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Freeman, W., Vitiello, G.
Matter and mind are entangled in two streams of images guiding behavior and informing the subject through awareness
(2016) Mind and Matter, 14 (1), pp. 7-24. 
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AFFILIATIONS: Department of Molecular and Cell Biology, University of California, Berkeley, United States; 
Department of Physics ‘E.R. Caianiello’, University of Salerno, Fisciano, Salerno, Italy; 
National Institute of Nuclear Physics, Italy
ABSTRACT: Brains acquire knowledge by acting into the environment to confirm or reject hypotheses imagined from memory in the actionperception cycle. Memories are created and updated through phase transitions from a gas-like ground state to a liquid-like condensate that we model as a dissipative quantum field. Each retrieved memory is imposed in the amplitude modulation (AM) of a narrow band carrier frequency of a macroscopic wave packet in the beta-gamma range of brain waves. Brains imagine hypotheses about the world by copying AM patterns and mirroring them in time. We postulate that the AM patterns in forward thermodynamic time implements action (matter), while the time-reversed copy (mirrored time) governs perception (mind, awareness). They are entangled dynamical modes that we distinguish by patterns of phase modulation that accompany the AM patterns in the electrocorticogram. © 2016 Imprint Academic.
DOCUMENT TYPE: Article

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Grumetto, L., Russo, G., Barbato, F.
Immobilized Artificial Membrane HPLC Derived Parameters vs PAMPA-BBB Data in Estimating in Situ Measured Blood-Brain Barrier Permeation of Drugs
(2016) Molecular Pharmaceutics, 13 (8), pp. 2808-2816. 
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DOI: 10.1021/acs.molpharmaceut.6b00397
AFFILIATIONS: Dipartimento di Farmacia, Università degli Studi di Napoli Federico II, Via D. Montesano, 49, Naples, Italy
ABSTRACT: The affinity indexes for phospholipids (log kW IAM) for 42 compounds were measured by high performance liquid chromatography (HPLC) on two different phospholipid-based stationary phases (immobilized artificial membrane, IAM), i.e., IAM.PC.MG and IAM.PC.DD2. The polar/electrostatic interaction forces between analytes and membrane phospholipids (Δlog kW IAM) were calculated as the differences between the experimental values of log kW IAM and those expected for isolipophilic neutral compounds having polar surface area (PSA) = 0. The values of passage through a porcine brain lipid extract (PBLE) artificial membrane for 36 out of the 42 compounds considered, measured by the so-called PAMPA-BBB technique, were taken from the literature (P0 PAMPA-BBB). The values of blood-brain barrier (BBB) passage measured in situ, P0 in situ, for 38 out of the 42 compounds considered, taken from the literature, represented the permeability of the neutral forms on "efflux minimized" rodent models. The present work was aimed at verifying the soundness of Δlog kW IAM at describing the potential of passage through the BBB as compared to data achieved by the PAMPA-BBB technique. In a first instance, the values of log P0 PAMPA-BBB (32 data points) were found significantly related to the n-octanol lipophilicity values of the neutral forms (log PN) (r2 = 0.782) whereas no significant relationship (r2 = 0.246) was found with lipophilicity values of the mixtures of ionized and neutral forms existing at the experimental pH 7.4 (log D7.4) as well as with either log kW IAM or Δlog kW IAM values. log P0 PAMPA-BBB related moderately to log P0 in situ values (r2 = 0.604). The latter did not relate with either n-octanol lipophilicity indexes (log PN and log D7.4) or phospholipid affinity indexes (log kW IAM). In contrast, significant inverse linear relationships were observed between log P0 in situ (38 data points) and Δlog kW IAM values for all the compounds but ibuprofen and chlorpromazine, which behaved as moderate outliers (r2 = 0.656 and r2 = 0.757 for values achieved on IAM.PC.MG and IAM.PC.DD2, respectively). Since log P0 in situ refer to the "intrinsic permeability" of the analytes regardless their ionization degree, no correction for ionization of Δlog kW IAM values was needed. Furthermore, log P0 in situ were found roughly linearly related to log BB values (i.e., the logarithm of the ratio brain concentration/blood concentration measured in vivo) for all the analytes but those predominantly present at the experimental pH 7.4 as anions. These results suggest that, at least for the data set considered, Δlog kW IAM parameters are more effective than log P0 PAMPA-BBB at predicting log P0 in situ values for all the analytes. Furthermore, ionization appears to affect differently, and much more markedly, BBB passage of acids (yielding anions) than that of the other ionizable compounds. © 2016 American Chemical Society.
CORRESPONDENCE ADDRESS: Barbato, F.; Dipartimento di Farmacia, Università degli Studi di Napoli Federico II, Via D. Montesano, 49, Italy; email: fbarbato@unina.it

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Curcio, M., Salazar, I.L., Mele, M., Canzoniero, L.M.T., Duarte, C.B.
Calpains and neuronal damage in the ischemic brain: The swiss knife in synaptic injury
(2016) Progress in Neurobiology, 143, pp. 1-35. 
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DOI: 10.1016/j.pneurobio.2016.06.001
AFFILIATIONS: CNC – Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; 
Doctoral Programme in Experimental Biology and Biomedicine, Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal, Institute for Interdisciplinary Research, University of Coimbra (IIIUC), Coimbra, Portugal; 
Department of Science and Technology, University of Sannio, Benevento, Italy; 
Department of Life Sciences, University of Coimbra, Coimbra, Portugal
ABSTRACT: The excessive extracellular accumulation of glutamate in the ischemic brain leads to an overactivation of glutamate receptors with consequent excitotoxic neuronal death. Neuronal demise is largely due to a sustained activation of NMDA receptors for glutamate, with a consequent increase in the intracellular Ca2+ concentration and activation of calcium- dependent mechanisms. Calpains are a group of Ca2+-dependent proteases that truncate specific proteins, and some of the cleavage products remain in the cell, although with a distinct function. Numerous studies have shown pre- and post-synaptic effects of calpains on glutamatergic and GABAergic synapses, targeting membrane- associated proteins as well as intracellular proteins. The resulting changes in the presynaptic proteome alter neurotransmitter release, while the cleavage of postsynaptic proteins affects directly or indirectly the activity of neurotransmitter receptors and downstream mechanisms. These alterations also disturb the balance between excitatory and inhibitory neurotransmission in the brain, with an impact in neuronal demise. In this review we discuss the evidence pointing to a role for calpains in the dysregulation of excitatory and inhibitory synapses in brain ischemia, at the pre- and post-synaptic levels, as well as the functional consequences. Although targeting calpain-dependent mechanisms may constitute a good therapeutic approach for stroke, specific strategies should be developed to avoid non-specific effects given the important regulatory role played by these proteases under normal physiological conditions. © 2016 Elsevier Ltd
CORRESPONDENCE ADDRESS: Duarte, C.B.; Center for Neuroscience and Cell Biology, University of CoimbraPortugal; email: cbduarte@ci.uc.pt

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Barbosa, J.S., Di Giaimo, R., Götz, M., Ninkovic, J.
Single-cell in vivo imaging of adult neural stem cells in the zebrafish telencephalon
(2016) Nature Protocols, 11 (8), pp. 1360-1370. 
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DOI: 10.1038/nprot.2016.077
AFFILIATIONS: Institute of Stem Cell Research, Helmholtz Center Munich, Neuherberg/Munich, Germany; 
Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; 
Department of Biology, University of Naples Federico II, Naples, Italy; 
Biomedical Center, University of Munich, Munich, Germany; 
Excellence Cluster of Systems Neurology SYNERGY, Ludwig Maximilian University of Munich, Munich, Germany
ABSTRACT: Adult neural stem cells (aNSCs) in zebrafish produce mature neurons throughout their entire life span in both the intact and regenerating brain. An understanding of the behavior of aNSCs in their intact niche and during regeneration in vivo should facilitate the identification of the molecular mechanisms controlling regeneration-specific cellular events. A greater understanding of the process in regeneration-competent species may enable regeneration to be achieved in regeneration-incompetent species, including humans. Here we describe a protocol for labeling and repetitive imaging of aNSCs in vivo. We label single aNSCs, allowing nonambiguous re-identification of single cells in repetitive imaging sessions using electroporation of a red-reporter plasmid in Tg(gfap:GFP)mi2001 transgenic fish expressing GFP in aNSCs. We image using two-photon microscopy through the thinned skull of anesthetized and immobilized fish. Our protocol allows imaging every 2 d for a period of up to 1 month. This methodology allowed the visualization of aNSC behavior in vivo in their natural niche, in contrast to previously available technologies, which rely on the imaging of either dissociated cells or tissue slices. We used this protocol to follow the mode of aNSC division, fate changes and cell death in both the intact and injured zebrafish telencephalon. This experimental setup can be widely used, with minimal prior experience, to assess key factors for processes that modulate aNSC behavior. A typical experiment with data analysis takes up to 1.5 months. © 2016 Nature America, Inc.
CORRESPONDENCE ADDRESS: Ninkovic, J.; Institute of Stem Cell Research, Helmholtz Center MunichGermany; email: ninkovic@helmholtz-muenchen.de

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Bisogno, T., Oddi, S., Piccoli, A., Fazio, D., Maccarrone, M.
Type-2 cannabinoid receptors in neurodegeneration
(2016) Pharmacological Research, 111, pp. 721-730. 
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DOI: 10.1016/j.phrs.2016.07.021
AFFILIATIONS: Endocannabinoid Research Group, Institute of Biomolecular Chemistry, National Research Council, Pozzuoli, Italy; 
Department of Medicine, Campus Bio-Medico University of Rome, Via Alvaro del Portillo 21, Rome, Italy; 
Faculty of Veterinary Medicine, University of Teramo, Via Balzarini 1, Teramo, Italy; 
European Center for Brain Research/IRCCS Santa Lucia Foundation, Via del Fosso di Fiorano 64, Rome, Italy
ABSTRACT: Based on its wide expression in immune cells, type-2 cannabinoid (CB2) receptors were traditionally thought to act as “peripheral receptors” with an almost exclusively immunomodulatory function. However, their recent identification in mammalian brain areas, as well as in distinct neuronal cells, has opened the way to a re-consideration of CB2 signaling in the context of brain pathophysiology, synaptic plasticity and neuroprotection. To date, accumulated evidence from several independent preclinical studies has offered new perspectives on the possible involvement of CB2 signaling in brain and spinal cord traumatic injury, as well as in the most relevant neurodegenerative disorders like Alzheimer's disease, Parkinson's disease and Huntington's chorea. Here, we will review available information on CB2 in these disease conditions, along with data that support also its therapeutic potential to treat them. © 2016 Elsevier Ltd
CORRESPONDENCE ADDRESS: Maccarrone, M.; Department of Medicine, Campus Bio-Medico University of Rome, Via Alvaro del Portillo 21, Italy; email: m.maccarrone@unicampus.it

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Fraldi, A., Klein, A.D., Medina, D.L., Settembre, C.
Brain Disorders Due to Lysosomal Dysfunction
(2016) Annual Review of Neuroscience, 39, pp. 277-295. 
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DOI: 10.1146/annurev-neuro-070815-014031
AFFILIATIONS: Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy; 
Dulbecco Telethon Institute, Pozzuoli, Italy; 
Medical Genetics Unit, Department of Medical and Translational Science, Federico II University, Naples, Italy
ABSTRACT: Recent studies of autophagic and lysosomal pathways have significantly changed our understanding of lysosomes; once thought to be simple degradative and recycling centers, lysosomes are now known to be organelles capable of influencing signal transduction, via the mammalian target of rapamycin complex 1 (mTORC1), and regulating gene expression, via transcription factor EB (TFEB) and other transcription factors. These pathways are particularly relevant to maintaining brain homeostasis, as dysfunction of the endolysosomal and autophagic pathways has been associated with common neurodegenerative diseases, such as Alzheimer's, Parkinson's, and Huntington's, and lysosomal storage disorders, a group of inherited disorders characterized by the intralysosomal buildup of partially degraded metabolites. This review focuses on the cellular biology of lysosomes and discusses the possible mechanisms by which disruption of their function contributes to neurodegeneration. We also review and discuss how targeting TFEB and lysosomes may offer innovative therapeutic approaches for treating a wide range of neurological conditions. Copyright ©2016 by Annual Reviews.

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Perruolo, G., Viggiano, D., Fiory, F., Cassese, A., Nigro, C., Liotti, A., Miele, C., Beguinot, F., Formisano, P.
Parkinson-like phenotype in insulin-resistant PED/PEA-15 transgenic mice
(2016) Scientific Reports, 6, art. no. 29967, . 
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DOI: 10.1038/srep29967
AFFILIATIONS: URT- Genomica del Diabete, Istituto di Endocrinologia ed Oncologia Sperimentale (IEOS-CNR), Naples, Italy; 
Dipartimento di Scienze Mediche Traslazionali, Università degli Studi di Napoli Federico II, Naples, Italy; 
Dept Medicine and Health Sciences, Univ. Molise, Italy
ABSTRACT: Neurological abnormalities, such as Parkinson-like disorders (PlD), are often co-morbidities of Type 2 Diabetic (T2D) patients, although the epidemiological link between these two disorders remains controversial. The PED/PEA-15 protein represents a possible candidate linking T2D and PD, because it is increased in subjects with T2D and is highly expressed in the brain. To test this hypothesis, we have analyzed the neurological and neurochemical phenotype of transgenic mice overexpressing PED/PEA-15 (tgPED). These mice develop impaired glucose tolerance and insulin resistance, accompanied by neurological features resembling PlD: feet clasping, slow and delayed locomotor movements in different behavioral tests in absence of clear cognitive deficits, ataxia or anxiety. Morphological analysis of the brains showed selective modifications of metabolic activity in the striatal region. In the same region, we have observed 26% decrease of dopamine fibers, confirmed by immunohistochemistry and Western Blot for tyrosine hydroxylase. Moreover, they also showed 48% reduction of dopamine levels in the striatum. Thus the tgPED mice may represent a genetic animal model of neurological disease linked to T2D.
CORRESPONDENCE ADDRESS: Formisano, P.; URT- Genomica del Diabete, Istituto di Endocrinologia ed Oncologia Sperimentale (IEOS-CNR)Italy; email: fpietro@unina.it

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Lanzillo, R., Quarantelli, M., Pozzilli, C., Trojano, M., Amato, M.P., Marrosu, M.G., Francia, A., Florio, C., Orefice, G., Tedeschi, G., Bellantonio, P., Annunziata, P., Grimaldi, L.M., Comerci, M., Brunetti, A., Bonavita, V., Alfano, B., Marini, S., Brescia Morra, V.
No evidence for an effect on brain atrophy rate of atorvastatin add-on to interferon β1b therapy in relapsing-remitting multiple sclerosis (the ARIANNA study)
(2016) Multiple Sclerosis, 22 (9), pp. 1163-1173. 
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DOI: 10.1177/1352458515611222
AFFILIATIONS: Department of Neurosciences, Reproductive and Odontostomatological Sciences, Federico II University of Naples, Via Pansini 5, Italy; 
National Research Council (CNR), Biostructure and Bioimaging Institute (IBB), Naples Multiple Sclerosis Centre, Italy; 
Department of Neurology and Psychiatry, Sapienza University, Italy; 
Department of Neurosciences and Organs of Senses, University of Bari, Italy; 
Department of NEUROFARBA, University of Florence, Italy; 
Department of Public Health, Clinical and Molecular Medicine, University of Cagliari, Italy; 
Multiple Sclerosis Regional Center, Azienda Ospedaliera Antonio Cardarelli, Italy; 
Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, Second University of Naples, Italy; 
IRCCS Neuromed-Pozzilli (IS), Italy; 
Department of Neurological, Neurosurgical and Behavioural Sciences, University of Siena, Italy; 
Neurology Unit, Fondazione Istituto San Raffaele G. Giglio, Italy; 
Department of Biomedical Advanced Sciences, Federico II University, Italy; 
IDC Hermitage Capodimonte, Italy; 
Dimensione Ricerca S.r.l., Italy
ABSTRACT: Background: A previous phase 2 trial has suggested that statins might delay brain atrophy in secondary progressive multiple sclerosis. Objectives: The objective of this study was to evaluate the effect of atorvastatin add-on therapy on cerebral atrophy in relapsing-remitting multiple sclerosis. Methods: This randomised, placebo-controlled study compared atorvastatin 40 mg or placebo add-on therapy to interferon β1b for 24 months. Brain magnetic resonance imaging, multiple sclerosis functional composite score, Rao neuropsychological battery and expanded disability status scale were evaluated over 24 months. Results: A total of 154 patients were randomly assigned, 75 in the atorvastatin and 79 in the placebo arms, with a comparable drop-out rate (overall 23.4%). Brain atrophy over 2 years was not different in the two arms (-0.38% and -0.32% for the atorvastatin and placebo groups, respectively). Relapse rate, expanded disability status scale, multiple sclerosis functional composite score or cognitive changes were not different in the two arms. Patients withdrawing from the study had a higher number of relapses in the previous 2 years (P=0.04) and a greater probability of relapsing within 12 months. Conclusions: Our results suggest that the combination of atorvastatin and interferon β1b is not justified in early relapsing-remitting multiple sclerosis and adds to the body of evidence indicating an absence of significant radiological and clinical benefit of statins in relapsing-remitting multiple sclerosis. © SAGE Publications.
CORRESPONDENCE ADDRESS: Lanzillo, R.; Department of Neurosciences, Reproductive and Odontostomatological Sciences, Federico II University of Naples, Via Pansini 5, Italy; email: robertalanzillo@libero.it

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Esposito, C.L., Nuzzo, S., Kumar, S.A., Rienzo, A., Lawrence, C.L., Pallini, R., Shaw, L., Alder, J.E., Ricci-Vitiani, L., Catuogno, S., de Franciscis, V.
A combined microRNA-based targeted therapeutic approach to eradicate glioblastoma stem-like cells
(2016) Journal of Controlled Release, 238, pp. 43-57. 
https://www.scopus.com/inward/record.uri?eid=2-s2.0-84979645423&partnerID=40&md5=e6e2a50bdbe5bc664a5fcc89b202676b
DOI: 10.1016/j.jconrel.2016.07.032
AFFILIATIONS: Istituto di Endocrinologia ed Oncologia Sperimentale “G. Salvatore”, CNR, Naples, Italy; 
School of Pharmacy & Biomedical Sciences, University of Central Lancashire, Preston, United Kingdom; 
Institute of Neurosurgery, Università Cattolica del Sacro Cuore, Rome, Italy; 
Istituto Superiore di Sanità, Department of Hematology, Oncology and Molecular Medicine, Rome, Italy
ABSTRACT: A minor population of glioblastoma stem-like cells (GSCs) has been implicated in the relapse and resistance of glioblastoma to therapeutic treatments. Based on knowledge of the involvement of multiple microRNAs in GSC propagation, we designed a combinational approach to target the GSC population with multiple miRNA-based therapeutics. As carriers for the targeted delivery we took advantage of two aptamers that bind to, and inhibit, the receptor tyrosine kinases, Axl and PDGFRβ. We showed that the aptamer conjugates are transported through an in vitro blood-brain barrier (BBB) model. Furthermore, combining miR-137 and antimiR-10b synergizes with the receptor inhibitory function of aptamer carriers and prevents GSC expansion. Results highlighted the potential of combining multifunctional RNA-based therapeutics for selective targeting of GSCs and offer a proof of principle strategy to potentially fulfill the still unmet need for effective and safe treatment of glioma. © 2016
CORRESPONDENCE ADDRESS: de Franciscis, V.; IEOS-CNR, Via T. de Amicis 95, Italy; email: defranci@unina.it

L' NBG ha il patrocinio morale dell'Università di Napoli "Federico II"

In data 2 Agosto 2016 (Rettorato Tit I-14) al Neapolitan Brain Group è stato concesso dal Rettore Manfredi il patrocinio morale dell'Università degli studi di Napoli "Federico II".