ABSTRACT
Fragile X syndrome (FXS) is the leading genetic cause of autism. Mutations in Fmr1 (fragile X mental retardation 1 gene) engender exaggerated translation resulting in dendritic spine dysmorphogenesis, synaptic plasticity alterations, and behavioral deficits in mice, which are reminiscent of FXS phenotypes. Using postmortem brains from FXS patients and Fmr1 knockout mice (Fmr1(-/y)), we show that phosphorylation of the mRNA 5' cap binding protein, eukaryotic initiation factor 4E (eIF4E), is elevated concomitant with increased expression of matrix metalloproteinase 9 (MMP-9) protein. Genetic or pharmacological reduction of eIF4E phosphorylation rescued core behavioral deficits, synaptic plasticity alterations, and dendritic spine morphology defects via reducing exaggerated translation of Mmp9 mRNA in Fmr1(-/y) mice, whereas MMP-9 overexpression produced several FXS-like phenotypes. These results uncover a mechanism of regulation of synaptic function by translational control of Mmp-9 in FXS, which opens the possibility of new treatment avenues for the diverse neurological and psychiatric aspects of FXS.
Subject(s)
Benzofurans/pharmacology , Eukaryotic Initiation Factor-4E/physiology , Fragile X Syndrome/drug therapy , Matrix Metalloproteinase 9/genetics , Protein Biosynthesis/drug effects , Adenosine Triphosphatases/antagonists & inhibitors , Animals , Autistic Disorder/enzymology , Benzofurans/therapeutic use , Brain/enzymology , Cation Transport Proteins/antagonists & inhibitors , Cells, Cultured , Copper-Transporting ATPases , Dendritic Spines/pathology , Enzyme Induction/drug effects , Female , Fragile X Syndrome/enzymology , Fragile X Syndrome/genetics , Humans , Male , Matrix Metalloproteinase 9/metabolism , Mice, Inbred C57BL , Mice, Transgenic , Phenotype , Phosphorylation , Protein Processing, Post-Translational , Receptors, Metabotropic Glutamate/genetics , Receptors, Metabotropic Glutamate/metabolismABSTRACT
The enantiomeric naphthoquinones alkannins and shikonins (A/S) have been established as potent wound healing agents. The purpose of this study was to evaluate the effectiveness of an A/S based ointment for humans on second intention wound healing in the dog, as compared to wound flushing with Lactated Ringer's solution (LRS). Ten mixed breed dogs, aged 2 to 5 y, were used. One 2.5 × 2.5 cm full-thickness skin defect was created on the lateral aspect of each arm for subjective evaluation, laser-Doppler flowmetry (LDF), and planimetry. Additionally, 3 matching 2 × 2 cm wounds were created on opposite sides of the dorsal midline for histologic evaluation. Wounds were treated once daily with the A/S based ointment on the right side and by flushing with LRS on the left until healed (about 20 d). During the healing process, tissue perfusion (mean LDF value) was found to be significantly higher on the side treated with the A/S based ointment compared with the LRS-treated side. Histologically, angiogenesis (on days 4 and 11), collagen production score (on days 4, 11, and 20), and epithelial thickness score (on day 11) were significantly higher in the wounds treated with the A/S based ointment. Wound size, as evaluated by planimetry, decreased significantly from day 0 to day 20 on both sides, but no significant differences were found between the A/S based ointment and LRS-treated wounds.
