A New Nerve Growth Factor-Mimetic Peptide Active on Neuropathic Pain in Rats

Colangelo, Anna Maria; Bianco, Mimma; Vitagliano, Luigi; Cavaliere, Carlo; Cirillo, Giovanni; Gioia, Luca De; Diana, Donatella; Colombo, Daniele; Redaelli, Cristina; Zaccaro, Laura; Morelli, Giancarlo; Papa, Michèle; Sarmientos, Paolo; Alberghina, Lilia; Martegani, Enzo

doi:10.1523/jneurosci.5201-07.2008

Cited by 108 publications

(93 citation statements)

References 60 publications

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“…Our findings provide evidence that this mouse model exhibits features of inflammatory pathology and that it might be useful for studying the role of inflammatory pathways in CAG triplet diseases. Moreover, Colangelo et al (2008), have reported a novel, crucial role of intrathecal administration of nerve growth factor as a strong modulator of plasticity in the neuronal-glial network by reducing reactive astrocytosis. Therefore, our model might also provide a new approach for testing glial-specific drugs that are designed to reduce CNS inflammatory process in the hope of curing this devastating disease.…”

Section: Discussionmentioning

confidence: 99%

Reactive astrocytosis and glial glutamate transporter clustering are early changes in a spinocerebellar ataxia type 1 transgenic mouse model

Giovannoni

Maggio²,

Bianco³

et al. 2007

Neuron Glia Biol.

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Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disorder caused by an expanded CAG trinucleotide repeats within the coding sequence of the ataxin-1 protein. In the present study, we used a conditional transgenic mouse model of SCA1 to investigate very early molecular and morphological changes related to the behavioral phenotype. In mice with neural deficits detected by rotarod performance, and simultaneous spatial impairments in exploratory activity and uncoordinated gait, we observed both significant altered expression and patchy distribution of excitatory amino acids transporter 1. The molecular changes observed in astroglial compartments correlate with changes in synapse morphology; synapses have a dramatic reduction of the synaptic area external to the postsynaptic density. By contrast, Purkinje cells demonstrate preserved structure. In addition, severe reactive astrocytosis matches changes in the glial glutamate transporter and synapse morphology. We propose these morpho-molecular changes are the cause of altered synaptic transmission, which, in turn, determines the onset of the neurological symptoms by altering the synaptic transmission in the cerebellar cortex of transgenic animals. This model might be suitable for testing drugs that target activated glial cells in order to reduce CNS inflammation.Keywords: EAAT1, synaptic plasticity, SCA1, neurodegeneration INTRODUCTIONThe contribution of non-neuronal cells to the pathogenesis of neurodegenerative diseases has been described although the mechanism remains poorly understood. The role of neuron-glia interactions is also being investigated in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (Sheldon and Robinson, 2007). Moreover, glial dysfunction is likely to contribute to the pathogenesis of cerebellar ataxia in a mouse model of spinocerebellar ataxia type 7 (SCA7) (Custer et al., 2006).Excitatory amino acids transporter 1 (EAAT1, also known as GLAST) is the major glutamate transporter in the cerebellum (Lehre and Danbolt, 1998). It is expressed strongly by astrocytes in the molecular layer of the cerebellum and is at highest density on Bergmann glia. EAAT1 is not detected in neurons (Ginsberg et al., 1995). EAAT1 present on the plasma membrane of the astrocytic processes and cell bodies (Chaudhry et al., 1995). Targeting of EAAT1 is regulated carefully on astroglial membranes facing the neuropil, large dendrites, cell bodies and capillary endothelium (Danbolt, 2001). Therefore, its distribution follows the morphological changes of astrocytes during inflammatory processes. Recently, in a mouse model of reactive astrocytosis in the spinal cord, it has been reported that this glial process includes a marked proteolytic cascade having as substrates glial transporters. Subsequent changes in neurotransmitter uptake represent the basis of morphological and functional changes that sustain central plasticity . Moreover, glial activation involves changes in cell phenotype and gene expression that might trig...

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Section: Discussionmentioning

confidence: 99%

Reactive astrocytosis and glial glutamate transporter clustering are early changes in a spinocerebellar ataxia type 1 transgenic mouse model

Giovannoni

Maggio²,

Bianco³

et al. 2007

Neuron Glia Biol.

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“…The use of these factors has a number of limitations as mentioned earlier. One alternative to the use of large neurotrophic factor is the use of small molecule mimetics [94,96,115,116]. These neurotrophic factor mimetics have the advantages of low immunogenicity, low molecular mass with relatively low manufacturing costs, compared with the use of whole proteins [94].…”

Section: Neurotrophic Factor Mimetics: Future Molecular Therapiesmentioning

confidence: 99%

A biomaterials approach to peripheral nerve regeneration: bridging the peripheral nerve gap and enhancing functional recovery

Daly

Yao

Zeugolis

et al. 2011

J. R. Soc. Interface.

481

508

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Microsurgical techniques for the treatment of large peripheral nerve injuries (such as the gold standard autograft) and its main clinically approved alternative-hollow nerve guidance conduits (NGCs)-have a number of limitations that need to be addressed. NGCs, in particular, are limited to treating a relatively short nerve gap (4 cm in length) and are often associated with poor functional recovery. Recent advances in biomaterials and tissue engineering approaches are seeking to overcome the limitations associated with these treatment methods. This review critically discusses the advances in biomaterial-based NGCs, their limitations and where future improvements may be required. Recent developments include the incorporation of topographical guidance features and/or intraluminal structures, which attempt to guide Schwann cell (SC) migration and axonal regrowth towards their distal targets. The use of such strategies requires consideration of the size and distribution of these topographical features, as well as a suitable surface for cell-material interactions. Likewise, cellular and molecular-based therapies are being considered for the creation of a more conductive nerve microenvironment. For example, hurdles associated with the short half-lives and low stability of molecular therapies are being surmounted through the use of controlled delivery systems. Similarly, cells (SCs, stem cells and genetically modified cells) are being delivered with biomaterial matrices in attempts to control their dispersion and to facilitate their incorporation within the host regeneration process. Despite recent advances in peripheral nerve repair, there are a number of key factors that need to be considered in order for these new technologies to reach the clinic.

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“…As such, therapeutics targeting astrocyte activation, like a recently developed TrkA agonist, has shown promise by reducing reactive gliosis and subsequent neural sequelae of neuroinflammation [71] . Additionally, in vitro studies have shown that reactive astrogliosis can be suppressed by up-regulation of mitofusin 2 (Mfn2), a key protein in mitochondrial networks [72] .…”

Section: Immunological Molecules Effects Conditionsmentioning

confidence: 99%

New advances on glial activation in health and disease

Lee

MacLean

2015

WJV

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In addition to being the support cells of the central nervous system (CNS), astrocytes are now recognized as active players in the regulation of synaptic function, neural repair, and CNS immunity. Astrocytes are among the most structurally complex cells in the brain, and activation of these cells has been shown in a wide spectrum of CNS injuries and diseases. Over the past decade, research has begun to elucidate the role of astrocyte activation and changes in astrocyte morphology in the progression of neural pathologies, which has led to glial-specific interventions for drug development. Future therapies for CNS infection, injury, and neurodegenerative disease are now aimed at targeting astrocyte responses to such insults including astrocyte activation, astrogliosis and other morphological changes, and innate and adaptive immune responses.

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A New Nerve Growth Factor-Mimetic Peptide Active on Neuropathic Pain in Rats

Cited by 108 publications

References 60 publications

Reactive astrocytosis and glial glutamate transporter clustering are early changes in a spinocerebellar ataxia type 1 transgenic mouse model

Reactive astrocytosis and glial glutamate transporter clustering are early changes in a spinocerebellar ataxia type 1 transgenic mouse model

A biomaterials approach to peripheral nerve regeneration: bridging the peripheral nerve gap and enhancing functional recovery

New advances on glial activation in health and disease

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