ABSTRACT
Fragile X syndrome (FXS), a disorder of synaptic development and function, is the most prevalent genetic form of intellectual disability and autism spectrum disorder. FXS mouse models display clinically-relevant phenotypes, such as increased anxiety and hyperactivity. Despite their availability, so far advances in drug development have not yielded new treatments. Therefore, testing novel drugs that can ameliorate FXS' cognitive and behavioral impairments is imperative. ANAVEX2-73 (blarcamesine) is a sigma-1 receptor (S1R) agonist with a strong safety record and preliminary efficacy evidence in patients with Alzheimer's disease and Rett syndrome, other synaptic neurodegenerative and neurodevelopmental disorders. S1R's role in calcium homeostasis and mitochondrial function, cellular functions related to synaptic function, makes blarcamesine a potential drug candidate for FXS. Administration of blarcamesine in 2-month-old FXS and wild type mice for 2 weeks led to normalization in two key neurobehavioral phenotypes: open field test (hyperactivity) and contextual fear conditioning (associative learning). Furthermore, there was improvement in marble-burying (anxiety, perseverative behavior). It also restored levels of BDNF, a converging point of many synaptic regulators, in the hippocampus. Positron emission tomography (PET) and ex vivo autoradiographic studies, using the highly selective S1R PET ligand [18F]FTC-146, demonstrated the drug's dose-dependent receptor occupancy. Subsequent analyses also showed a wide but variable brain regional distribution of S1Rs, which was preserved in FXS mice. Altogether, these neurobehavioral, biochemical, and imaging data demonstrates doses that yield measurable receptor occupancy are effective for improving the synaptic and behavioral phenotype in FXS mice. The present findings support the viability of S1R as a therapeutic target in FXS, and the clinical potential of blarcamesine in FXS and other neurodevelopmental disorders.
Subject(s)
Fragile X Syndrome/drug therapy , Furans/therapeutic use , Neuroprotective Agents/therapeutic use , Receptors, sigma/agonists , Animals , Brain-Derived Neurotrophic Factor/metabolism , Fragile X Mental Retardation Protein/genetics , Fragile X Syndrome/genetics , Furans/pharmacokinetics , Furans/pharmacology , Hippocampus/drug effects , Hippocampus/metabolism , Hippocampus/physiopathology , Male , Maze Learning , Mice , Mice, Inbred C57BL , Neuroprotective Agents/pharmacokinetics , Neuroprotective Agents/pharmacology , Phenotype , Protein Binding , Receptors, sigma/metabolism , Sigma-1 ReceptorABSTRACT
Alzheimer's disease (AD) is the most common cause of dementia, affecting more than 36 million people worldwide. Octodon degus, a South American rodent, has been found to spontaneously develop neuropathological signs of AD, including amyloid-ß (Aß) and tau deposits, as well as a decline in cognition with age. Firstly, the present work introduces a novel behavioral assessment for O. degus - the burrowing test - which appears to be a useful tool for detecting neurodegeneration in the O. degus model for AD. Such characterization has potentially wide-ranging implications, because many of these changes in species-typical behaviors are reminiscent of the impairments in activities of daily living (ADL), so characteristic of human AD. Furthermore, the present work characterizes the AD-like neuropathology in O. degus from a gene expression point of view, revealing a number of previously unreported AD biomarkers, which are found in human AD: amyloid precursor protein (APP), apolipoprotein E (ApoE), oxidative stress-related genes from the NFE2L2 and PPAR pathway, as well as pro-inflammatory cytokines and complement proteins, in agreement with the known link between neurodegeneration and neuroinflammation. In summary, the present results confirm a natural neuropathology in O. degus with similar characteristics to AD at behavioral, cellular and molecular levels. These characteristics put O. degus in a singular position as a natural rodent model for research into AD pathogenesis and therapeutics against AD.
Subject(s)
Alzheimer Disease/pathology , Alzheimer Disease/physiopathology , Behavior, Animal , Brain/metabolism , Brain/pathology , Motor Activity/physiology , Animals , Disease Models, Animal , Female , Gene Expression , Male , OctodonABSTRACT
Fragile X syndrome (FXS) is the most common form of inherited intellectual disability. Previous studies have implicated mGlu5 in the pathogenesis of the disease, and many agents that target the underlying pathophysiology of FXS have focused on mGluR5 modulation. In the present work, a novel pharmacological approach for FXS is investigated. NNZ-2566, a synthetic analog of a naturally occurring neurotrophic peptide derived from insulin-like growth factor-1 (IGF-1), was administered to fmr1 knockout mice correcting learning and memory deficits, abnormal hyperactivity and social interaction, normalizing aberrant dendritic spine density, overactive ERK and Akt signaling, and macroorchidism. Altogether, our results indicate a unique disease-modifying potential for NNZ-2566 in FXS. Most importantly, the present data implicate the IGF-1 molecular pathway in the pathogenesis of FXS. A clinical trial is under way to ascertain whether these findings translate into clinical effects in FXS patients.
