Disclaimer: CME certification for these activities has expired. All information is pertinent to the timeframe in which it was released.
Neurodegeneration And Neuroprotection In Multiple Sclerosis II
To examine the molecular mechanisms of apoptosis and necrosis, the mechanisms and consequences of axonal injury and degeneration, the role of oligodendrocyte precursor cells, and the inhibition of remyelination and axonal regeneration.
This activity is designed for neurologists, neuropathologists, and neuroradiologists.
No prerequisites required.
The Johns Hopkins University School of Medicine takes responsibility for the content,
quality, and scientific integrity of this CME activity. At the conclusion of this activity,
participants should be able to:
- Understand the underlying mechanisms and consequences of neuronal and axonal apoptosis and necrosis in multiple sclerosis.
- Discuss the role of oligodendrocyte precursor cells in brain injury and repair.
- Examine inhibitors of remyelination and axonal regeneration.
- Assess the role of various imaging modalities in detecting and quantifying neurodegeneration in multiple sclerosis.
- Summarize ongoing neuroprotective therapeutic trials..
The Johns Hopkins University School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.
CREDIT DESIGNATION STATEMENT
The Johns Hopkins University School of Medicine designates this educational activity for
a maximum of 3 category 1 credits toward the AMA Physician's Recognition Award.
Each physician should claim only those credits that he/she actually spent in the activity.
The estimated time to complete this educational activity: 3 hours.
Release date: April 15, 2005. Expiration date: April 15, 2007.
The opinions and recommendations expressed by faculty and other experts whose input is included in this program are their own. This enduring material is produced for educational purposes only. Use of Johns Hopkins University School of Medicine name implies review of educational format, design, and approach. Please review the complete prescribing information of specific drugs or combinations of drugs, including indications, contraindications, warnings, and adverse effects, before administering pharmacologic therapy to patients.
This program is supported by an educational grant from Biogen Idec.
Full Disclosure Policy Affecting CME Activities:
As a provider accredited by the Accreditation Council for Continuing Medical Education (ACCME), it is the policy of Johns Hopkins University School of Medicine to require the disclosure of the existence of any significant financial interest or any other relationship a faculty member or a sponsor has with the manufacturer(s) of any commercial product(s) discussed in an educational presentation. The Program Directors and Participating Faculty reported the following:
Peter A. Calabresi, MD
Associate Professor of Neurology
Director, Multiple Sclerosis Center
Johns Hopkins Hospital
• Dr Calabresi reports receiving grants/research support and honoraria from, and serving as a consultant to Berlex, Inc, Biogen Inc, Genentech, Inc, and Teva Pharmaceutical Industries Ltd.
Jeffrey I. Greenstein, MD
Director, Multiple Sclerosis Institute
Chair, Department of Neurology
Clinical Professor of Neurology
Drexel University School of Medicine
Adjunct Professor of Microbiology and Immunology
Temple University School of Medicine
• Dr Greenstein reports receiving grants/research support from Berlex Inc, BiogenIdec, Merck & Co, Inc, Protein Design Labs,and Teva Pharmaceutical Industries Ltd;and receiving honoraria from Biogen Idec.
Valina L. Dawson, PhD
Director, Program in Neuroregeneration and Repair
Institute for Cell Engineering
Professor and Vice Chairman
Department of Neurology
Professor, Departments of Neuroscience and Physiology
Johns Hopkins UniversitySchool of Medicine
• Dr Dawson reports receiving royalties from Guilford Pharmaceuticals Inc.
Robin J.M. Franklin, PhD, DVM
Reader in Experimental Neurology
Cambridge Centre for Brain Repair & School of Veterinary Medicine
University of Cambridge
Cambridge, United Kingdom
• Dr Franklin reports having no financial or advisory relationships with corporate organizations related to this activity.
Zhigang He, PhD
Department of Neurology
Harvard Medical School
• Dr He reports serving as a consultant to Biogen Idec and Renovis, and holding stock in Renovis.
Joel Levine, PhD
Department of Neurobiology and Behavior
State University of New York at Stony Brook
Stony Brook, New York
• Dr Levine reports having no financial or advisory relationships with corporate organizations related to this activity.
Daniel Pelletier, MD
Assistant Professor of Neurology
Department of Neurology
UCSF Multiple Sclerosis Center
University of California, San Francisco
San Francisco, California
• Dr Pelletier reports having no financial or advisory relationships with corporate organizations related to this activity.
V. Hugh Perry, MA DPhil
Professor of Experimental Neuropathology
School of Biological Sciences
University of Southampton
Southampton, United Kingdom
• Dr Perry reports having no financial or advisory relationships with corporate organizations related to this activity.
Nancy Richert, MD, PhD
National Institutes of Health
• Dr Richert reports having no financial or advisory relationships with corporate organizations related to this activity.
Jack H. Simon, MD, PhD
Professor and Director of Neuroradiology and MRI
University of Colorado Health Sciences Center
• Dr Simon reports having no financial or advisory relationships with corporate organizations related to this activity.
Notice: The audience is advised that an article in this CME activity contains reference(s) to unlabeled or unapproved uses of drugs or devices.
Drs Calabresi and Greenstein—phenytoin.
Dr He—PKC inhibitors.
Dr Greenstein—flecainide, interferon beta-1A, lidocaine, phenytoin, phospholipase A2 inhibitors, topiramate.
All other faculty have indicated that they have not referenced unlabeled/unapproved uses of drugs or devices.
Advanced Studies in Medicine provides disclosure information from contributing authors, lead presenters, and participating faculty. Advanced Studies in Medicine does not provide disclosure information from authors of abstracts and poster presentations. The reader shall be advised that these contributors may or may not maintain financial relationships with pharmaceutical companies.
Neurodegeneration And Neuroprotection In Multiple Sclerosis
Peter A. Calabresi, MD,* and Jeffrey I. Greenstein, MD
The purpose of this monograph is to elucidate some current areas of core investigation and transitional research that will be particularly important in the understanding and development of therapies for patients with multiple sclerosis (MS). It brings together cutting-edge information from diverse fields ranging from neurobiology, molecular biology, and neuropharmacology to more clinically directed areas such as neuroimaging, which is vital to detecting and tracking degenerative changes. The following is a summary of what is being learned about the enigmatic etiology of MS.
Figure 1 depicts the various aspects of MS over time. It is commonly recognized that early in the course of the disease relapses occur that are sometimes followed by complete remission, and other times followed by accumulation of disability. As time goes on, most patients will convert into a secondary progressive form of MS where there are few, if any, relapses, and eventual accumulation of disability. In addition, a rare subset of approximately 10% or 15% of people with MS will follow a primary progressive course, also highlighting the degenerative aspects of the disease. Imaging has provided scientists and clinicians with a ÒwindowÓ into the brain, and has shown that there are many inflammatory events, and that they are occurring between clinical relapses. With time, these clinically silent events become less prominent, just as the relapses do, and patients evolve more into a degenerative phase. Due to progress in neuroimaging techniques, it is now possible to quantify the brain parenchymal fraction and brain atrophy measures and to document that the brain progressively atrophies over time, even during periods of clinical remission. Thus, researchers know that demyelination accumulates, and in the beginning there is partial remyelination, but over time the capacity to effectively remyelinate is diminished and many axons are rendered chronically demyelinated.
In addition, pathological studies have shown that axonal transections occur early on in the disease in both white and gray matter, as a result of inflammation. In the demyelinated state, there is redistribution of sodium channels over the areas of demyelination that may temporarily allow improved conduction, but this may be a vulnerable state, and those demyelinated axons are likely more susceptible to both transections and Wallerian degeneration. Dissecting the molecular mechanisms by which axons become transected and degenerate is critical to developing rational neuroprotective and neuroreparative strategies.
The classical model for explaining the pathogenesis of MS has been that immunogenetically predisposed hosts develop an aberrant immune response to myelin antigens following an environmental trigger. However, increasingly sophisticated and detailed pathological studies suggest in some situations the primary event may be death of the myelin-producing oligodendrocyte itself leading to secondary microglial activation and recruitment of T cells. Conversely, inflammation may be secondary to the release of myelin antigens after an initial viral or toxic insult to the central nervous system (CNS). While the early events in disease pathogenesis remain unclear, it is increasingly clear that the subsequent mechanisms of injury share final common pathways with other neurodegenerative diseases.
Oligodendrocytes are vulnerable to excitotoxicity. On the biochemical level, excitotoxicity secondary to glutamate, the role of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors, and/or abnormalities of the sodium channels could ultimately lead to impaired reversal of the sodium calcium exchanger and accumulation of intracellular calcium. This may set off an entire series of cell death events mediated through calpain and a variety of other molecules. Indeed, research with animal models of MS (experimental autoimmune encephalitis [EAE]) has demonstrated that via AMPA receptor blockade, it is possible to ameliorate EAE. Also, AMPA receptors exist not only on axons but on glial cells, and that it may be possible to preserve oligodendrocytes through such an intervention. Likewise, it has been shown that a sodium channel blocker can inhibit the loss of axons in the optic nerve, and thus perhaps through this mechanism of blocking sodium channels and thereby inhibiting the abnormal reversal of the exchange of sodium and calcium, toxic calcium accumulation may be curtailed. This has led to the commencement of a clinical trial evaluating the anticonvulsant medication phenytoin, a known sodium channel blocker, as a neuroprotective agent in MS.
Furthermore, myelin is important for maintaining healthy axons and conversely, healthy axons also are important for maintaining myelin, thus there is cross-talk that is just beginning to be understood at the molecular level. Several experimental paradigms demonstrate that myelin proteins are inhibitory to neurite outgrowth. At certain times, neurite outgrowth is desirable (eg, in an unmyelinated nerve), and the absence of myelin in the embryonic and early postnatal stages may allow normal neurite outgrowth and connection. However, in the mature adult setting, after full myelination has occurred, myelin actually may be important for trophic support of the axon and maintaining axon caliber and proper transport of proteins. At that point it would not be beneficial to have growth cones and new process formation. Thus, it appears that myelin interaction with the axolemma are tightly regulated.
Myelin-associated glycoprotein (MAG) is particularly interesting because it is the innermost componenet of the myelin lamellae and contacts the axolemma. Work with genetically altered MAG or complex ganglioside knockout mice reveal evidence of axonal loss in the spinal cord and optic nerves suggesting an important role for MAG and gangliosides in mediating trophic signals to axons. Indeed, recent in vitro studies also support a role for MAG-induced phosphorylation of downstream signaling molecules and ultimately neurofilament phosphorylation. The exact MAG receptor on the axolemma remains undetermined but there are several studies demonstrating that a receptor complex that includes the Nogo receptor, the P-75 neurotrophin receptor, and a newly described subunit Lingo are critical in mediating the inhibitory signals. Whether different receptors mediate trophic support is unknown, but clearly, understanding the molecular mechanisms of trophic support and neurite outgrowth inhibiton will be critical to designing rational therapeutic interventions. Thus, it may be that promoting neurite outgrowth is appropriate in some settings, but that in chronically demyelinated axons, in which there is deficient MAG signaling, further blockade of the signaling pathway with Nogo receptor antagonists may actually aggravate the situation and promote further Wallerian degeneration.
In summary, examination of this experimental evidence suggests that the targets of therapeutic intervention do not have to involve only inflammatory inhibitors. It is necessary to start looking at the mechanisms of degeneration in MS, excitotoxicity abnormalities in ion channels, calcium, and the processes by which neurons and glial cells die. Furthermore, because arresting inflammation early may have a neuroprotective role, and some of the excitotoxic avenues are driven initially by inflammation, it will be important to consider combination therapy in treatment of MS.
Neuroprotective approaches may include selective immunomodulation that inhibits damaging upstream inflammation with specific targeting of proteolytic enzymes and promotion of reparative and trophic inflammation. It may also involve inhibition of cell death pathways by blocking soluble mediators such as nitrous oxide, interleukin-6, and tumor necrosis factor; by blocking membrane death receptors such as AMPA, and also by blocking apoptotic signaling. Finally, promotion of remyelination and oligodendrocyte precursor cells, myelin signaling, and trophic factors may inhibit the Wallerian degeneration that occurs with MS (Figure 2).
As we gain understanding and begin to unlock the mystery of this illness, we can make progress in the preservation and even restoration of CNS function and diminish the disability that is often encountered by those affected.
*Associate Professor of Neurology, Director, Multiple Sclerosis Center, Johns Hopkins Hospital, Baltimore, Maryland.
Director, Multiple Sclerosis Institute, Chair, Department of Neurology, Graduate Hospital; Clinical Professor of Neurology, Drexel University School of Medicine; Adjunct Professor of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, Pennsylvania.
Address correspondence to: Peter A. Calabresi, MD, Johns Hopkins Hospital, Pathology Room 627A, 600 N Wolfe St, Baltimore, MD 21287.