ABSTRACT
Permanent damage to white matter tracts, comprising axons and myelinating oligodendrocytes, is an important component of brain injuries of the newborn that cause cerebral palsy and cognitive disabilities, as well as multiple sclerosis in adults. However, regulatory factors relevant in human developmental myelin disorders and in myelin regeneration are unclear. We found that AXIN2 was expressed in immature oligodendrocyte progenitor cells (OLPs) in white matter lesions of human newborns with neonatal hypoxic-ischemic and gliotic brain damage, as well as in active multiple sclerosis lesions in adults. Axin2 is a target of Wnt transcriptional activation that negatively feeds back on the pathway, promoting ß-catenin degradation. We found that Axin2 function was essential for normal kinetics of remyelination. The small molecule inhibitor XAV939, which targets the enzymatic activity of tankyrase, acted to stabilize Axin2 levels in OLPs from brain and spinal cord and accelerated their differentiation and myelination after hypoxic and demyelinating injury. Together, these findings indicate that Axin2 is an essential regulator of remyelination and that it might serve as a pharmacological checkpoint in this process.
Subject(s)
Brain Injuries/metabolism , Brain Injuries/therapy , Cytoskeletal Proteins/metabolism , Gene Expression Regulation/physiology , Myelin Proteins/metabolism , Adult , Animals , Animals, Newborn , Axin Protein , Basic Helix-Loop-Helix Transcription Factors/genetics , Brain Injuries/etiology , Cell Differentiation/drug effects , Cell Differentiation/physiology , Cells, Cultured , Cerebellum/drug effects , Cerebellum/metabolism , Cerebellum/ultrastructure , Cerebral Cortex/cytology , Corpus Callosum/drug effects , Corpus Callosum/metabolism , Cytoskeletal Proteins/deficiency , Demyelinating Diseases/chemically induced , Demyelinating Diseases/pathology , Disease Models, Animal , Dose-Response Relationship, Drug , Female , Gene Expression Regulation/genetics , Heterocyclic Compounds, 3-Ring/pharmacology , Heterocyclic Compounds, 3-Ring/therapeutic use , Humans , Hypoxia-Ischemia, Brain/metabolism , Hypoxia-Ischemia, Brain/pathology , Hypoxia-Ischemia, Brain/therapy , Infant, Newborn , Ki-67 Antigen/metabolism , Lysophosphatidylcholines/toxicity , Male , Mice , Mice, Transgenic , Microscopy, Electron, Transmission , Multiple Sclerosis/complications , Multiple Sclerosis/pathology , Multiple Sclerosis/therapy , Myelin Proteins/genetics , Myelin Proteins/therapeutic use , Myelin Sheath/drug effects , Myelin Sheath/pathology , Myelin Sheath/ultrastructure , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Neurons/drug effects , Oligodendrocyte Transcription Factor 2 , Oligodendroglia/drug effects , Oligodendroglia/physiology , Organ Culture TechniquesABSTRACT
Remyelination following central nervous system (CNS) demyelination restores rapid saltatory conduction of action potentials and contributes to the maintenance of axonal integrity. This robust regenerative phenomenon stands in contrast to the limited repair capacity that is characteristic of CNS neuronal injury. However, despite its efficiency in experimental models and some clinical diseases, remyelination failure becomes an increasingly pronounced feature of the pathology of chronic multiple sclerosis (MS) lesions. Chronic demyelination predisposes axons to atrophy, an irreversible event that is a major pathological correlate of progressive functional decline. This has created a compelling case for developing therapies that promote remyelination: evidence from experimental animal models suggests that hormones may have a beneficial role to play in this regard.
Subject(s)
Central Nervous System/physiology , Hormones/therapeutic use , Multiple Sclerosis/physiopathology , Myelin Sheath/physiology , Regeneration/physiology , Adult Stem Cells/cytology , Adult Stem Cells/physiology , Animals , Central Nervous System/cytology , Humans , Multiple Sclerosis/drug therapy , Oligodendroglia/cytology , Oligodendroglia/physiologyABSTRACT
Although the treatment of multiple sclerosis has made significant strides in the last decade, the therapeutic enhancement of repair has yet to make the successful translation from laboratory to clinic. Nevertheless, advances in the biology of stem and precursor cells, particularly in relation to myelin damage, make this a realistic proposition during the next decade. Replacing lost myelin (remyelination) is currently thought to be an important clinical objective because of the role it might play in slowing or preventing axonal degeneration. Stem/precursor cell-based strategies for enhancing remyelination can be divided into those in which cells are transplanted into a patient (exogenous or cell therapies) and those in which the patient's own stem/precursor cells are mobilised to more efficiently engage in healing areas of demyelination (endogenous or pharmacological therapies). While the two approaches tend to be regarded separately they are not mutually exclusive. This article focuses on the endogenous approach and reviews the nature and nomenclature of the stem and precursor cells present within the adult CNS that engage in remyelination and that are therefore potential targets for pharmacological manipulation.
Subject(s)
Adult Stem Cells/physiology , Cell Differentiation/physiology , Multiple Sclerosis/physiopathology , Nerve Regeneration/physiology , Animals , Cell Proliferation , Humans , Myelin Basic Protein/metabolismABSTRACT
Although amphetamine-derived stimulants are widely associated with neurotoxicity, it is poorly understood whether extended exposure to such drugs produces lasting effects on neurocognitive function. This study investigates whether chronically self-administered d-amphetamine, methamphetamine (MA), or methylenedioxymethamphetamine (MDMA) leads to residual deficits in a rodent test of sustained visual attention and impulsivity. Rats were trained on a five-choice serial reaction time task and subsequently trained to self-administer d-amphetamine, MA, or MDMA (all 50 microg/infusion), intravenously, for 3 weeks. Effects on performance were evaluated 24 h after drug discontinuation and for several weeks thereafter, including various challenge sessions to increase the attentional demands of the task. The results indicate divergent patterns of self-administration among the three drugs tested with increasing rates of intake evident in rats self-administering amphetamine, but not MA, and widely fluctuating rates in the MDMA group. Withdrawal of MA resulted in severe behavioral disturbances, with significant effects on accuracy, omissions, response latency, and impulsivity that lasted up to 2 weeks in some cases. Amphetamine and MDMA withdrawal were associated with similar, but shorter-lasting effects on performance. However, when challenged with a high event rate session 6 weeks after drug discontinuation, rats previously exposed to MDMA continued to show deficits in the accuracy and speed of responding. These findings show that amphetamine-derived stimulants have both short- and long-term consequences for psychomotor functioning. The demonstration of residual deficits in rats chronically exposed to MDMA raises some concern about the potential harm caused by this drug in human ecstasy users.