Papers by Francesca Biagioni
Pharmaceuticals, 2021
Methamphetamine (METH) is a widely abused psychostimulant and a stress-inducing compound, which l... more Methamphetamine (METH) is a widely abused psychostimulant and a stress-inducing compound, which leads to neurotoxicity for nigrostriatal dopamine (DA) terminals in rodents and primates including humans. In vitro studies indicate that autophagy is a strong modulator of METH toxicity. In detail, suppressing autophagy increases METH toxicity, while stimulating autophagy prevents METH-induced toxicity in cell cultures. In the present study, the role of autophagy was investigated in vivo. In the whole brain, METH alone destroys meso-striatal DA axon terminals, while fairly sparing DA cell bodies within substantia nigra pars compacta (SNpc). No damage to either cell bodies or axons from ventral tegmental area (VTA) is currently documented. According to the hypothesis that ongoing autophagy prevents METH-induced DA toxicity, we tested whether systemic injection of autophagy inhibitors such as asparagine (ASN, 1000 mg/Kg) or glutamine (GLN, 1000 mg/Kg), may extend METH toxicity to DA cell b...
Norepinephrine (NE) neurons and extracellular NE exert some protective effects against a variety ... more Norepinephrine (NE) neurons and extracellular NE exert some protective effects against a variety of insults, including methamphetamine (Meth)-induced cell damage. The intimate mechanism of protection remains difficult to be analyzed in vivo. In fact, this may occur directly on target neurons or as the indirect consequence of NE-induced alterations in the activity of trans-synaptic loops. Therefore, to elude neuronal networks, which may contribute to these effects in vivo, the present study investigates whether NE still protects when directly applied to Meth-treated PC12 cells. Meth was selected based on its detrimental effects along various specific brain areas. The study shows that NE directly protects in vitro against Meth-induced cell damage. The present study indicates that such an effect fully depends on the activation of plasma membrane β2-adrenergic receptors (ARs). Evidence indicates that β2-ARs activation restores autophagy, which is impaired by Meth administration. This oc...
Cancers
Recently, exosomal release has been related to the acquisition of a malignant phenotype in gliobl... more Recently, exosomal release has been related to the acquisition of a malignant phenotype in glioblastoma cancer stem cells (GSCs). Remarkably, intriguing reports demonstrate that GSC-derived extracellular vesicles (EVs) contribute to glioblastoma multiforme (GBM) tumorigenesis via multiple pathways by regulating tumor growth, infiltration, and immune invasion. In fact, GSCs release tumor-promoting macrovesicles that can disseminate as paracrine factors to induce phenotypic alterations in glioma-associated parenchymal cells. In this way, GBM can actively recruit different stromal cells, which, in turn, may participate in tumor microenvironment (TME) remodeling and, thus, alter tumor progression. Vice versa, parenchymal cells can transfer their protein and genetic contents to GSCs by EVs; thus, promoting GSCs tumorigenicity. Moreover, GBM was shown to hijack EV-mediated cell-to-cell communication for self-maintenance. The present review examines the role of the mammalian Target of Rapa...
Journal of Neural Transmission
Spinal muscular atrophy (SMA) is a heritable, autosomal recessive neuromuscular disorder characte... more Spinal muscular atrophy (SMA) is a heritable, autosomal recessive neuromuscular disorder characterized by a loss of the survival of motor neurons (SMN) protein, which leads to degeneration of lower motor neurons, and muscle atrophy. Despite SMA being nosographically classified as a motor neuron disease, recent advances indicate that peripheral alterations at the level of the neuromuscular junction (NMJ), involving the muscle, and axons of the sensory-motor system, occur early, and may even precede motor neuron loss. In the present study, we used a mouse model of slow progressive (type III) SMA, whereby the absence of the mouse SMN protein is compensated by the expression of two human genes (heterozygous SMN1A2G, and SMN2). This leads to late disease onset and prolonged survival, which allows for dissecting slow degenerative steps operating early in SMA pathogenesis. In this purely morphological study carried out at transmission electron microscopy, we extend the examination of motor...
Neurotoxicity Research
The neurotoxin 1-methyl, 4-phenyl, 1, 2, 3, 6-tetrahydropiridine (MPTP) is widely used to produce... more The neurotoxin 1-methyl, 4-phenyl, 1, 2, 3, 6-tetrahydropiridine (MPTP) is widely used to produce experimental parkinsonism. Such a disease is characterized by neuronal damage in multiple regions beyond the nigrostriatal pathway including the spinal cord. The neurotoxin MPTP damages spinal motor neurons. So far, in Parkinson’s disease (PD) patients alpha-synuclein aggregates are described in the dorsal horn of the spinal cord. Nonetheless, no experimental investigation was carried out to document whether MPTP affects the sensory compartment of the spinal cord. Thus, in the present study, we investigated whether chronic exposure to small doses of MPTP (5 mg/kg/X2, daily, for 21 days) produces any pathological effect within dorsal spinal cord. This mild neurotoxic protocol produces a damage only to nigrostriatal dopamine (DA) axon terminals with no decrease in DA nigral neurons assessed by quantitative stereology. In these experimental conditions we documented a decrease in enkephalin...
Molecules
Curcumin (CUR), a natural polyphenol extracted from rhizome of the Curcuma longa L, has received ... more Curcumin (CUR), a natural polyphenol extracted from rhizome of the Curcuma longa L, has received great attention for its multiple potential health benefits as well as disease prevention. For instance, CUR protects against toxic agents acting on the human body, including the nervous system. In detail, CUR possesses, among others, strong effects as an autophagy activator. The present study indicates that CUR counteracts methamphetamine (METH) toxicity. Such a drug of abuse is toxic by disturbing the autophagy machinery. We profited from an unbiased, low variable cell context by using rat pheochromocytoma PC12 cell line. In such a system, a strong protection was exerted by CUR against METH toxicity. This was associated with increased autophagy flux, merging of autophagosomes with lysosomes and replenishment of autophagy vacuoles with LC3, which instead is moved out from the vacuoles by METH. This is expected to enable the autophagy machinery. In fact, while in METH-treated cells the au...
Archives italiennes de biologie, 2017
In the present study we evaluated the long-term effects of lithium administration to a knock-out ... more In the present study we evaluated the long-term effects of lithium administration to a knock-out double transgenic mouse model (Smn-/-; SMN1A2G+/-; SMN2+/+) of Spinal Muscle Atrophy type III (SMA-III). This model is characterized by very low levels of the survival motor neuron protein, slow disease progression and motor neuron loss, which enables to detect disease-modifying effects at delayed time intervals. Lithium administration attenuates the decrease in motor activity and provides full protection from motor neuron loss occurring in SMA-III mice, throughout the disease course. In addition, lithium prevents motor neuron enlargement and motor neuron heterotopy and suppresses the occurrence of radial-like glial fibrillary acidic protein immunostaining in the ventral white matter of SMA-III mice. In SMA-III mice long-term lithium administration determines a dramatic increase of survival motor neuron protein levels in the spinal cord. These data demonstrate that long-term lithium admi...
Histology and histopathology, 2018
Counting motor neurons within the spinal cord and brainstem represents a seminal step to comprehe... more Counting motor neurons within the spinal cord and brainstem represents a seminal step to comprehend the anatomy and physiology of the final common pathway sourcing from the CNS. Motor neuron loss allows to assess the severity of motor neuron disorders while providing a tool to assess disease modifying effects. Counting motor neurons at first implies gold standard identification methods. In fact, motor neurons may occur within mixed nuclei housing a considerable amount of neurons other than motor neurons. In the present review, we analyse various approaches to count motor neurons emphasizing both the benefits and bias of each protocol. A special emphasis is placed on discussing automated stereology. When automated stereology does not take into account site-specificity and does not distinguish between heterogeneous neuronal populations, it may confound data making such a procedure a sort of "guide for the perplex". Thus, if on the one hand automated stereology improves our a...
International journal of molecular sciences, Jan 13, 2018
Autophagy primarily works to counteract nutrient deprivation that is strongly engaged during star... more Autophagy primarily works to counteract nutrient deprivation that is strongly engaged during starvation and hypoxia, which happens in hypoperfusion. Nonetheless, autophagy is slightly active even in baseline conditions, when it is useful to remove aged proteins and organelles. This is critical when the mitochondria and/or proteins are damaged by toxic stimuli. In the present review, we discuss to that extent the recruitment of autophagy is beneficial in counteracting brain hypoperfusion or, vice-versa, its overactivity may per se be detrimental for cell survival. While analyzing these opposite effects, it turns out that the autophagy activity is likely not to be simply good or bad for cell survival, but its role varies depending on the timing and amount of autophagy activation. This calls for the need for an appropriate autophagy tuning to guarantee a beneficial effect on cell survival. Therefore, the present article draws a theoretical pattern of autophagy activation, which is hypo...
Frontiers in pharmacology, 2017
3-Iodothyronamine (T1AM) is an endogenous high-affinity ligand of the trace amine-associated rece... more 3-Iodothyronamine (T1AM) is an endogenous high-affinity ligand of the trace amine-associated receptor 1 (TAAR1), detected in mammals in many organs, including the brain. Recent evidence indicates that pharmacological TAAR1 activation may offer a novel therapeutic option for the treatment of a wide range of neuropsychiatric and metabolic disorders. To assess potential neuroprotection by TAAR1 agonists, in the present work, we initially investigated whether T1AM and its corresponding 3-methylbiaryl-methane analog SG-2 can improve learning and memory when systemically administered to mice at submicromolar doses, and whether these effects are modified under conditions of MAO inhibition by clorgyline. Our results revealed that when i.p. injected to mice, both T1AM and SG-2 produced memory-enhancing and hyperalgesic effects, while increasing ERK1/2 phosphorylation and expression of transcription factor-fos. Notably, both compounds appeared to rely on the action of ubiquitous enzymes MAO t...
Frontiers in Neuroanatomy
In June 2017 we celebrate the 90th anniversary of the pioneer discovery of cerebral angiography, ... more In June 2017 we celebrate the 90th anniversary of the pioneer discovery of cerebral angiography, the seminal imaging technique used for visualizing cerebral blood vessels and vascular alterations as well as other intracranial disorders. Egas Moniz (1874-1955) was the first to describe the use of this revolutionary technique which, until 1975 (when computed tomography, CT, scan was introduced in the clinical practice), was the sole diagnostic tool to provide an imaging of cerebral vessels and therefore alterations due to intracranial pathology. Moniz introduced in the clinical practice this fundamental and important diagnostic tool. The present contribution wishes to pay a tribute to the Portuguese neurosurgeon, who was also a distinguished neurologist and statesman. Despite his tremendous contribution in modern brain imaging, Egas Moniz was awarded the Nobel Prize in Physiology or Medicine in 1949 for prefrontal leucotomy, the neurosurgical intervention nowadays unacceptable, but should rather be remembered for his key contribution to modern brain imaging.
Immunity & Ageing, 2016
The acute phase protein Pentraxin 3 (PTX3) plays a non-redundant role as a soluble pattern recogn... more The acute phase protein Pentraxin 3 (PTX3) plays a non-redundant role as a soluble pattern recognition receptor for selected pathogens and it represents a rapid biomarker for primary local activation of innate immunity and inflammation. Recent evidence indicates that PTX3 exerts an important role in modulating the cardiovascular system in humans and experimental models. In particular, there are conflicting points concerning the effects of PTX3 in cardiovascular diseases (CVD) since several observations indicate a cardiovascular protective effect of PTX3 while others speculate that the increased plasma levels of PTX3 in subjects with CVD correlate with disease severity and with poor prognosis in elderly patients. In the present review, we discuss the multifaceted effects of PTX3 on the cardiovascular system focusing on its involvement in atherosclerosis, endothelial function, hypertension, myocardial infarction and angiogenesis. This may help to explain how the specific modulation of PTX3 such as the use of different dosing, time, and target organs could help to contain different vascular diseases. These opposite actions of PTX3 will be emphasized concerning the modulation of cardiovascular system where potential therapeutic implications of PTX3 in humans are discussed.
Current topics in medicinal chemistry, 2009
Autophagy is the mechanism through which cells degrade oxidized membranes-organelles and mis/unfo... more Autophagy is the mechanism through which cells degrade oxidized membranes-organelles and mis/unfolded proteins, in this latter function cooperating with the ubiquitin-proteasome system (UP system). Although autophagy has been known for a long time, its involvement in the pathogenesis of neurodegenerative diseases has been investigated only recently. The most fascinating data are very recent and show an impressive connection between proteins that are mutated in different forms of familial Parkinson's Disease (PD) and the critical role that these proteins play in the physiology of the Autophagy (ATG) pathway. This evidence is supported by neuropathological data showing at the ultrastructural level, the occurrence of an altered ATG in the dopamine (DA) neurons of the Substantia Nigra of patients affected by PD. Accordingly, by using experimental models of PD the involvement of ATG is documented as well. In particular, administration of the DA neurotoxin methamphetamine produces dam...
Archives italiennes de biologie, 2013
&... more "Striatal plasticity" is a term describing a variety of morphological and functional changes occurring both at pre- and post-synaptic level within the basal ganglia. In most cases striatal plasticity occurs when a loss of dopamine (DA) fibers in the striatum, in the course of Parkinsonism takes place. Plastic events include early pre-synaptic and long-term post-synaptic changes. In the context of long-term changes associated with striatal plasticity the role of intrinsic striatal catecholamine cells is emerging. This neuronal population expresses both tyrosine hydroxylase (TH) and DA transporter (DAT). These TH-positive cells are normally resident within the human caudate putamen but they dramatically increase during parkinsonism reaching an amount roughly corresponding to 50% of nigrostriatal neurons counted in control brains. This evidence led to hypothesize fascinating mechanisms bridging these neurons either with compensatory changes or the onset of aberrant behavioral activity. Very recently the occurrence of these neurons was described during DA replacement therapy in parkinsonism, thus suggesting that these cells may represent the anatomical basis for plastic phenomena. Thus, the present article, in the attempt to describe novel mechanisms generating striatal plasticity, details these cells in development and adult life and their potential role in maturation phenomena occurring in parkinsonism.
Glioblastoma (GB, grade IV astrocytoma) is highly proliferating, infiltrating, and relapsing. So ... more Glioblastoma (GB, grade IV astrocytoma) is highly proliferating, infiltrating, and relapsing. So far, no therapy cures the disease and on average lethality occurs within 2 years from diagnosis. Despite the intimate molecular mechanisms of GB remain unknown, the mammalian Target Of Rapamycin (mTOR) is constantly upregulated within GB and in other astrocytomas. Consistently, mTOR was proposed as a target to cure GB. In fact, the mTOR inhibitor rapamycin was tested in order to prevent the growth of GB in human primary cultures and in mouse xenograft. Cytopathology of GB is highly heterogeneous for the co-existence of various cell types and the occurrence progressive steps in cell differentiation. Remarkably, the non differentiated stem-like cells represent primary GB precursors which initiate the tumor growth. Altered transmission of pathological proteins was recently claimed to underly the growth of GB and its infiltration. These proteins are controlled by the mTOR pathway and spread from cell to cell suggesting a prion-like mechanism in GB. Therefore, in the present study, using the human GB cell line U87MG, we evaluated the effect of a wide range of rapamycin concentrations (between 1 nM to 1 x 103 nM) at 24 h on: cell survival; cell morphology and electrophysiology; cell differentiation and migration; expression of PrP and other prion-like proteins. We found that effects of rapamycin on U87MG are dose-dependent. While high doses (100 nM up to 1000 nM) reduce cell viability, lower rapamycin doses (1nm up to 10 nM) produce cell differentiation consisting of morphological and immunohistochemical changes. Rapamycin promotes a neuronal shape with process elongation and increased cell size. This associates with the loss of the staminal marker nestin while the early neuronal marker betaIII-tubulin increases. At 24 h rapamycin inhibits U87MG cell migration dose-dependently. The neuronal morphology associates with altered intracellular calcium flux but not neuronal electrophysiological properties. Finally, expression of prionoids which we found to be high in baseline conditions was suppressed by rapamycin. This is consistent with our ultrastructural findings which substantiate the dramatic effects induced by mTOR inhibition. Our results suggests pathological cell communication in GB while providing cellular evidence supporting the use of rapamycin as well rapalogs as effective drugs to treat malignant astrocytoma. This work was supported by a research grant from PRIN 2010/2011.
Current Medicinal Chemistry, 2014
Despite a number of genetic mutations and molecular mechanisms are recognized to participate in a... more Despite a number of genetic mutations and molecular mechanisms are recognized to participate in amyotrophic lateral sclerosis (ALS), such a devastating neurological disorder still lacks a substantial cure. The present manuscript rather than a general overview of potential therapeutic approaches focuses on novel research findings detailing novel molecular mechanisms which appear to be promising for developing future ALS therapeutics. A special emphasis is given to the abnormal autophagy status and to those autophagy substrates which aggregate in the form of misfolded proteins. In fact, as reviewed in the first part of the manuscript, altered autophagy pathway is present in most genetic mutations responsible for familial ALS. These mutations impair clearance of autophagy substrates, which determines accumulation of giant altered mitochondria and misfolded proteins. Therefore, a considerable piece of the review is dedicated to unconventional processing of misfolded proteins leading to unconventional protein secretions which may underlie a prionoid cellto- cell spreading of ALS neuropathology. The intimate mechanisms regulating these steps are analyzed in order to comprehend which potential therapeutic targets might be considered in future studies. At the same time, negative findings concerning recent trials are explained in light of novel disease mechanisms. In the final part of the review the replacement therapy with focal stem cells implantation is discussed in relationship with toxic mechanisms operating in the intercellular space of the spinal cord and motor-related areas.
Behavioural Pharmacology, 2006
Neurobiology of Disease
Status epilepticus (SE) of limbic onset might cause degenerative phenomena in different brain str... more Status epilepticus (SE) of limbic onset might cause degenerative phenomena in different brain structures, and may be associated with chronic cognitive and EEG effects. In the present study SE was evoked focally by microinfusing picomolar doses of cyclothiazide+bicuculline into the anterior extent of the piriform cortex (APC) in rats, the so-called area tempestas, an approach which allows to evaluate selectively the effects of seizure spreading through the natural anatomical circuitries up to secondary generalization. In the brain of rats submitted to SE we analyzed neuronal density, occurrence of degenerative phenomena (by Fluoro-Jade B-FJB- staining) and expression of heat shock protein-70 (HSP-70) in the piriform cortex, the hippocampus and ventromedial thalamus. We further analyzed in detail, the loss of cholinergic neurons, and the presence of FJB- and HSP-70 positive neurons in basal forebrain cholinergic areas, i.e. the medial septal nucleus (MSN, Ch1), the diagonal band of Broca (DBB, Ch2 and Ch3) and the Nucleus basalis of Meynert (NBM, Ch4). In fact, these nuclei are strictly connected with limbic structures, and play a key pivotal role in different cognitive functions and vigilance. Although recent studies begun to investigate these nuclei in experimental epilepsy and in persons with epilepsy, conflicting results were obtained so far. We showed that after severe and long-lasting, focally induced limbic SE there is a significant cell loss within all of the abovementioned cholinergic nuclei ipsi- and contra-laterally to the infusion site. In parallel, these nuclei show also FJB and heat shock protein-70 expression. Those effects vary depending on the single nucleus assessed and on the severity of the SE seizure score. We also showed the occurrence of cell loss and degenerative phenomena in limbic cortex, hippocampus and limbic thalamic areas. These novel findings show direct evidence of SE-induced neuronal damage which is solely due to seizure activity ruling out potential confounding effects produced by systemic pro-convulsant neurotoxins. A damage to basal forebrain cholinergic nuclei, which may underlie cognitive alterations, is documented for the first time in a model of SE triggered focally.
Experimental Eye Research
The study was designed to investigate the effects of a new ophthalmic solution containing 0.05% v... more The study was designed to investigate the effects of a new ophthalmic solution containing 0.05% vitamin B12 0.05% on corneal nerve regeneration in rats after corneal injury. Eyes of anesthetized male Wistar rats were subjected to corneal injury by removing the corneal epithelium with corneal brush (Algerbrush). After the epithelial debridement, the right eye of each animal received the instillation of one drop of the ophthalmic solution containing vitamin B12 0.05% plus taurine 0.5% and sodium hyaluronate 0.5% four time per day for 10 or 30 days. Left eyes were used as control and treated with solution containing taurine 0.5% and sodium hyaluronate 0.5% alone following the same regimen. Fluorescein staining by slit-lamp and morphological analysis was used to determine corneal wound healing. Immunohistochemistry, immunoblot and confocal microscopy were used to examine corneal re-innervation. Slit-lamp and histological analyses showed that re-epithelization of the corneas was accelera...
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Papers by Francesca Biagioni