Antonio Pellegrini

Bio: Antonio Pellegrini is an academic researcher from University of Pisa. The author has contributed to research in topics: Adrenal cortex & Corticosterone. The author has an hindex of 18, co-authored 57 publications receiving 1305 citations.

Parkinson-like syndrome induced by continuous MPTP infusion: Convergent roles of the ubiquitin-proteasome system and α-synuclein

Abstract: 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 ubiquitinproteasome 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-synuclein-dependent manner.

Noradrenaline in Parkinson's disease: from disease progression to current therapeutics.

Abstract: The loss of the neurotransmitter noradrenaline occurs constantly in Parkinsons disease. This is supposed to worsen disease progression, either by increasing the vulnerability of dopamine-containing neurons or by reducing the recovery once they are damaged. Novel data also show that the loss of noradrenergic innervation facilitates the onset of dyskinesia occurring in Parkinsonian patients during dopamine replacement therapy. In the first part of the manuscript we review the evidence showing the loss of the noradrenergic system as an early event in the natural history of Parkinsonism. This evidence is discussed in light of novel reports showing the deleterious effects produced by the noradrenergic deficit on the survival of nigral dopamine neurons. In particular, we analyze the biochemical and morphological changes produced in the nigrostriatal system by the loss of endogenous noradrenaline. In a dedicated paragraph we specifically evaluate the cross affinity between dopamine and noradrenaline systems. In fact, this is critical during dopamine/noradrenaline replacement therapy in Parkinsons disease. In the last part, we overview novel therapeutic approaches aimed at restoring the activation of noradrenaline receptors to reduce the dyskinesia occurring in the treatment of Parkinsons disease.

On the development of the coronary arteries in human embryos, stages 14-19.

Abstract: Each coronary artery in humans develops, initially, from two anlagen, one distal and the other proximal. The distal anlage, which is forerunner of the subepicardial branches of the coronary arteries, develops as subepicardial vascular networks on the atrioventricular and interventricular sulci and on the walls of the ventricles and bulbus; these networks are the right-posterior and left-anterior ones. The proximal anlage, which is forerunner of the truncus of the right and left coronary arteries, develops as several endothelial buds of the truncus arteriosus. Normally, only two buds, right and left, hollow out, increase in length and connect with the right and the left vascular networks, respectively, so that the coronary arteries are formed. The cardiac veins appear together with the coronary arteries, but as independent vessels. The authors advance a number of hypotheses as to the origin of certain variations and malformations of the coronary arteries.

DNA damage and ubiquitinated neuronal inclusions in the substantia nigra and striatum of mice following MDMA (ecstasy)

Abstract: 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 ×4, 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.

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

Abstract: 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.

Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases

Abstract: Many lines of evidence suggest that mitochondria have a central role in ageing-related neurodegenerative diseases. Mitochondria are critical regulators of cell death, a key feature of neurodegeneration. Mutations in mitochondrial DNA and oxidative stress both contribute to ageing, which is the greatest risk factor for neurodegenerative diseases. In all major examples of these diseases there is strong evidence that mitochondrial dysfunction occurs early and acts causally in disease pathogenesis. Moreover, an impressive number of disease-specific proteins interact with mitochondria. Thus, therapies targeting basic mitochondrial processes, such as energy metabolism or free-radical generation, or specific interactions of disease-related proteins with mitochondria, hold great promise.

Mitochondrial fragmentation in neurodegeneration

Abstract: Mitochondria are remarkably dynamic organelles that migrate, divide and fuse. Cycles of mitochondrial fission and fusion ensure metabolite and mitochondrial DNA mixing and dictate organelle shape, number and bioenergetic functionality. There is mounting evidence that mitochondrial dysfunction is an early and causal event in neurodegeneration. Mutations in the mitochondrial fusion GTPases mitofusin 2 and optic atrophy 1, neurotoxins and oxidative stress all disrupt the cable-like morphology of functional mitochondria. This results in impaired bioenergetics and mitochondrial migration, and can trigger neurodegeneration. These findings suggest potential new treatment avenues for neurodegenerative diseases.

Mitochondria take center stage in aging and neurodegeneration

Abstract: A critical role of mitochondrial dysfunction and oxidative damage has been hypothesized in both aging and neurodegenerative diseases. Much of the evidence has been correlative, but recent evidence has shown that the accumulation of mitochondrial DNA mutations accelerates normal aging, leads to oxidative damage to nuclear DNA, and impairs gene transcription. Furthermore, overexpression of the antioxidant enzyme catalase in mitochondria increases murine life span. There is strong evidence from genetics and transgenic mouse models that mitochondrial dysfunction results in neurodegeneration and may contribute to the pathogenesis of Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, hereditary spastic paraplegia, and cerebellar degenerations. Therapeutic approaches targeting mitochondrial dysfunction and oxidative damage in these diseases therefore have great promise.