Irccs National Institute Of Neurology C Mondino

Pavia, Italy

Irccs National Institute Of Neurology C Mondino

Pavia, Italy
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Melcangi R.C.,University of Milan | Caruso D.,University of Milan | Levandis G.,Irccs National Institute Of Neurology C Mondino | Abbiati F.,University of Milan | And 2 more authors.
Journal of Molecular Neuroscience | Year: 2012

An important link between neuroactive steroids and neurodegenerative disorders has recently been suggested. Indeed, in several neurodegenerative experimental models the levels of neuroactive steroids are affected and their administration exerts neuroprotective effects. However, scarce information has so far been obtained on the neuroactive steroid levels present in Parkinson's disease. To this aim, using an experimental model of loss of nigrostriatal dopaminergic neurons obtained by stereotaxic injection of the neurotoxin 6-hydroxydopamine (6-OHDA), we evaluated by liquid chromatography tandem mass spectrometry the levels of several neuroactive steroids in the striatum and cerebral cortex of 6-OHDA-lesioned male rats. Among the neuroactive steroid levels assessed (i.e., pregnenolone, progesterone, dihydroprogesterone, tetrahydroprogesterone, isopregnanolone, testosterone, dihydrotestosterone, 3α-diol, dehydroepiandrosterone, 17α-estradiol, and 17β-estradiol), we observed a significant decrease of pregnenolone in the striatum. A similar effect was also observed on the levels of dihydroprogesterone present in this cerebral area and also in the cerebral cortex. Interestingly, an increase of isopregnanolone also occurred in the striatum and in the cerebral cortex. Altogether, these results suggesting that progesterone metabolism is affected in an experimental model of Parkinson's disease further highlight the link between neuroactive steroids and the neurodegenerative diseases. © Springer Science+Business Media, LLC 2011.


Armentero M.-T.,Irccs National Institute Of Neurology C Mondino | Levandis G.,Irccs National Institute Of Neurology C Mondino | Bazzini E.,Irccs National Institute Of Neurology C Mondino | Cerri S.,Irccs National Institute Of Neurology C Mondino | And 2 more authors.
Neurobiology of Disease | Year: 2011

Cell adhesion molecules might play an important role in the inflammatory mechanisms associated with neurodegeneration. We have previously observed, in rats, that subcutaneous injection of complete Freund's adjuvant (CFA), a pro-inflammatory agent that induces a peripheral inflammatory stimulus, reduces the nigrostriatal degeneration and microglial activation caused by stereotaxic injection of 6-hydroxydopamine (6-OHDA). Here we further investigated the effects of CFA in 6-OHDA-lesioned rats by evaluating the expression of selected adhesion molecules, both at central and peripheral levels.Male, Sprague-Dawley rats received a subcutaneous injection of CFA followed, 10 days later, by intrastriatal injection of 6-OHDA. Animals were sacrificed at various time points and changes affecting intercellular (ICAM-1), vascular (VCAM-1), platelet endothelial (PECAM-1) and neural (NCAM-1) cell adhesion molecules were analyzed in striatum, ventral midbrain (containing the substantia nigra) and sera. Our results confirmed the protective effect of systemic CFA on 6-OHDA-induced nigrostriatal degeneration. Injection of 6-OHDA increased striatal ICAM-1 and PECAM-1 expression, while opposite changes (decreased expression) were detected in the ventral midbrain, particularly for VCAM-1 and NCAM-1. Pretreatment with CFA counteracted these changes. Nigrostriatal degeneration also affected peripheral immune function, with lesioned animals showing increased sPECAM levels with respect to intact animals. Also in this case, CFA pretreatment blocked the 6-OHDA induced increase of sPECAM.Our findings confirm that a pre-existing, peripheral pro-inflammatory condition reduces the neuroinflammatory response and associated neurodegeneration provoked by centrally-administered 6-OHDA, with a mechanism that seems to involve selected adhesion molecules. The link between peripheral and central immune responses may, therefore, represent a target for new therapeutic strategies aimed at reducing the neuroinflammatory component associated with neurodegeneration. © 2011 Elsevier Inc.


Perrotta A.,IRCCS Mediterranean Neurological Institute Neuromed | Arce-Leal N.,IRCCS Mediterranean Neurological Institute Neuromed | Arce-Leal N.,University of Pavia | Tassorelli C.,University of Pavia | And 12 more authors.
Headache | Year: 2012

Objectives.-We investigated (1) a possible relationship between the functional activity of the endocannabinoid system and the facilitation of pain processing in migraineurs with medication-overuse headache, and (2) the effect of withdrawal treatment on both. Background.-The endocannabinoid system antinociception effect includes prevention of nociceptive pathways sensitization. The sensitization of the pain pathways has been demonstrated to be pivotal in the development and maintenance of chronic form of migraine, including medication-overuse headache. Methods.-We used the temporal summation threshold of the nociceptive withdrawal reflex to explore the spinal cord pain processing, and the platelet activity of the enzyme fatty acid amide hydrolase to detect the functional state of the endocannabinoid system in 27 medication-overuse headache subjects before and 10 and 60 days after a standard withdrawal treatment and compared results with those of 14 controls. Results.-A significantly reduced temporal summation threshold and increased related pain sensation was found in subjects before withdrawal treatment when compared with controls. A significant fatty acid amide hydrolase activity reduction coupled with a significant improvement (reduction) in facilitation of spinal cord pain processing (increase in temporal summation threshold and reduction in related pain sensation) was found in medication-overuse headache subjects at both 10 and 60 days after withdrawal treatment when compared with medication-overuse headache subjects before withdrawal treatment. Conclusions.-We demonstrated a marked facilitation in spinal cord pain processing in medication-overuse headache before withdrawal treatment when compared with controls. Furthermore, the acute reduction of the fatty acid amide hydrolase activity coupled with a reduction of the facilitation in pain processing immediately (10 days) after withdrawal treatment and its persistence 60 days after withdrawal treatment could represent the consequence of a mechanism devoted to acutely reduce the degradation of endocannabinoids and aimed to increase the activity of the endocannabinoid system that results in an antinociceptive effect. © 2012 American Headache Society.


Bossolasco P.,University of Milan | Cova L.,Instituto Auxologico Italiano | Levandis G.,IRCCS National Institute of Neurology C Mondino | Diana V.,Instituto Auxologico Italiano | And 7 more authors.
International Journal of Nanomedicine | Year: 2012

Background: We have previously shown that human mesenchymal stem cells (hMSCs) can reduce toxin-induced neurodegeneration in a well characterized rodent model of Parkinson's disease. However, the precise mechanisms, optimal cell concentration required for neuroprotection, and detailed cell tracking need to be defned. We exploited a near-infrared imaging platform to perform noninvasive tracing following transplantation of tagged hMSCs in live parkinsonian rats. Methods: hMSCs were labeled both with a membrane intercalating dye, emitting in the near-infrared 815 nm spectrum, and the nuclear counterstain, Hoechst 33258. Effects of near-infrared dye on cell metabolism and proliferation were extensively evaluated in vitro. Tagged hMSCs were then administered to parkinsonian rats bearing a 6-hydroxydopamine- induced lesion of the nigrostriatal pathway, via two alternative routes, ie, intrastriatal or intranasal, and the cells were tracked in vivo and ex vivo using near-infrared technology. Results: In vitro, NIR815 staining was stable in long-term hMSC cultures and did not interfere with cell metabolism or proliferation. A significant near-infrared signal was detectable in vivo, confined around the injection site for up to 14 days after intrastriatal transplantation. Conversely, following intranasal delivery, a strong near-infrared signal was immediately visible, but rapidly faded and was completely lost within 1 hour. After sacrifce, imaging data were confirmed by presence/absence of the Hoechst signal ex vivo in coronal brain sections. Semiquantitative analysis and precise localization of transplanted hMSCs were further performed ex vivo using near-infrared imaging. Conclusion: Near-infrared technology allowed longitudinal detection of fuorescent-tagged cells in living animals giving immediate information on how different delivery routes affect cell distribution in the brain. Near-infrared imaging represents a valuable tool to evaluate multiple outcomes of transplanted cells, including their survival, localization, and migration over time within the host brain. This procedure considerably reduces the number of animal experiments needed, as well as interindividual variability, and may favor the development of efficient therapeutic strategies promptly applicable to patients. 6-hydroxydopamine, intranasal, intrastriatal, neurodegeneration, cell tracking. © 2012 Bossolasco et al.


Armentero M.T.,Irccs National Institute Of Neurology C Mondino | Pinna A.,CNR Institute of Neuroscience | Ferre S.,U.S. National Institute on Drug Abuse | Lanciego J.L.,University of Navarra | And 3 more authors.
Pharmacology and Therapeutics | Year: 2011

Several selective antagonists for adenosine A2A receptors (A2AR) are currently under evaluation in clinical trials (phases I to III) to treat Parkinson's disease, and they will probably soon reach the market. The usefulness of these antagonists has been deduced from studies demonstrating functional interactions between dopamine D2 and adenosine A2A receptors in the basal ganglia. At present it is believed that A2AR antagonists can be used in combination with the dopamine precursor L-DOPA to minimize the motor symptoms of Parkinson's patients. However, a considerable body of data indicates that in addition to ameliorating motor symptoms, adenosine A2AR antagonists may also prevent neurodegeneration. Despite these promising indications, one further issue must be considered in order to develop fully optimized antiparkinsonian drug therapy, namely the existence of (hetero)dimers/oligomers of G protein-coupled receptors, a topic that is currently the focus of intense debate within the scientific community. Dopamine D2 receptors (D 2Rs) expressed in the striatum are known to form heteromers with A2A adenosine receptors. Thus, the development of heteromer-specific A2A receptor antagonists represents a promising strategy for the identification of more selective and safer drugs. © 2011 Elsevier Inc. All rights reserved.


PubMed | IRCCS National Institute of Neurology C Mondino
Type: Journal Article | Journal: Neurobiology of disease | Year: 2011

Cell adhesion molecules might play an important role in the inflammatory mechanisms associated with neurodegeneration. We have previously observed, in rats, that subcutaneous injection of complete Freunds adjuvant (CFA), a pro-inflammatory agent that induces a peripheral inflammatory stimulus, reduces the nigrostriatal degeneration and microglial activation caused by stereotaxic injection of 6-hydroxydopamine (6-OHDA). Here we further investigated the effects of CFA in 6-OHDA-lesioned rats by evaluating the expression of selected adhesion molecules, both at central and peripheral levels. Male, Sprague-Dawley rats received a subcutaneous injection of CFA followed, 10 days later, by intrastriatal injection of 6-OHDA. Animals were sacrificed at various time points and changes affecting intercellular (ICAM-1), vascular (VCAM-1), platelet endothelial (PECAM-1) and neural (NCAM-1) cell adhesion molecules were analyzed in striatum, ventral midbrain (containing the substantia nigra) and sera. Our results confirmed the protective effect of systemic CFA on 6-OHDA-induced nigrostriatal degeneration. Injection of 6-OHDA increased striatal ICAM-1 and PECAM-1 expression, while opposite changes (decreased expression) were detected in the ventral midbrain, particularly for VCAM-1 and NCAM-1. Pretreatment with CFA counteracted these changes. Nigrostriatal degeneration also affected peripheral immune function, with lesioned animals showing increased sPECAM levels with respect to intact animals. Also in this case, CFA pretreatment blocked the 6-OHDA induced increase of sPECAM. Our findings confirm that a pre-existing, peripheral pro-inflammatory condition reduces the neuroinflammatory response and associated neurodegeneration provoked by centrally-administered 6-OHDA, with a mechanism that seems to involve selected adhesion molecules. The link between peripheral and central immune responses may, therefore, represent a target for new therapeutic strategies aimed at reducing the neuroinflammatory component associated with neurodegeneration.


PubMed | Irccs National Institute Of Neurology C Mondino
Type: Journal Article | Journal: Pharmacology & therapeutics | Year: 2011

Several selective antagonists for adenosine A(2A) receptors (A(2A)R) are currently under evaluation in clinical trials (phases I to III) to treat Parkinsons disease, and they will probably soon reach the market. The usefulness of these antagonists has been deduced from studies demonstrating functional interactions between dopamine D and adenosine A(2A) receptors in the basal ganglia. At present it is believed that A(2A)R antagonists can be used in combination with the dopamine precursor L-DOPA to minimize the motor symptoms of Parkinsons patients. However, a considerable body of data indicates that in addition to ameliorating motor symptoms, adenosine A(2A)R antagonists may also prevent neurodegeneration. Despite these promising indications, one further issue must be considered in order to develop fully optimized antiparkinsonian drug therapy, namely the existence of (hetero)dimers/oligomers of G protein-coupled receptors, a topic that is currently the focus of intense debate within the scientific community. Dopamine D receptors (DRs) expressed in the striatum are known to form heteromers with A(2A) adenosine receptors. Thus, the development of heteromer-specific A(2A) receptor antagonists represents a promising strategy for the identification of more selective and safer drugs.

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