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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.

Cirillo G, Colangelo AM, De Luca C, Savarese L, Barillari MR, Alberghina L, Papa M - PLoS ONE (2016)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Neuronal Networks, Department. of Mental and Physical Health and Preventive Medicine, Second University of Naples, 80138 Naples, Italy.

ABSTRACT
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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Expression of spinal glial and neuronal aminoacid transporters.Sections of ventral horn of lumbar spinal cord from SHAM and SNI animals treated for 7 days with ACSF (vehicle), BB14 (0.9 mg/kg b.w.), or GM6001 (100 mg/kg. b.w.) and immunostained for glial glutamate (A–B) or glycine (C–D) transporters, or the neuronal glutamate transporter EAAC1 (E–F). Data are the mean±SEM (**p≤0.001, ACSF vs. SHAM/BB14/GM6001; ANOVA and Holm–Sidak test). Scale bar: 50 μm.
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pone.0152750.g004: Expression of spinal glial and neuronal aminoacid transporters.Sections of ventral horn of lumbar spinal cord from SHAM and SNI animals treated for 7 days with ACSF (vehicle), BB14 (0.9 mg/kg b.w.), or GM6001 (100 mg/kg. b.w.) and immunostained for glial glutamate (A–B) or glycine (C–D) transporters, or the neuronal glutamate transporter EAAC1 (E–F). Data are the mean±SEM (**p≤0.001, ACSF vs. SHAM/BB14/GM6001; ANOVA and Holm–Sidak test). Scale bar: 50 μm.

Mentions: Here, we analyzed the connection between reactive gliosis and the alteration of glial glutamate/glycine transporters in the ventral horn of the lumbar spinal cord. IHC analyses of lamina IX displayed a decrease of GLT1 expression in SNI animals (ACSF group) (0.92±0.03), compared to the SHAM group (1.12±0.07) (Fig 4A and 4B). Reduced GLT1 levels in ACSF-treated animals were paralleled by a similar significant decrease of the glycine transporter (GlyT1) expression (1.81±0.42), compared to the levels measured in the SHAM group (2.82±0.31) (Fig 4C and 4D). Both GLT1 and GlyT1 expression were fully recovered by i.t. administration of GM6001 (1.72±0.21 and 2.63±0.32, respectively) or BB14 (1.54±0.22 and 2.52±0.43, respectively).


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.

Cirillo G, Colangelo AM, De Luca C, Savarese L, Barillari MR, Alberghina L, Papa M - PLoS ONE (2016)

Expression of spinal glial and neuronal aminoacid transporters.Sections of ventral horn of lumbar spinal cord from SHAM and SNI animals treated for 7 days with ACSF (vehicle), BB14 (0.9 mg/kg b.w.), or GM6001 (100 mg/kg. b.w.) and immunostained for glial glutamate (A–B) or glycine (C–D) transporters, or the neuronal glutamate transporter EAAC1 (E–F). Data are the mean±SEM (**p≤0.001, ACSF vs. SHAM/BB14/GM6001; ANOVA and Holm–Sidak test). Scale bar: 50 μm.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4814041&req=5

pone.0152750.g004: Expression of spinal glial and neuronal aminoacid transporters.Sections of ventral horn of lumbar spinal cord from SHAM and SNI animals treated for 7 days with ACSF (vehicle), BB14 (0.9 mg/kg b.w.), or GM6001 (100 mg/kg. b.w.) and immunostained for glial glutamate (A–B) or glycine (C–D) transporters, or the neuronal glutamate transporter EAAC1 (E–F). Data are the mean±SEM (**p≤0.001, ACSF vs. SHAM/BB14/GM6001; ANOVA and Holm–Sidak test). Scale bar: 50 μm.
Mentions: Here, we analyzed the connection between reactive gliosis and the alteration of glial glutamate/glycine transporters in the ventral horn of the lumbar spinal cord. IHC analyses of lamina IX displayed a decrease of GLT1 expression in SNI animals (ACSF group) (0.92±0.03), compared to the SHAM group (1.12±0.07) (Fig 4A and 4B). Reduced GLT1 levels in ACSF-treated animals were paralleled by a similar significant decrease of the glycine transporter (GlyT1) expression (1.81±0.42), compared to the levels measured in the SHAM group (2.82±0.31) (Fig 4C and 4D). Both GLT1 and GlyT1 expression were fully recovered by i.t. administration of GM6001 (1.72±0.21 and 2.63±0.32, respectively) or BB14 (1.54±0.22 and 2.52±0.43, respectively).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Neuronal Networks, Department. of Mental and Physical Health and Preventive Medicine, Second University of Naples, 80138 Naples, Italy.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus