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.
Highlights
Matrix metalloproteinases (MMPs) are a family of enzymes essential for the plastic response of the extracellular matrix (ECM) in the central nervous system (CNS) [1]
Analysis of glial markers in the lamina IX of the lumbar spinal cord following spared nerve injury (SNI) revealed a sharp increase of Glial Fibrillary Acidic Protein (GFAP) (3.22±0.53) (Figs 1 and 2A and 2B) and ionized calcium binding adaptor molecule 1 (Iba1) expression (3.32±0.41) (Figs 1 and 2C and 2D) in the SNI/artificial CSF (ACSF)-treated animals, as compared to the shamoperated control group (SHAM) group (1.54±0.12 and 1.10±0.05 for GFAP and Iba1, respectively)
Analysis of endogenous nerve growth factor (NGF) levels revealed that NGF expression was significantly decreased in the ventral horn of ACSF-treated animals (1.25±0.22), compared to the SHAM rats (1.60±0.43) (Fig 3) and i.t. administration of GM6001 fully restored the neurotrophin density (1.73±0.13)
Summary
Matrix metalloproteinases (MMPs) are a family of enzymes essential for the plastic response of the extracellular matrix (ECM) in the central nervous system (CNS) [1]. Through the formation of mature ECM perineuronal nets (PNNs), ECM ensures the synaptogenesis and synaptic maturation, reshaping of neuronal connections [3] and angiogenesis, and vascular integrity [4]. This system, has strong connections with cytokines and neurotrophins, such as nerve growth factor (NGF) [5]. In experimental models of peripheral nerve and spinal cord injury or neurodegenerative disorders, modulation of MMPs activity, through administration of specific MMPs inhibitors, was found to restore neuronal plasticity [8,9] and boost functional recovery [10]
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