Publications by authors named "Valentina Vacca"

22 Publications

  • Page 1 of 1

Sexually Dimorphic Immune and Neuroimmune Changes Following Peripheral Nerve Injury in Mice: Novel Insights for Gender Medicine.

Int J Mol Sci 2021 Apr 22;22(9). Epub 2021 Apr 22.

IRCCS Fondazione Santa Lucia, 00143 Rome, Italy.

Neuropathic pain (NeP) in humans is often a life-long condition with no effective therapy available. The higher incidence of female gender in NeP onset is worldwide reported, and although the cause is generally attributed to sex hormones, the actual mechanisms and the players involved are still unclear. Glial and immune cells take part in NeP development, and orchestrate the neuroimmune and inflammatory response, releasing pro-inflammatory factors with chemoattractant properties that activate resident immune cells and recruit immune cells from circulation. The neuro-immune crosstalk is a key contributor to pain hypersensitivity following peripheral nervous system injury. Our previous works showed that in spite of the fact that female mice had an earlier analgesic response than males following nerve lesion, the recovery from NeP was never complete, suggesting that this difference could occur in the very early stages after injury. To further investigate gender differences in immune and neuroimmune responses to NeP, we studied the main immune cells and mediators elicited both in plasma and sciatic nerves by peripheral nerve lesion. After injury, we found a different pattern of distribution of immune cell populations showing either a higher infiltration of T cells in nerves from females or a higher infiltration of macrophages in nerves from males. Moreover, in comparison to male mice, the levels of cytokines and chemokines were differently up- and down-regulated in blood and nerve lysates from female mice. Our study provides some novel insights for the understanding of gender-associated differences in the generation and perseveration of NeP as well as for the isolation of specific neurodegenerative mechanisms underlying NeP. The identification of gender-associated inflammatory profiles in neuropathy is of key importance for the development of differential biomarkers and gender-specific personalized medicine.
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http://dx.doi.org/10.3390/ijms22094397DOI Listing
April 2021

Very Early Involvement of Innate Immunity in Peripheral Nerve Degeneration in SOD1-G93A Mice.

Front Immunol 2020 20;11:575792. Epub 2020 Nov 20.

CNR-National Research Council, Institute of Biochemistry and Cell Biology, Rome, Italy.

Recent preclinical and clinical evidence suggest that immune system has a role in the progression and prognosis of Amyotrophic Lateral Sclerosis (ALS), but the identification of a clear mechanism and immune players remains to be elucidated. Here, we have investigated, in 30 and 60 days (presymptomatic) and 120 days (symptomatic) old SOD1-G93A mice, systemic, peripheral, and central innate and adaptive immune and inflammatory response, correlating it with the progression of the neurodegeneration in neuromuscular junction, sciatic nerves, and spinal cord. Surprisingly, we found a very initial (45-60 days) presence of IgG in sciatic nerves together with a gradual enhancement of A20/TNFAIP3 (protein controlling NF-κB signalling) and a concomitantly significant increase and activation of circulating mast cells (MCs) as well as MCs and macrophages in sciatic nerve and an enhancement of IL-6 and IL-10. This immunological frame coincided with a myelin aggregation. The 30-60 days old SOD1-G93A mice didn't show real elements of neuroinflammation and neurodegeneration in spinal cord. In 120 days old mice macrophages and monocytes are widely diffused in sciatic nerves, peripheral neurodegeneration reaches the tip, high circulating levels of TNFα and IL-2 were found and spinal cord exhibits clear signs of neural damage and infiltrating immune cells. Our results underpin a clear immunological disorder at the origin of ALS axonopathy, in which MCs are involved in the initiation and sustaining of inflammatory events. These data cannot be considered a mere epiphenomenon of motor neuron degeneration and reveal new potential selective immune targets in ALS therapy.
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http://dx.doi.org/10.3389/fimmu.2020.575792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7714949PMC
November 2020

Revealing the Therapeutic Potential of Botulinum Neurotoxin Type A in Counteracting Paralysis and Neuropathic Pain in Spinally Injured Mice.

Toxins (Basel) 2020 07 31;12(8). Epub 2020 Jul 31.

CNR-National Research Council, Institute of Biochemistry and Cell Biology, 00015 Monterotondo Scalo (RM), Italy.

Botulinum neurotoxin type A (BoNT/A) is a major therapeutic agent that has been proven to be a successful treatment for different neurological disorders, with emerging novel therapeutic indications each year. BoNT/A exerts its action by blocking SNARE complex formation and vesicle release through the specific cleavage of SNAP-25 protein; the toxin is able to block the release of pro-inflammatory molecules for months after its administration. Here we demonstrate the extraordinary capacity of BoNT/A to neutralize the complete paralysis and pain insensitivity induced in a murine model of severe spinal cord injury (SCI). We show that the toxin, spinally administered within one hour from spinal trauma, exerts a long-lasting proteolytic action, up to 60 days after its administration, and induces a complete recovery of muscle and motor function. BoNT/A modulates SCI-induced neuroglia hyperreactivity, facilitating axonal restoration, and preventing secondary cells death and damage. Moreover, we demonstrate that BoNT/A affects SCI-induced neuropathic pain after moderate spinal contusion, confirming its anti-nociceptive action in this kind of pain, as well. Our results provide the intriguing and real possibility to identify in BoNT/A a therapeutic tool in counteracting SCI-induced detrimental effects. Because of the well-documented BoNT/A pharmacology, safety, and toxicity, these findings strongly encourage clinical translation.
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http://dx.doi.org/10.3390/toxins12080491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7472120PMC
July 2020

Publisher Correction: Innovative mouse model mimicking human-like features of spinal cord injury: efficacy of Docosahexaenoic acid on acute and chronic phases.

Sci Rep 2019 Nov 14;9(1):17043. Epub 2019 Nov 14.

CNR - National Research Council, Institute of Cell Biology and Neurobiology, 00015, Monterotondo Scalo, Italy.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41598-019-53787-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6856343PMC
November 2019

Impact of caloric restriction on peripheral nerve injury-induced neuropathic pain during ageing in mice.

Eur J Pain 2020 02 27;24(2):374-382. Epub 2019 Oct 27.

CNR - Institute of Cell Biology and Neurobiology, Monterotondo scalo, Italy.

The incidence of peripheral neuropathy development and chronic pain is strongly associated with the arrival of senescence. The gradual physiological decline that begins after the mature stage produces myelin dysregulation and pathological changes in peripheral nervous system, attributed to reduction in myelin proteins expression and thinner myelin sheath. Moreover in elder subjects, when nerve damage occurs, the regenerative processes are seriously compromised and neuropathic pain (NeP) is maintained. We previously demonstrated that caloric restriction (CR) in adult (4 months) nerve-lesioned mice was able to facilitate remyelination and axons regeneration, to have anti-inflammatory action and to prevent NeP chronification. Here, we show CR therapeutic potential on nerve injury-induced neuropathy in mice at the beginning of the senescence (12 months). Long lasting decrease in hypersensitvity induced by peripheral nerve lesion and powerful reduction in proinflammatory circulating agents have been observed. Moreover, our results evidence that CR is able to counteract the ageing-related delay in axonal regeneration, enhancing Schwann cells proliferation and accelerating recovery processes. Differently from adults, it does not affect fibres myelination. In light of a continuous growth in elderly population and correlated health problems, including metabolic disorders, the prevalence of neuropathy is enhancing, generating a significant public cost and social concern. In this context energy depletion by dietary restriction can be a therapeutic option in NeP.
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http://dx.doi.org/10.1002/ejp.1493DOI Listing
February 2020

Innovative mouse model mimicking human-like features of spinal cord injury: efficacy of Docosahexaenoic acid on acute and chronic phases.

Sci Rep 2019 06 20;9(1):8883. Epub 2019 Jun 20.

CNR - National Research Council, Institute of Cell Biology and Neurobiology, 00015, Monterotondo Scalo, Italy.

Traumatic spinal cord injury has dramatic consequences and a huge social impact. We propose a new mouse model of spinal trauma that induces a complete paralysis of hindlimbs, still observable 30 days after injury. The contusion, performed without laminectomy and deriving from the pressure exerted directly on the bone, mimics more closely many features of spinal injury in humans. Spinal cord was injured at thoracic level 10 (T10) in adult anesthetized female CD1 mice, mounted on stereotaxic apparatus and connected to a precision impactor device. Following severe injury, we evaluated motor and sensory functions, and histological/morphological features of spinal tissue at different time points. Moreover, we studied the effects of early and subchronic administration of Docosahexaenoic acid, investigating functional responses, structural changes proximal and distal to the lesion in primary and secondary injury phases, proteome modulation in injured spinal cord. Docosahexaenoic acid was able i) to restore behavioural responses and ii) to induce pro-regenerative effects and neuroprotective action against demyelination, apoptosis and neuroinflammation. Considering the urgent health challenge represented by spinal injury, this new and reliable mouse model together with the positive effects of docosahexaenoic acid provide important translational implications for promising therapeutic approaches for spinal cord injuries.
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http://dx.doi.org/10.1038/s41598-019-45037-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6586623PMC
June 2019

Effects of caloric restriction on neuropathic pain, peripheral nerve degeneration and inflammation in normometabolic and autophagy defective prediabetic Ambra1 mice.

PLoS One 2018 10;13(12):e0208596. Epub 2018 Dec 10.

National Research Council-CNR, Institute of Cell Biology and Neurobiology, Rome, Italy.

There is a growing interest on the role of autophagy in diabetes pathophysiology, where development of neuropathy is one of the most frequent comorbidities. We have previously demonstrated that neuropathic pain after nerve damage is exacerbated in autophagy-defective heterozygous Ambra1 mice. Here, we show the existence of a prediabetic state in Ambra1 mice, characterized by hyperglycemia, intolerance to glucose and insulin resistance. Thus, we further investigate the hypothesis that prediabetes may account for the exacerbation of allodynia and chronic pain and that counteracting the autophagy deficit may relieve the neuropathic condition. We took advantage from caloric restriction (CR) able to exert a double action: a powerful increase of autophagy and a control on the metabolic status. We found that CR ameliorates neuropathy throughout anti-inflammatory and metabolic mechanisms both in Ambra1 and in WT animals subjected to nerve injury. Moreover, we discovered that nerve lesion represents, per se, a metabolic stressor and CR reinstates glucose homeostasis, insulin resistance, incomplete fatty acid oxidation and energy metabolism. As autophagy inducer, CR promotes and anticipates Schwann cell autophagy via AMP-activated protein kinase (AMPK) that facilitates remyelination in peripheral nerve. In summary, we provide new evidence for the role of autophagy in glucose metabolism and identify in energy depletion by dietary restriction a therapeutic approach in the fight against neuropathic pain.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0208596PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287902PMC
May 2019

Botulinum Toxin B Affects Neuropathic Pain but Not Functional Recovery after Peripheral Nerve Injury in a Mouse Model.

Toxins (Basel) 2018 03 18;10(3). Epub 2018 Mar 18.

National Research Council of Italy-CNR, Institute of Cell Biology and Neurobiology-IBCN, 00143 Roma, Italy.

Clinical use of neurotoxins from is well established and is continuously expanding, including in treatment of pain conditions. : The serotype A (BoNT/A) has been widely investigated, and current data demonstrate that it induces analgesia and modulates nociceptive processing initiated by inflammation or nerve injury. Given that data concerning the serotype B (BoNT/B) are limited, the aim of the present study was to verify if also BoNT/B is able not only to counteract neuropathic pain, but also to interfere with inflammatory and regenerative processes associated with the nerve injury. : As model of neuropathic pain, chronic constriction injury (CCI) of the sciatic nerve was performed in CD1 male mice. Mice were intraplantarly injected with saline (control) or BoNT/B (5 or 7.5 pg/mouse) into the injured hindpaw. For comparison, another mouse group was injected with BoNT/A (15 pg/mouse). Mechanical allodynia and functional recovery of the injured paw was followed for 101 days. Spinal cords and sciatic nerves were collected at day 7 for immunohistochemistry. The results of this study show that BoNT/B is a powerful biological molecule that, similarly to BoNT/A, can reduce neuropathic pain over a long period of time. However, the analgesic effects are not associated with an improvement in functional recovery, clearly highlighting an important difference between the two serotypes for the treatment of this chronic pain state.
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http://dx.doi.org/10.3390/toxins10030128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5869416PMC
March 2018

Exosomal cargo including microRNA regulates sensory neuron to macrophage communication after nerve trauma.

Nat Commun 2017 11 24;8(1):1778. Epub 2017 Nov 24.

Wolfson Centre for Age Related Diseases, King's College London, London, SE1 1UL, UK.

Following peripheral axon injury, dysregulation of non-coding microRNAs (miRs) occurs in dorsal root ganglia (DRG) sensory neurons. Here we show that DRG neuron cell bodies release extracellular vesicles, including exosomes containing miRs, upon activity. We demonstrate that miR-21-5p is released in the exosomal fraction of cultured DRG following capsaicin activation of TRPV1 receptors. Pure sensory neuron-derived exosomes released by capsaicin are readily phagocytosed by macrophages in which an increase in miR-21-5p expression promotes a pro-inflammatory phenotype. After nerve injury in mice, miR-21-5p is upregulated in DRG neurons and both intrathecal delivery of a miR-21-5p antagomir and conditional deletion of miR-21 in sensory neurons reduce neuropathic hypersensitivity as well as the extent of inflammatory macrophage recruitment in the DRG. We suggest that upregulation and release of miR-21 contribute to sensory neuron-macrophage communication after damage to the peripheral nerve.
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http://dx.doi.org/10.1038/s41467-017-01841-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5701122PMC
November 2017

17beta-estradiol counteracts neuropathic pain: a behavioural, immunohistochemical, and proteomic investigation on sex-related differences in mice.

Sci Rep 2016 Jan 8;6:18980. Epub 2016 Jan 8.

CNR-National Research Council, Institute of Cell Biology and Neurobiology, 00143 Roma, Italy.

Sex differences play a role in pain sensitivity, efficacy of analgesic drugs and prevalence of neuropathic pain, even if the underlying mechanisms are far from being understood. We demonstrate that male and female mice react differently to structural and functional changes induced by sciatic nerve ligature, used as model of neuropathic pain. Male mice show a gradual decrease of allodynia and a complete recovery while, in females, allodynia and gliosis are still present four months after neuropathy induction. Administration of 17β-estradiol is able to significantly attenuate this difference, reducing allodynia and inducing a complete recovery also in female mice. Parallel to pain attenuation, 17β-estradiol treated-mice show a functional improvement of the injured limb, a faster regenerative process of the peripheral nerve and a decreased neuropathy-induced gliosis. These results indicate beneficial effects of 17β-estradiol on neuropathic pain and neuronal regeneration and focuses on the importance of considering gonadal hormones also in clinical studies.
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http://dx.doi.org/10.1038/srep18980DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4705539PMC
January 2016

Role of extracellular calcitonin gene-related peptide in spinal cord mechanisms of cancer-induced bone pain.

Pain 2016 Mar;157(3):666-676

Wolfson Centre for Age-Related Diseases, King's College London, London, United Kingdom CNR, National Research Council, Cell Biology and Neurobiology Institute, Rome, Italy IRCCS Santa Lucia Foundation, Rome, Italy.

Severe pain is a common and debilitating complication of metastatic bone cancer. Current analgesics provide insufficient pain relief and often lead to significant adverse effects. In models of cancer-induced bone pain, pathological sprouting of sensory fibers at the tumor-bone interface occurs concomitantly with reactive astrocytosis in the dorsal horn of the spinal cord. We observed that calcitonin gene-related peptide (CGRP)-fiber sprouting in the bone was associated with an increase in CGRP content in sensory neuron cell bodies in the dorsal root ganglia (DRG) and increased basal and activity-evoked release of CGRP from their central terminals in the dorsal horn. Intrathecal administration of a peptide antagonist (α-CGRP8-37) attenuated referred allodynia in the hind paw ipsilateral to bone cancer. CGRP receptor components (CLR and RAMP1) were up-regulated in dorsal horn neurons and expressed by reactive astrocytes. In primary cultures of astrocytes, CGRP incubation led to a concentration-dependent increase of forskolin-induced cAMP production, which was attenuated by pretreatment with CGRP8-37. Furthermore, CGRP induced ATP release in astrocytes, which was inhibited by CGRP8-37. We suggest that the peripheral increase in CGRP content observed in cancer-induced bone pain is mirrored by a central increase in the extracellular levels of CGRP. This increase in CGRP not only may facilitate glutamate-driven neuronal nociceptive signaling but also act on astrocytic CGRP receptors and lead to release of ATP.
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http://dx.doi.org/10.1097/j.pain.0000000000000416DOI Listing
March 2016

D-aspartate modulates nociceptive-specific neuron activity and pain threshold in inflammatory and neuropathic pain condition in mice.

Biomed Res Int 2015 5;2015:905906. Epub 2015 Jan 5.

Laboratory of Behavioural Neuroscience, Ceinge Biotecnologie Avanzate, Via G. Salvatore 486, 80145 Naples, Italy ; Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, The Second University of Naples, Naples, Italy.

D-Aspartate (D-Asp) is a free D-amino acid found in the mammalian brain with a temporal-dependent concentration based on the postnatal expression of its metabolizing enzyme D-aspartate oxidase (DDO). D-Asp acts as an agonist on NMDA receptors (NMDARs). Accordingly, high levels of D-Asp in knockout mice for Ddo gene (Ddo (-/-)) or in mice treated with D-Asp increase NMDAR-dependent processes. We have here evaluated in Ddo (-/-) mice the effect of high levels of free D-Asp on the long-term plastic changes along the nociceptive pathway occurring in chronic and acute pain condition. We found that Ddo (-/-) mice show an increased evoked activity of the nociceptive specific (NS) neurons of the dorsal horn of the spinal cord (L4-L6) and a significant decrease of mechanical and thermal thresholds, as compared to control mice. Moreover, Ddo gene deletion exacerbated the nocifensive responses in the formalin test and slightly reduced pain thresholds in neuropathic mice up to 7 days after chronic constriction injury. These findings suggest that the NMDAR agonist, D-Asp, may play a role in the regulation of NS neuron electrophysiological activity and behavioral responses in physiological and pathological pain conditions.
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http://dx.doi.org/10.1155/2015/905906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4299315PMC
October 2015

Analgesic effects of botulinum neurotoxin type A in a model of allyl isothiocyanate- and capsaicin-induced pain in mice.

Toxicon 2015 Feb 19;94:23-8. Epub 2014 Dec 19.

Child Neuropsychiatry Clinic, AOU, University of Cagliari, Cagliari, Italy. Electronic address:

We evaluate analgesic effects of BoNT/A in relation to the two main transient receptor potentials (TRP), the vanilloid 1 (TRPV1) and the ankyrin 1 (TRPA1), having a role in migraine pain. BoNT/A (15 pg/mouse) was injected in the inner side of the medial part of hindlimb thigh of mice, where the superficial branch of femoral artery is located. We chosen this vascular structure because it is similar to other vascular structures, such as the temporal superficial artery, whose perivascular nociceptive fibres probably contributes to migraine pain. After an interval, ranging from 7 to 30 days, capsaicin (agonist of TRPV1) or allyl isothiocyanate (AITC; agonist of TRPA1) were injected in the same region previously treated with BoNT/A and nocifensive response to chemicals-induced pain was recorded. In absence of BoNT/A, capsaicin and AITC induced extensive nocifensive response, with a markedly different temporal profile: capsaicin induced maximal pain during the first 5 min, while AITC induced maximal pain at 15-30 min after injection. Pretreatment with BoNT/A markedly reduced both the capsaicin- and AITC-induced pain for at least 21 days. These data suggest a long lasting analgesic effect of BoNT/A exerted via prevention of responsiveness of TRPV1 and TRPA1 toward their respective agonists.
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http://dx.doi.org/10.1016/j.toxicon.2014.12.007DOI Listing
February 2015

Effects of age-related loss of P/Q-type calcium channels in a mice model of peripheral nerve injury.

Neurobiol Aging 2015 Jan 25;36(1):352-64. Epub 2014 Jul 25.

CNR National Research Council of Italy, Cell Biology and Neurobiology Institute, IRCCS Santa Lucia Foundation, Rome, Italy. Electronic address:

We analyzed the role of P/Q-type calcium channels in sciatic nerve regeneration after lesion induced by chronic constriction injury (CCI) in heterozygous null mutant mice lacking the CaV2.1α1 subunit of these channels (Cacna1a+/-). Compared with wild type, Cacna1a+/- mice showed an initial reduction of the CCI-induced allodynia, indicating a reduced pain perception, but they also evidenced a lack of recovery over time, with atrophy of the injured hindpaw still present 3 months after CCI when wild-type mice fully recovered. In parallel, Cacna1a+/- mice exhibited an early onset of age-dependent loss of P/Q-type channels, which can be responsible for the lack of functional recovery. Moreover, Cacna1a+/- mice showed an early age-dependent reduction of muscular strength, as well as of Schwann cells proliferation and sciatic nerve remyelination. This study demonstrates the important role played by P/Q-type channels in recovery from nerve injury and has important implications for the knowledge of age-related processes.
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http://dx.doi.org/10.1016/j.neurobiolaging.2014.07.025DOI Listing
January 2015

Higher pain perception and lack of recovery from neuropathic pain in females: a behavioural, immunohistochemical, and proteomic investigation on sex-related differences in mice.

Pain 2014 Feb 11;155(2):388-402. Epub 2013 Nov 11.

CNR - National Research Council, Cell Biology and Neurobiology Institute, Roma, Italy IRCCS Santa Lucia Foundation, Roma, Italy Department of Experimental Medicine and Surgery, Division of Biochemistry, University of "Tor Vergata", Roma, Italy.

In experimental and clinical pain studies, the sex of subjects was rarely taken into account, even if nociceptive inputs appear to be processed and modulated by partially distinct neural mechanisms in each sex. In this study we analysed, in male and female mice, behavioural and neuronal responses in developing, maintaining, and recovering from neuropathic pain. Experiments were carried out in adult CD1 mice by using Chronic Constriction Injury (CCI) as neuropathic pain model. We investigated the temporal trend of mechanical nociceptive threshold together with functional recovery of the injured paw, and the immunofluorescence staining of proteins associated with nerve injury and repair and with spinal gliosis, 7 and 121days after CCI. A proteomic analysis on proteins extracted from sciatic nerves was also performed. Male mice showed a gradual decrease of CCI-induced allodynia, the complete recovery occurring 81days after the sciatic nerve ligation. On the contrary, in female mice, allodynia was still present 121days after CCI. Sex-dependent differences also resulted from immunofluorescence experiments: in sciatic nerve, the expression of P0 and Neu200 is greater in neuropathic males than in neuropathic females, suggesting faster nerve regeneration. Proteomic analysis confirmed sex-related differences of proteins associated with nerve regenerative processes. In addition, the reactive gliosis induced by CCI at day 7, as revealed by colocalization of glial fibrillary acidic protein (astrocytes) and CD11b (microglia) with phosphorylated p38, disappeared 121 days after CCI in male but not in female mice. These results may have important therapeutic implications for the treatment of neuropathic pain.
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http://dx.doi.org/10.1016/j.pain.2013.10.027DOI Listing
February 2014

Schwann cell autophagy counteracts the onset and chronification of neuropathic pain.

Pain 2014 Jan 13;155(1):93-107. Epub 2013 Sep 13.

CNR - National Research Council, Cell Biology and Neurobiology Institute, Rome, Italy Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Fondazione Santa Lucia, Rome, Italy Department of Technology and Health, Istituto Superiore di Sanita', Rome, Italy Department of Therapeutic Research and Medicine Evaluation, Section of Cell Aging and Degeneration, Istituto Superiore di Sanita', Rome, Italy Medical School, University Campus-Biomedico, Rome, Italy Department of Experimental Medicine and Surgery, Division of Biochemistry, University of "Tor Vergata", Rome, Italy Dulbecco Telethon Institute, Department of Biology, University of "Tor Vergata", Rome, Italy San Raffaele Institute, Sulmona, L'Aquila, Italy Center of Integrated Metabolomics, Rome, Italy.

Axonal degeneration in peripheral nerves after injury is accompanied by myelin degradation initiated by Schwann cells (SCs). These cells activate autophagy, a ubiquitous cytoprotective process essential for degradation and recycling of cellular constituents. Concomitantly to nerve insult and axonal degeneration, neuropathic pain (NeP) arises. The role of SC autophagy in the mechanisms underlying NeP is still unknown. In this study, we examined the role of the autophagy during the early phase of Wallerian degeneration in NeP induction and chronification by using a murine model of peripheral nerve lesion (chronic constriction injury). We demonstrate that the autophagy inducer rapamycin, administered in the first week after nerve damage, induces long-lasting analgesic and antiinflammatory effects, facilitates nerve regeneration, and prevents pain chronification. Conversely, when autophagy is altered, by means of autophagic inhibitor 3-methyladenine administration or as occurs in activating molecule in Beclin-1-regulated autophagy transgenic mice (Ambra1(+/gt)), NeP is dramatically enhanced and prolonged. Immunohistochemical and ultrastructural evaluations show that rapamycin is able to increase autophagic flux in SCs, to accelerate myelin compaction, and to reduce inflammatory and immune reaction. Proteomic analysis combined with bioinformatic analysis suggests that a redox-sensitive mechanism could be responsible for SC autophagy activation. These data suggest that a deficiency of autophagic activity in SCs can be an early event in the origin of NeP chronification and that autophagy modulation may represent a powerful pharmacological approach to prevent the onset and chronification of NeP in the clinical setting.
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http://dx.doi.org/10.1016/j.pain.2013.09.013DOI Listing
January 2014

Acute diverticulitis in the young: the same disease in a different patient.

Gastroenterol Res Pract 2013 10;2013:867961. Epub 2013 Mar 10.

Clinica Chirurgica, Department of Surgery, University of Cagliari, Azienda Ospedaliero-Universitaria, Presidio Policlinico di Monserrato, Blocco G, SS 554 km 4,500, 09042 Monserrato (CA), Italy.

Background. Natural history and risk factors for diverticulitis in young patients are still debatable. This study aimed to assess whether difference exists in patients aged 50 and younger when compared to older patients and to identify risk factors for acute diverticulitis in the young. Patients and Methods. From January 2006 to December 2011, 80 patients were admitted to our department for acute diverticulitis. We carried out a cross-sectional study in 23 patients (28.7%) aged 50 and younger and 57 older patients (71.3%). Results. Acute diverticulitis in the young was not more aggressive than in the older patient. Diverticulitis at patient's admission was similar with respect to Hinchey's stage and prior history of diverticulitis. No significant difference was found for both medical and surgical treatment. The rate of recurrent diverticulitis in nonoperated patients was similar. Male gender, body mass index ≥25, and assumption of alcohol were independent risk factors for the occurrence of an acute diverticulitis in the young. Conclusions. The same disease seems to be affecting young patients such as overweight or obese male individual. Current policies to prevent diverticular disease and its related complications must include obesity control together with high-fiber diet and regular exercise.
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http://dx.doi.org/10.1155/2013/867961DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3608115PMC
April 2013

Botulinum toxin A increases analgesic effects of morphine, counters development of morphine tolerance and modulates glia activation and μ opioid receptor expression in neuropathic mice.

Brain Behav Immun 2013 Aug 9;32:40-50. Epub 2013 Feb 9.

CNR - National Research Council of Italy, Cell Biology and Neurobiology Institute/IRCCS - Santa Lucia Foundation, Rome, Italy.

The use of botulinum neurotoxin type A (BoNT/A) against pain, with emphasis for its possible use in alleviating chronic pain, still represents an outstanding challenge for experimental research. In this study, we examined the effects of BoNT/A on morphine-induced tolerance during chronic morphine treatment in neuropathic CD1 mice subjected to sciatic nerve lesion according to the Chronic Constriction Injury (CCI) model of neuropathic pain. We measured the effects of BoNT/A on CCI-induced allodynia and hyperalgesia and on the expression of glial fibrillary acidic protein (GFAP, marker of astrocytes), complement receptor 3/cluster of differentiation 11b (CD11b, marker of microglia), and neuronal nuclei (NeuN) at the spinal cord level. We also analyzed the colocalized expression of GFAP, CD11b and NeuN with phosphorylated p-38 mitogen-activated protein kinase and with μ-opioid receptor (MOR). A single intraplantar injection of BoNT/A (15 pg/paw) into the injured hindpaw, the day before the beginning of chronic morphine treatment (9 days of twice daily injections of 40 mg/kg morphine), was able to counteract allodynia and enhancement of astrocytes expression/activation induced by CCI. In addition, BoNT/A increased the analgesic effect of morphine and countered morphine-induced tolerance during chronic morphine treatment. These effects were accompanied, in neurons, by re-expression of MORs that had been reduced by repeated morphine administration. The combinatory effects of BoNT/A and morphine could have relevant therapeutic implications for sufferers of chronic pain who could benefit of pain relief reducing tolerance due to repeated treatment with opiates.
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http://dx.doi.org/10.1016/j.bbi.2013.01.088DOI Listing
August 2013

The analgesic effect on neuropathic pain of retrogradely transported botulinum neurotoxin A involves Schwann cells and astrocytes.

PLoS One 2012 24;7(10):e47977. Epub 2012 Oct 24.

National Research Council of Italy-Cell Biology and Neurobiology Institute/Istituto Di Ricovero e Cura a Carattere Scientifico Fondazione Santa Lucia, Rome, Italy.

In recent years a growing debate is about whether botulinum neurotoxins are retrogradely transported from the site of injection. Immunodetection of cleaved SNAP-25 (cl-SNAP-25), the protein of the SNARE complex targeted by botulinum neurotoxin serotype A (BoNT/A), could represent an excellent approach to investigate the mechanism of action on the nociceptive pathways at peripheral and/or central level. After peripheral administration of BoNT/A, we analyzed the expression of cl-SNAP-25, from the hindpaw's nerve endings to the spinal cord, together with the behavioral effects on neuropathic pain. We used the chronic constriction injury of the sciatic nerve in CD1 mice as animal model of neuropathic pain. We evaluated immunostaining of cl-SNAP-25 in the peripheral nerve endings, along the sciatic nerve, in dorsal root ganglia and in spinal dorsal horns after intraplantar injection of saline or BoNT/A, alone or colocalized with either glial fibrillar acidic protein, GFAP, or complement receptor 3/cluster of differentiation 11b, CD11b, or neuronal nuclei, NeuN, depending on the area investigated. Immunofluorescence analysis shows the presence of the cl-SNAP-25 in all tissues examined, from the peripheral endings to the spinal cord, suggesting a retrograde transport of BoNT/A. Moreover, we performed in vitro experiments to ascertain if BoNT/A was able to interact with the proliferative state of Schwann cells (SC). We found that BoNT/A modulates the proliferation of SC and inhibits the acetylcholine release from SC, evidencing a new biological effect of the toxin and further supporting the retrograde transport of the toxin along the nerve and its ability to influence regenerative processes. The present results strongly sustain a combinatorial action at peripheral and central neural levels and encourage the use of BoNT/A for the pathological pain conditions difficult to treat in clinical practice and dramatically impairing patients' quality of life.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0047977PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3480491PMC
April 2013

The novel reversible fatty acid amide hydrolase inhibitor ST4070 increases endocannabinoid brain levels and counteracts neuropathic pain in different animal models.

J Pharmacol Exp Ther 2012 Jul 18;342(1):188-95. Epub 2012 Apr 18.

Sigma-Tau Industrie Farmaceutiche Riunite S.p.A., Via Pontina km. 30,400, 00040 Pomezia, Italy.

The effect of the enol carbamate 1-biphenyl-4-ylethenyl piperidine-1-carboxylate (ST4070), a novel reversible inhibitor of fatty acid amide hydrolase (FAAH), was investigated for acute pain sensitivity and neuropathic pain in rats and mice. Brain enzymatic activity of FAAH and the endogenous levels of its substrates, anandamide (AEA; N-arachidonoylethanolamine), 2-arachidonoylglycerol (2-AG), and N-palmitoylethanolamine (PEA), were measured in control and ST4070-treated mice. ST4070 (10, 30, and 100 mg/kg) was orally administered to assess mechanical nociceptive thresholds and allodynia by using the Randall-Selitto and von Frey tests, respectively. Neuropathy was induced in rats by either the chemotherapeutic agent vincristine or streptozotocin-induced diabetes, whereas the chronic constriction injury (CCI) model was chosen to evaluate neuropathy in mice. ST4070 produced a significant increase of nociceptive threshold in rats and counteracted the decrease of nociceptive threshold in the three distinct models of neuropathic pain. In diabetic mice, ST4070 inhibited FAAH activity and increased the brain levels of AEA and PEA, without affecting that of 2-AG. The administration of ST4070 generated long-lasting pain relief compared with pregabalin and the FAAH inhibitors 1-oxo-1[5-(2-pyridyl)-2-yl]-7-phenylheptane (OL135) and cyclohexylcarbamic acid 3'-carbamoylbiphenyl-3-ylester (URB597) in CCI neuropathic mice. The antiallodynic effects of ST4070 were prevented by pretreatment with cannabinoid type 1 and cannabinoid type 2 receptor antagonists and by the selective peroxisome proliferator-activated receptor α antagonist [(2S)-2-[[(1Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl]amino]-3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]propyl]-carbamic acid ethyl ester (GW6471). The administration of ST4070 generated long-lasting neuropathic pain relief compared with pregabalin and the FAAH inhibitors OL135 and URB597. Taken together, the reversible FAAH inhibitor ST4070 seems to be a promising novel therapeutic agent for the management of neuropathic pain.
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http://dx.doi.org/10.1124/jpet.111.191403DOI Listing
July 2012

Botulinum neurotoxin A enhances the analgesic effects on inflammatory pain and antagonizes tolerance induced by morphine in mice.

Brain Behav Immun 2012 Mar 20;26(3):489-99. Epub 2012 Jan 20.

CNR-National Research Council of Italy (Cell Biology and Neurobiology Institute IBCN)/IRCCS Fondazione Santa Lucia, Roma, Italy.

Over the recent years compelling evidence has accumulated indicating that botulinum neurotoxin serotype A (BoNT/A) results in analgesic effects on neuropathic as well as inflammatory pain, both in humans and in animal models. In the present study, the pharmacological interaction of BoNT/A with morphine in fighting inflammatory pain was investigated in mice using the formalin test. Moreover, the effects of BoNT/A on the tolerance-induced by chronic administration of morphine were tested and the behavioral effects were correlated with immunofluorescence staining of glial fibrillary acidic protein, the specific marker of astrocytes, at the spinal cord level. An ineffective dose of BoNT/A (2 pg/paw) combined with an ineffective dose of morphine (1 mg/kg) exerted a significant analgesic action both during the early and the late phases of formalin test. A single intraplantar injection of BoNT/A (15 pg/paw; i.pl.), administered the day before the beginning of chronic morphine treatment (7 days of s.c. injections of 20 mg/kg), was able to counteract the occurrence of tolerance to morphine. Moreover, BoNT/A reduces the enhancement of the expression of astrocytes induced by inflammatory formalin pain. Side effects of opiates, including the development of tolerance during repeated use, may limit their therapeutic use, the possibility of using BoNT/A for lowering the effective dose of morphine and preventing the development of opioid tolerance would have relevant implications in terms of potential therapeutic perspectives.
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http://dx.doi.org/10.1016/j.bbi.2012.01.002DOI Listing
March 2012