ABSTRACT
Axonal injury is considered the major cause of disability in patients with multiple sclerosis (MS), but the underlying effector mechanisms are poorly understood. Starting with a proteomics-based approach, we identified neurofascin-specific autoantibodies in patients with MS. These autoantibodies recognize the native form of the extracellular domains of both neurofascin 186 (NF186), a neuronal protein concentrated in myelinated fibers at nodes of Ranvier, and NF155, the oligodendrocyte-specific isoform of neurofascin. Our in vitro studies with hippocampal slice cultures indicate that neurofascin antibodies inhibit axonal conduction in a complement-dependent manner. To evaluate whether circulating antineurofascin antibodies mediate a pathogenic effect in vivo, we cotransferred these antibodies with myelin oligodendrocyte glycoprotein-specific encephalitogenic T cells to mimic the inflammatory pathology of MS and breach the blood-brain barrier. In this animal model, antibodies to neurofascin selectively targeted nodes of Ranvier, resulting in deposition of complement, axonal injury, and disease exacerbation. Collectively, these results identify a novel mechanism of immune-mediated axonal injury that can contribute to axonal pathology in MS.
Subject(s)
Autoantibodies/immunology , Axons/immunology , Axons/pathology , Cell Adhesion Molecules/immunology , Nerve Growth Factors/immunology , Animals , Autoantigens/immunology , Central Nervous System/immunology , Central Nervous System/metabolism , Central Nervous System/pathology , Disease Models, Animal , Electrophysiology , Encephalomyelitis, Autoimmune, Experimental/immunology , Encephalomyelitis, Autoimmune, Experimental/pathology , HeLa Cells , Humans , Multiple Sclerosis/immunology , Multiple Sclerosis/pathology , Myelin Sheath/metabolism , RatsABSTRACT
A case of Bell's palsy after acupuncture is presented. It concerns a healthy 47 year old man who developed Bell's palsy less than 24 hours after local acupuncture treatment for temporomandibular dysfunction. The Bell's palsy recovered within two weeks, and may have been caused by a haematoma around the facial nerve.
Subject(s)
Acupuncture Therapy/adverse effects , Bell Palsy/etiology , Acupuncture Therapy/methods , Facial Paralysis/etiology , Humans , Male , Middle Aged , Temporomandibular Joint Disorders/therapy , Treatment OutcomeABSTRACT
BACKGROUND: Whole cell patch clamp recording and intracellular Ca2+ imaging were carried out on rat cultured dorsal root ganglion (DRG) neurones to characterize the actions of crude extracts and purified samples from Red Sea soft corals. The aim of the project was to identify compounds that would alter the excitability of DRG neurones. RESULTS: Crude extracts of Sarcophyton glaucum and Lobophyton crassum attenuated spike frequency adaptation causing DRG neurones to switch from firing single action potentials to multiple firing. The increase in excitability was associated with enhanced KCl-evoked Ca2+ influx. The mechanism of action of the natural products in the samples from the soft corals involved inhibition of voltage-activated K+ currents. An active component of the crude marine samples was identified as 3-carboxy-1-methyl pyridinium (trigonelline). Application of synthetic 3-carboxy-1-methyl pyridinium at high concentration (0.1 mM) also induced multiple firing and reduced voltage-activated K+ current. The changes in excitability of DRG neurones induced by 3-carboxy-1-methyl pyridinium suggest that this compound contributes to the bioactivity produced by the crude extracts from two soft corals. CONCLUSION: Sarcophyton glaucum and Lobophyton crassum contain natural products including 3-carboxy-1-methyl pyridinium that increase the excitability of DRG neurones. We speculate that in addition to developmental control and osmoregulation these compounds may contribute to chemical defenses.