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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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Evaluation of glial markers in the ventral horn of spinal cord.Sections (A and C) and densitometric quantitation (B and D) of ventral horn of lumbar spinal cords from SHAM and SNI-operated animals treated for 7 days with BB14 (0.9 mg/kg b.w.), GM6001 (100 mg/kg. b.w.) or ACSF (vehicle) and immunostained for GFAP (A–B) or Iba1 (C–D). 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.g002: Evaluation of glial markers in the ventral horn of spinal cord.Sections (A and C) and densitometric quantitation (B and D) of ventral horn of lumbar spinal cords from SHAM and SNI-operated animals treated for 7 days with BB14 (0.9 mg/kg b.w.), GM6001 (100 mg/kg. b.w.) or ACSF (vehicle) and immunostained for GFAP (A–B) or Iba1 (C–D). Data are the mean±SEM (**p≤0.001, ACSF vs. SHAM/BB14/GM6001; ANOVA and Holm–Sidak test). Scale bar: 50 μm.

Mentions: Analysis of glial markers in the lamina IX of the lumbar spinal cord following SNI revealed a sharp increase of GFAP (3.22±0.53) (Figs 1 and 2A and 2B) and Iba1 expression (3.32±0.41) (Figs 1 and 2C and 2D) in the SNI/ACSF-treated animals, as compared to the SHAM group (1.54±0.12 and 1.10±0.05 for GFAP and Iba1, 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)

Evaluation of glial markers in the ventral horn of spinal cord.Sections (A and C) and densitometric quantitation (B and D) of ventral horn of lumbar spinal cords from SHAM and SNI-operated animals treated for 7 days with BB14 (0.9 mg/kg b.w.), GM6001 (100 mg/kg. b.w.) or ACSF (vehicle) and immunostained for GFAP (A–B) or Iba1 (C–D). 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.g002: Evaluation of glial markers in the ventral horn of spinal cord.Sections (A and C) and densitometric quantitation (B and D) of ventral horn of lumbar spinal cords from SHAM and SNI-operated animals treated for 7 days with BB14 (0.9 mg/kg b.w.), GM6001 (100 mg/kg. b.w.) or ACSF (vehicle) and immunostained for GFAP (A–B) or Iba1 (C–D). Data are the mean±SEM (**p≤0.001, ACSF vs. SHAM/BB14/GM6001; ANOVA and Holm–Sidak test). Scale bar: 50 μm.
Mentions: Analysis of glial markers in the lamina IX of the lumbar spinal cord following SNI revealed a sharp increase of GFAP (3.22±0.53) (Figs 1 and 2A and 2B) and Iba1 expression (3.32±0.41) (Figs 1 and 2C and 2D) in the SNI/ACSF-treated animals, as compared to the SHAM group (1.54±0.12 and 1.10±0.05 for GFAP and Iba1, 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