Patricia Inacio, PhD, science writer —

Patricia holds her PhD in cell biology from the University Nova de Lisboa, Portugal, and has served as an author on several research projects and fellowships, as well as major grant applications for European agencies. She also served as a PhD student research assistant in the Department of Microbiology & Immunology, Columbia University, New York, for which she was awarded a Luso-American Development Foundation (FLAD) fellowship.

Articles by Patricia Inacio

2 Potassium Channels Key to Fast Transmission of Impulses Along Myelin-rich Nerve Fibers, Study Shows

Two potassium ion channels located at gaps between segments of myelin are required for high frequency and high-speed conduction of electrical impulses along myelin-rich nerves, a study shows. Loss of the workings of these potassium channels in what are called the nodes of Ranvier slowed nerve conduction, and impaired the sensory response of a rat. These findings suggest that similar problems with these channels may exist in people with multiple sclerosis (MS). The study “TREK-1 and TRAAK Are Principal K+ Channels at the Nodes of Ranvier for Rapid Action Potential Conduction on Mammalian Myelinated Afferent Nerves” was published in the journal Neuron. Myelin, the fat-rich substance that wraps around nerve fibers (axons), works to insulate and increase the velocity of the signals relayed by nerve cells. Gaps between segments of myelin, or nodes of Ranvier, also work to amplify these signals. Nerve impulses must travel and arrive at relay points extremely quickly for effective connection and communication between brain regions. Researchers at the University of Alabama at Birmingham (UAB) showed for the first time that the nodes of Ranvier have potassium channels that allow the myelinated nerves to propagate nerve impulses at very high frequencies, and with high conduction speeds. This is key for fast transmission of sensations and rapid muscle control in mammals. The nodes of Ranvier were first discovered in 1878 by the French scientist Louis-Antoine Ranvier. Later research, dating from 1939, showed that they work as relay stations placed along myelinated nerves — about 1 millimeter apart — for proper conduction of nerve impulses at rates of 50 to 200 meters per second. Between these nodes, the nerve is wrapped in myelin. When the nerve fires, the electrical impulse travels along the nerve (called action potential) from one node to the other at a speed 100 times faster than that of impulses in nerves lacking myelin. Neuroscientists know that ions crossing the membrane of nerve cells are required to fire electrical impulses along nerves, but whether potassium ion channels were present in the nodes of Ranvier remained a matter of debate. No one had been able to use patch clamps — a technique that allows recording of whole-cell or single-ion channel currents flowing across membranes — to the nodes of the small intact nerves in mammals. UAB researchers led by Jianguo Gu, PhD, worked with a rat and identified two ion channels, called TREK-1 and TRAAK, as the main potassium channels in the nodes of Ranvier of the rat’s myelinated nerve. Most importantly, they showed these ion channels allow high-speed and high frequency conduction of nerve impulses along the myelinated afferent nerves — those carrying information from the sensory organs (like the eyes or skin) to the central nervous system (the brain and spinal cord). TREK-1 and TRAAK channels were highly enriched — 3,000 times higher — at the nodes of Ranvier in afferent nerves than in the nerve cell’s body. When the scientists removed (knocked down) these channels, conduction speed in the rat's nerve dropped by 50 percent, and the rat's "aversion reaction" to its whisker being flicked was slower. "TREK-1 and TRAAK are clustered at nodes of Ranvier of myelinated afferent nerves," the researchers concluded, and "suppressing these channels retards nerve conduction and impairs sensory functions." Increasing evidence shows that dysfunction in the nodes of Ranvier are present in neurological diseases, including MS. Whether autoantibodies (antibodies that attack the body’s own tissues) target the TREK-1 and TRAAK to affect nerve conduction, leading to sensory and motor problems such as those seen in MS, remains to be investigated, Gu said in a UAB news release written by Jeff Hansen.

Generic Version of Gilenya, pms-Fingolimod, Now Available for RRMS Patients in Canada

Pharmascience recently launched pms-Fingolimod, a generic version of Novartis’ Gilenya (fingolimod), to treat adults with relapsing-remitting multiple sclerosis (RRMS) in Canada. The new generic is now available in that country, and has demonstrated efficacy and safety similar to Gilenya. Generic medicines are chemically identical to the original branded therapy, but carry a…

Vumerity Approved in US as Treatment for RRMS and Active SPMS

The U.S. Food and Drug Administration (FDA) has approved Vumerity (diroximel fumarate) for the treatment of relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome (CIS), relapsing-remitting MS (RRMS), and active secondary progressive disease (SPMS). Vumerity (previously known as ALKS 8700) was developed by Alkermes…

Profiling Inflammatory Markers in Cerebrospinal Fluid of Importance in Active MS, Case Study Finds

Careful profiling of inflammatory markers in cerebrospinal fluid (CSF) of multiple sclerosis patients, coupled with standard exams and scans, helps in understanding disease evolution and treatment response, a case report suggests. It followed a relapsing-remitting multiple sclerosis (RRMS) patient whose inflammatory markers in the CSF remained high over time, and…

#ECTRIMS2019 – Acthar Gel Seen as Cost-effective Late-line Treatment Option for MS Relapses

Late-line use of H.P. Acthar Gel to treat relapses in adults with multiple sclerosis (MS) is linked with lower costs than other therapies used after an initial poor response, including plasmapheresis and intravenous immunoglobulin, according to an analysis by Mallinckrodt Pharmaceuticals, the treatment’s marketer. George Wan, PhD, Mallinckrodt’s vice president and…

Autoimmune Complications Associated with Lemtrada Solved Using Anti-CD20 Therapies, Case Studies Suggest

Relapsing-remitting multiple sclerosis (RRMS) patients treated with Lemtrada (alemtuzumab) may develop additional (secondary) autoimmune reactions. Anti-CD20 therapies, including rituximab or Ocrevus (ocrelizumab), are a potential treatment for Lemtrada-associated autoimmune complications in patients who fail to respond to other conventional immunotherapies, according to a case report about two women in…

Less-frequent Dosing with Arbaclofen ER Tablets Decreases Spasticity As Well As Standard Baclofen, MS Trial Data Show

Arbaclofen extended-release (ER) tablets taken twice a day can effectively reduce spasticity (muscle stiffness) in patients with multiple sclerosis (MS) with similar potency to that of standard and more-frequently-dosed baclofen (brand name Lioresal), Phase 3 clinical trials show. Latest trial data were presented in two posters during the 33rd Annual Meeting…

Aubagio Targets Highly Metabolic Auto-reactive T-Cells, Study Shows

Aubagio (teriflunomide), an approved medicine for relapsing forms of multiple sclerosis (MS), specifically targets highly metabolic and more autoreactive T-cells, analysis of the Phase 3 TERI-DYNAMIC clinical trial data shows. The findings, contrary to expectations, support a selective effect of Aubagio on different T-cell populations. The study “Teriflunomide treatment for multiple sclerosis modulates T cell mitochondrial respiration with affinity-dependent effects” was published in the Science Translational Medicine journal. In MS, immune cells, or lymphocytes known as T-cells, attack and destroy myelin, the fat-rich substance that wraps around nerve fibers (axons). Myelin loss creates lesions that affect nerves of the brain and spinal cord. Previous evidence suggested that T-cells, depending on their active or resting state, rely on specific ways of energy production or metabolism. Aubagio, marketed by Sanofi Genzyme, is a well-known inhibitor of a mitochondrial enzyme called dihydroorotate dehydrogenase (DHODH), that is crucial for the activity of T-cells. However, how Aubagio selectively targets the autoreactive T-cells is poorly understood. To shed light on this matter, an international group of researchers used data from the TERI-DYNAMIC clinical trial that tested Aubagio in patients with relapsing form of MS to better understand how the therapy inhibited the patients' self-immune responses. The Phase 3, open-label TERI-DYNAMIC trial (NCT01863888) included 70 patients from Belgium, Germany, and The Netherlands, aged 18 to 56. Participants received Aubagio as a 14 milligram (mg) once-daily, oral dose, and researchers assessed the changes in immune cells' profile up to 24 weeks. Results showed that, contrary to what was expected, Aubagio was not generally decreasing T-cell levels in treated patients. Instead, it significantly reduced a particular subset of T-cells, called "Th1 helper cells." Moreover, researchers found that the diversity of T-cell receptors — the surface proteins that can recognize a particular antigen (a protein that can elicit an immune response) — making T-cells specific to a certain target was reduced in MS patients after treatment with Aubagio. These findings suggested that some T-cells were particularly susceptible to Aubagio. Using a mouse model for MS, the experimental autoimmune encephalomyelitis (EAE) model, researchers showed that the CD4+ T-cells (helper T-cells) and CD8+ T-cells, those that reacted most strongly against self-antigens, were the most sensitive to DHODH inhibition by Aubagio. Moreover, researchers saw that Aubagio was not affecting the production of pro-inflammatory molecules — called cytokines — at the cell level, but their overall decrease probably was due to the reduction in T-cell numbers. In line with these findings, CD4+ T-cells that produced the cytokine interferon gamma were significantly reduced with Aubagio treatment, whereas CD4+ T-cells that produced interleukin 17A were unchanged. This suggests that Aubagio is able to interfere with specific sub-types of immune cells. When the team compared the metabolic profile of T-cells from healthy subjects with that from patients with relapsing-remitting MS (RRMS) in both remission and in relapse phases, they found that the metabolism of T-cells from the last group was significantly altered, and thus targetable. Altogether, the results suggested that T-cells with a high-affinity to self-antigens are more susceptible to inhibition of the DHODH enzyme by Aubagio. “Therapeutic targeting of metabolic alterations might represent an attractive concept in MS, and might represent an as yet unrecognized key mechanism of teriflunomide-mediated immune modulation in this disease,” the researchers concluded.

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