Modulation of matrix metalloproteinases activity in the ventral horn of the spinal cord re-stores neuroglial synaptic homeostasis and neurotrophic support following peripheral nerve injury.
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Modulation of extracellular matrix (ECM) remodeling after peripheral nerve injury (PNI) could represent a valid therapeutic strategy to prevent maladaptive synaptic plasticity in central nervous system (CNS). Inhibition of matrix metalloproteinases (MMPs) and maintaining a neurotrophic support could represent two approaches to prevent or reduce the maladaptive plastic changes in the ventral horn of spinal cord following PNI. The purpose of our study was to analyze changes in the ventral horn produced by gliopathy determined by the suffering of motor neurons following spared nerve injury (SNI) of the sciatic nerve and how the intrathecal (i.t.) administration of GM6001 (a MMPs inhibitor) or the NGF mimetic peptide BB14 modulate these events. Immunohistochemical analysis of spinal cord sections revealed that motor neuron disease following SNI was associated with increased microglial (Iba1) and astrocytic (GFAP) response in the ventral horn of the spinal cord, indicative of reactive gliosis. These changes were paralleled by decreased glial aminoacid transporters (glutamate GLT1 and glycine GlyT1), increased levels of the neuronal glutamate transporter EAAC1, and a net increase of the Glutamate/GABA ratio, as measured by HPLC analysis. These molecular changes correlated to a significant reduction of mature NGF levels in the ventral horn. Continuous i.t. infusion of both GM6001 and BB14 reduced reactive astrogliosis, recovered the expression of neuronal and glial transporters, lowering the Glutamate/GABA ratio. Inhibition of MMPs by GM6001 significantly increased mature NGF levels, but it was absolutely ineffective in modifying the reactivity of microglia cells. Therefore, MMPs inhibition, although supplies neurotrophic support to ECM components and restores neuro-glial transporters expression, differently modulates astrocytic and microglial response after PNI.
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Co-treatment with MMP-9 inhibitors and NGF peptide following peripheral nerve injury can restore synaptic homeostasis, i.e., normalize glutamate/GABA ratio and expression of glial amino acid transporters.
“recent work in peripheral nerve injury models indicates that co-treatment with MMP-9 inhibitors and NGF peptide following insult can restore synaptic homeostasis, i.e., normalize glutamate/GABA ratio and expression of glial amino acid transporters (De Luca et al., 2016; Cirillo et al., 2016).”
From The Perineuronal ‘Safety’ Net? Perineuronal Net Abnormalities in Neurological Disorders (2018) · cites this paper as Cirillo et al., 2016
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- Authors
- Cirillo, G., Colangelo, A. M., De Luca, C., Savarese, L., Barillari, M. R., Alberghina, L., & Papa, M.
- Affiliations
- University of Campania "Luigi Vanvitelli" (IT)
- University of Milano-Bicocca (IT)
- Corresponding author
- Cirillo, Giovanni
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2016-03-30
- Volume
- 11
- Issue
- 3
- Pages
- e0152750
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC4814041
- OpenAlex
- W2322217390
- Cited by
- 27
- References
- 40
- Citations by year
- 2024: 3 · 2023: 3 · 2022: 3 · 2021: 2 · 2020: 4 · 2019: 1 · 2018: 4 · 2017: 5 · 2016: 2
- FWCI
- 3.22
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- BOA (University of Milano-Bicocca) (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Archivio Istituzionale della Ricerca - Università degli Studi della Campania "Luigi Vanvitelli" (submittedVersion, cc-by)
- Funders
- Ministero dell’Istruzione, dell’Università e della Ricerca (PRIN2007)
- Regione Campania (L.R. N.5 Bando 2003)
- Topics
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
- Health Sciences › Medicine › Pathology and Forensic Medicine › Spinal Cord Injury Research
- Keywords
- matrix metalloproteinases, peripheral nerve injury, ventral horn, spinal cord, spared nerve injury, GM6001, reactive astrogliosis, microglial activation, glutamate/GABA ratio, glutamate transporters, glycine transporter, neurotrophic support, extracellular matrix remodeling, synaptic homeostasis, motor neurons
- MeSH terms
- Animals, Anterior Horn Cells, Astrocytes, Dipeptides, gamma-Aminobutyric Acid, Male, Sciatic Nerve, Spinal Cord, Synapses, Rats, Sprague-Dawley, Microglia, Gelatinases, Glutamic Acid, Glycine Plasma Membrane Transport Proteins, Glutamate Plasma Membrane Transport Proteins, Rats, Peripheral Nerve Injuries
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