Side Effects of Minocycline Treatment in Patients With Fragile X Syndrome and Exploration of Outcome Measures

M.I.N.D. Institute, University of California at Davis Medical Center, USA.
American Journal on Intellectual and Developmental Disabilities (Impact Factor: 2.08). 09/2010; 115(5):433-43. DOI: 10.1352/1944-7558-115.5.433
Source: PubMed


Minocycline can rescue the dendritic spine and synaptic structural abnormalities in the fragile X knock-out mouse. This is a review and preliminary survey to document side effects and potential outcome measures for minocycline use in the treatment of individuals with fragile X syndrome. We surveyed 50 patients with fragile X syndrome who received minocycline for at least 2 weeks and found that the most common reported side effect is gastrointestinal difficulty, including loss of appetite. The families reported an improvement in language and behavioral areas. Outcome measures in the design of future randomized clinical trials should include both behavioral and language measures. As with any other treatments, we emphasize that randomized clinical trials are needed to determine the efficacy of minocycline in fragile X syndrome.

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Available from: Andrea Schneider, Oct 14, 2015
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    • "analysis of postmortem FXS brain tissue samples also indicate elevated levels of MMP - 9 protein in both the hippocampus and neocortex ( Gkogkas et al . , 2014 ; Sidhu et al . , 2014 ) . Minocycline treatment reduces plasma levels of MMP - 9 in most but not all subjects , and is associated with improvements in behavior ( Paribello et al . , 2010 ; Utari et al . , 2010 ; Dziembowska et al . , 2013 ; Leigh et al . , 2013 ) and a reversal of habituation deficits in auditory event related potentials ( Schneider et al . , 2013 ) . This suggests that MMP - 9 suppression may be a useful therapeutic approach . Together these studies indicate that increased MMP - 9 levels in FXS may underlie molecular , cellu"
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    ABSTRACT: The extracellular matrix (ECM) is a critical regulator of neural network development and plasticity. As neuronal circuits develop, the ECM stabilizes synaptic contacts, while its cleavage has both permissive and active roles in the regulation of plasticity. Matrix metalloproteinase 9 (MMP-9) is a member of a large family of zinc-dependent endopeptidases that can cleave ECM and several cell surface receptors allowing for synaptic and circuit level reorganization. It is becoming increasingly clear that the regulated activity of MMP-9 is critical for central nervous system (CNS) development. In particular, MMP-9 has a role in the development of sensory circuits during early postnatal periods, called 'critical periods.' MMP-9 can regulate sensory-mediated, local circuit reorganization through its ability to control synaptogenesis, axonal pathfinding and myelination. Although activity-dependent activation of MMP-9 at specific synapses plays an important role in multiple plasticity mechanisms throughout the CNS, misregulated activation of the enzyme is implicated in a number of neurodegenerative disorders, including traumatic brain injury, multiple sclerosis, and Alzheimer's disease. Growing evidence also suggests a role for MMP-9 in the pathophysiology of neurodevelopmental disorders including Fragile X Syndrome. This review outlines the various actions of MMP-9 during postnatal brain development, critical for future studies exploring novel therapeutic strategies for neurodevelopmental disorders.
    Frontiers in Cellular Neuroscience 07/2015; 9:280. DOI:10.3389/fncel.2015.00280 · 4.29 Impact Factor
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    • "High MMP-9 activity levels are also lowered by minocycline in fragile X syndrome patients (Dziembowska et al., 2013). Notably, minocycline has been tested in clinical trials to treat fragile X syndrome and shown to provide significant functional benefits (Paribello et al., 2010; Utari et al., 2010; Leigh et al., 2013). Matrix metalloproteinases have also been implicated in other forms of autism (Abdallah and Miche1, 2013). "
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    ABSTRACT: Dendritic spines are the locus for excitatory synaptic transmission in the brain and thus play a major role in neuronal plasticity. The ability to alter synaptic connections includes volumetric changes in dendritic spines that are driven by scaffolds created by the extracellular matrix (ECM). Here, we review the effects of the proteolytic activity of ECM proteases in physiological and pathological structural plasticity. We use matrix metalloproteinase-9 (MMP-9) as an example of an ECM modifier that has recently emerged as a key molecule in regulating the morphology and dysmorphology of dendritic spines that underlie synaptic plasticity and neurological disorders, respectively. We summarize the influence of MMP-9 on the dynamic remodeling of the ECM via the cleavage of extracellular substrates. We discuss its role in the formation, modification, and maintenance of dendritic spines in learning and memory. Finally, we review research that implicates MMP-9 in aberrant synaptic plasticity and spine dysmorphology in neurological disorders, with a focus on morphological abnormalities of dendritic protrusions that are associated with epilepsy.
    Frontiers in Neuroanatomy 07/2014; 8:68. DOI:10.3389/fnana.2014.00068 · 3.54 Impact Factor
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    • "Following the results of studies that showed treatment with mGluR5 antagonists, including mavoglurant, could rescue several synaptic phenotypes in animal models (Choi et al. 2010; de Vrij et al. 2008; Levenga et al. 2011; McBride et al. 2005; Tucker et al. 2006; Yan et al. 2005), it was hypothesized that mavoglurant had the potential to treat the underlying pathophysiology of FXS, thus differing from current pharmacotherapy for FXS which is symptom-driven. Other agents targeting specific molecular pathways are in development for FXS (Table 3); these include RG7090 (RO4917523), another mGluR5 antagonist; STX209 (arbaclofen, R-baclofen), a γ-aminobutyric acid type B (GABA B ) receptor agonist (Berry-Kravis et al. 2012); and minocycline, a matrix metalloproteinase-9 antagonist (Bilousova et al. 2009; Leigh et al. 2013; Paribello et al. 2010; Utari et al. 2010). All of these agents aim to address the underlying pathology of FXS by targeting specific molecular pathways. "
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    ABSTRACT: Advances in understanding the underlying mechanisms of conditions such as fragile X syndrome (FXS) and autism spectrum disorders have revealed heterogeneous populations. Recent trials of novel FXS therapies have highlighted several challenges including subpopulations with possibly differential therapeutic responses, the lack of specific outcome measures capturing the full range of improvements of patients with FXS, and a lack of biomarkers that can track whether a specific mechanism is responsive to a new drug and whether the response correlates with clinical improvement. We review the phenotypic heterogeneity of FXS and the implications for clinical research in FXS and other neurodevelopmental disorders. Residual levels of fragile X mental retardation protein (FMRP) expression explain in part the heterogeneity in the FXS phenotype; studies indicate a correlation with both cognitive and behavioral deficits. However, this does not fully explain the extent of phenotypic variance observed or the variability of drug response. Post hoc analyses of studies involving the selective mGluR5 antagonist mavoglurant and the GABAB agonist arbaclofen have uncovered significant therapeutic responses following patient stratification according to FMR1 promoter methylation patterns or baseline severity of social withdrawal, respectively. Future studies designed to quantify disease modification will need to develop new strategies to track changes effectively over time and in multiple symptom domains. Appropriate selection of patients and outcome measures is central to optimizing future clinical investigations of these complex disorders.
    Psychopharmacology 10/2013; 231(6). DOI:10.1007/s00213-013-3289-0 · 3.88 Impact Factor
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