in all treatments, suggesting that noise stress affected mainly postreceptorial mechanisms linked to beta-adrenoceptors rather than their density or affinity; no significant functional modifications were observed when alpha-receptors were considered.

Ultracytochemical localization of the NADPH-d activity in the human nasal respiratory mucosa in vasomotor rhinitis.

Objectives Description of the ultrastructural localization of nitric oxide synthase in the blood vessels of the nasal respiratory mucosa in patients with vasomotor rhinitis.

Overexpression of α‐Synuclein following Methamphetamine

Abstract:  α‐Synuclein is a presynaptic protein involved in various degenerative disorders now defined as synucleinopathies. These include neurological diseases that share a few pathological features consisting of aggregates of both normal and altered α‐synuclein within specific neuronal populations and/or glial cells. The prototype of synucleinopathies is represented by Parkinsons disease (PD) in which α‐synuclein is identified as a constant component of neuronal pale eosinophilic inclusions: “the Lewy Bodies.” In the present article, we discuss the potential significance of amphetamine‐induced overexpression of α‐synuclein in light of clinical findings showing neurodegeneration following overexpression of α‐synuclein and recent experimental studies that measured increased expression of α‐synuclein following amphetamine derivatives.

Morphological and biochemical evidence that apomorphine rescues striatal dopamine terminals and prevents methamphetamine toxicity

Abstract: Apomorphine, given by a single injection, repeated injections, or by continuous infusion, was tested for neuroprotective effects in mice administered methamphetamine or N‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) in order to induce striatal dopamine (DA) depletion. In the first part of the study, the DA agonist (R)‐apomorphine was administered at various doses (1, 5, and 10 mg/kg), 15 min before methamphetamine (5 mg/kg × 3, 2 h apart). Mice were sacrificed 5 days later. In the second part, apomorphine was administered either continuously by subcutaneous minipump (cumulative daily dose of 0.5, 1, and 3.15 mg/kg), or as single, repeated daily injections (up to 5 mg/kg) starting 40 h after an acute administration of MPTP (30 mg/kg). Mice were sacrificed at different time intervals (up to 1 month) following MPTP injection. In all the animals, the integrity of striatal DA terminals was evaluated by measuring striatal DA levels and TH immunohistochemistry. Apomorphine dose‐dependently prevented methamphetamine toxicity. These effects were neither due to a decrease in the amount of striatal methamphetamine nor to the hypothermia, and they were not reversed by the DA antagonist haloperidol. Moreover, chronic, continuous (but not pulsatile) administration of apomorphine rescued damaged striatal dopaminergic terminals. These findings confirm a protective effect of apomorphine that also consists of a neurorescue of damaged striatal DA terminals. This suggests a new hypothesis about the long‐term benefits observed during continuous apomorphine administration in Parkinsons disease patients.