Multiple Sclerosis and Related Disorders (2013) 2, 261–262
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/msard
EDITORIAL
Promoting regeneration and repair in Multiple Sclerosis In the present issue of MSARD, several articles focus on cellular mechanisms of neuronal injury and discuss potential mechanisms to promote cellular regeneration in the inflammatory environment that characterizes Multiple Sclerosis (MS). The ability to improve the function in the central nervous system in patients with established relapsing remitting, secondary progressive or primary progressive MS is of paramount importance to sufferers of MS. As clearly articulated by advocates for the MS patient community, the paucity of therapies designed to improve function or halt disease progression has disenfranchised those with progressive forms of the disease. Restoration of function in an injured central nervous system or preservation of residual function is a key area for research. The critical importance of promoting return of function is reviewed by Drs. Gacia and Casaccia. The authors highlight that progressive neuronal damage leading to irreversible disability relates to failure of axonal protection, and to a limited potential for myelin regeneration. Both processes share, at a fundamental level, the capacity of intracellular processes to maintain cell survival. The authors discuss new explorations into the mechanisms of axonal damage, focusing on the axo-glial unit. The importance of glial support for neurons and their axons has been recognized for many years, but recent research has focused on mechanisms of trophic and biochemical support provided by glia to axons and more specifically on the maintenance of cellular metabolism by axonal mitochondria. The inflammatory environment of acute MS lesions is characterized by the release of factors such as TNFα and Nitric Oxide (NO), culminating in oxidative damage. As illustrated in the authors' diagram, immune cells, in particular activated microglia provide a source of both putatively harmful cytokines and NO. Accumulation of NO within an injured axon leads to increased energy demand for an already compromised axon, as well as coping with the intracellular accumulation of calcium. Furthermore, the short internode and increased build-up of sodium channels that characterizes a remyelinating axon, leads to enhanced sodium—calcium exchange, and subsequent calcium overload. Within a cell, a major source of calcium uptake and 2211-0348/$ - see front matter & 2013 Published by Elsevier B.V. http://dx.doi.org/10.1016/j.msard.2013.06.001
buffering is provided by mitochondria. The excessive calcium accumulation in an injured axon taxes mitochondrial reserve, leading to mitochondrial injury and failure of intracellular energy production. The end result is irreversible axonal degeneration and cumulative failure of neural networks. The authors emphasize that several components involved in this inflammatory-toxic milieu may be amendable to influence by extrinsic factors. Diet, smoking, and epigenetic factors may all influence the relative cellular reserve and subsequent preservation of cell function and/or efficacy of remyelination. While relatively little is known about the modifiable factors that promote more effective remyelination, polyunsaturated fatty acids and antioxidants have theoretical rationale. It has also been suggested that a ketogenic diet may be of value, as demonstrated in murine models of demyelination. None of the dietary considerations have been effectively studied to date. The authors underline the evidence that pathways targeted by the ketogenic diet are also implicated in the mechanistic pathway for dimethylfumarte (BG12) one of the most recently approved medications for MS. Also debated is the importance of rehabilitation to promote and preserve function. In animal models and studies of human populations with acute injury, repair, remyelination and clinical outcome are all favorably impacted by intensive early rehabilitation. While the biologic pathways marshaled through rehabilitation are not yet known, new imaging strategies that display cellular calcium and sodium content, and functional imaging studies that delineate established and compensatory neural networks may shed new insights. The importance of cell survival and regeneration in MS is discussed further in a review by Dr. Baker. The potential therapeutic mechanisms of potassium channel blockade are described, in particular, that provided by 4-aminopyridine (4-AP). Treatment of MS patients with 4-AP improves the motor activity and the potential benefit of 4-AP mediated potassium channel blockade is appraised. It is explained that blocking potassium channel activity leads to increased action potential duration and that such prolongation assists neuronal conduction in compromised axons (particularly
262 those that have been remyelinated), in turn leading to improved clinical function. Furthering the theme of neuroprotective and neural repair, Drs. Raftopoulos and Kapoor discuss mechanisms for neuroprotection in acute optic neuritis. The authors emphasize that the recent randomized placebo-controlled trial of Lamotrigine in secondary progressive Multiple Sclerosis did not succeed in its primary end point (to reduce brain volume loss) but did show that treated individuals were less likely to worsen in their walking ability. Phenytoin is now being trialed in patients with acute optic neuritis to determine whether influencing axonal health during acute inflammation limits toxic injury to the optic nerve. Phenytoin is an inhibitor of sodium channels, and thus would reduce the influx of excess sodium and enhanced sodium—calcium exchange thought to be relevant (as discussed above) in axonal injury. Retinal nerve fiber thickness measurements will be used as an outcome metric, given the evidence that retinal nerve fiber thinning is a sequel of acute optic neuritis. Phenytoin therapy for a brief period is likely to be well-tolerated. Whether such treatment for an acute inflammatory event such as optic neuritis
B. Banwell et al. would have any long-term influence on the chronic aspects of MS remains to be determined. The importance of therapeutic strategies for neural repair and regeneration cannot be overemphasized. The eloquent pleas of individuals with MS-related disability for a focus on progressive forms of MS have clearly resonated with the research community. It will be of importance to design treatments carefully as well as outcome measures capable of quantifying cellular health and repair using validated imaging or biological metric tools, and perhaps more importantly to design assessments that identify clinically-meaningful improvements in function.
B. Banwelln, G. Giovannoni, C.H. Hawkes, F. Lublin University of Pennsylvania, Division of Neurology, Department of Pediatrics, Children's Hospital of Philadelphia, Rm 10018, Colket Research Building, 3501 Civic Center Boulevard, Philadelphia 19104, PA, United States E-mail address: [email protected] (B. Banwell)
n
Corresponding author. Tel.: +1 215 590 1710; fax: +1 215 590 2950.
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/msard
EDITORIAL
Promoting regeneration and repair in Multiple Sclerosis In the present issue of MSARD, several articles focus on cellular mechanisms of neuronal injury and discuss potential mechanisms to promote cellular regeneration in the inflammatory environment that characterizes Multiple Sclerosis (MS). The ability to improve the function in the central nervous system in patients with established relapsing remitting, secondary progressive or primary progressive MS is of paramount importance to sufferers of MS. As clearly articulated by advocates for the MS patient community, the paucity of therapies designed to improve function or halt disease progression has disenfranchised those with progressive forms of the disease. Restoration of function in an injured central nervous system or preservation of residual function is a key area for research. The critical importance of promoting return of function is reviewed by Drs. Gacia and Casaccia. The authors highlight that progressive neuronal damage leading to irreversible disability relates to failure of axonal protection, and to a limited potential for myelin regeneration. Both processes share, at a fundamental level, the capacity of intracellular processes to maintain cell survival. The authors discuss new explorations into the mechanisms of axonal damage, focusing on the axo-glial unit. The importance of glial support for neurons and their axons has been recognized for many years, but recent research has focused on mechanisms of trophic and biochemical support provided by glia to axons and more specifically on the maintenance of cellular metabolism by axonal mitochondria. The inflammatory environment of acute MS lesions is characterized by the release of factors such as TNFα and Nitric Oxide (NO), culminating in oxidative damage. As illustrated in the authors' diagram, immune cells, in particular activated microglia provide a source of both putatively harmful cytokines and NO. Accumulation of NO within an injured axon leads to increased energy demand for an already compromised axon, as well as coping with the intracellular accumulation of calcium. Furthermore, the short internode and increased build-up of sodium channels that characterizes a remyelinating axon, leads to enhanced sodium—calcium exchange, and subsequent calcium overload. Within a cell, a major source of calcium uptake and 2211-0348/$ - see front matter & 2013 Published by Elsevier B.V. http://dx.doi.org/10.1016/j.msard.2013.06.001
buffering is provided by mitochondria. The excessive calcium accumulation in an injured axon taxes mitochondrial reserve, leading to mitochondrial injury and failure of intracellular energy production. The end result is irreversible axonal degeneration and cumulative failure of neural networks. The authors emphasize that several components involved in this inflammatory-toxic milieu may be amendable to influence by extrinsic factors. Diet, smoking, and epigenetic factors may all influence the relative cellular reserve and subsequent preservation of cell function and/or efficacy of remyelination. While relatively little is known about the modifiable factors that promote more effective remyelination, polyunsaturated fatty acids and antioxidants have theoretical rationale. It has also been suggested that a ketogenic diet may be of value, as demonstrated in murine models of demyelination. None of the dietary considerations have been effectively studied to date. The authors underline the evidence that pathways targeted by the ketogenic diet are also implicated in the mechanistic pathway for dimethylfumarte (BG12) one of the most recently approved medications for MS. Also debated is the importance of rehabilitation to promote and preserve function. In animal models and studies of human populations with acute injury, repair, remyelination and clinical outcome are all favorably impacted by intensive early rehabilitation. While the biologic pathways marshaled through rehabilitation are not yet known, new imaging strategies that display cellular calcium and sodium content, and functional imaging studies that delineate established and compensatory neural networks may shed new insights. The importance of cell survival and regeneration in MS is discussed further in a review by Dr. Baker. The potential therapeutic mechanisms of potassium channel blockade are described, in particular, that provided by 4-aminopyridine (4-AP). Treatment of MS patients with 4-AP improves the motor activity and the potential benefit of 4-AP mediated potassium channel blockade is appraised. It is explained that blocking potassium channel activity leads to increased action potential duration and that such prolongation assists neuronal conduction in compromised axons (particularly
262 those that have been remyelinated), in turn leading to improved clinical function. Furthering the theme of neuroprotective and neural repair, Drs. Raftopoulos and Kapoor discuss mechanisms for neuroprotection in acute optic neuritis. The authors emphasize that the recent randomized placebo-controlled trial of Lamotrigine in secondary progressive Multiple Sclerosis did not succeed in its primary end point (to reduce brain volume loss) but did show that treated individuals were less likely to worsen in their walking ability. Phenytoin is now being trialed in patients with acute optic neuritis to determine whether influencing axonal health during acute inflammation limits toxic injury to the optic nerve. Phenytoin is an inhibitor of sodium channels, and thus would reduce the influx of excess sodium and enhanced sodium—calcium exchange thought to be relevant (as discussed above) in axonal injury. Retinal nerve fiber thickness measurements will be used as an outcome metric, given the evidence that retinal nerve fiber thinning is a sequel of acute optic neuritis. Phenytoin therapy for a brief period is likely to be well-tolerated. Whether such treatment for an acute inflammatory event such as optic neuritis
B. Banwell et al. would have any long-term influence on the chronic aspects of MS remains to be determined. The importance of therapeutic strategies for neural repair and regeneration cannot be overemphasized. The eloquent pleas of individuals with MS-related disability for a focus on progressive forms of MS have clearly resonated with the research community. It will be of importance to design treatments carefully as well as outcome measures capable of quantifying cellular health and repair using validated imaging or biological metric tools, and perhaps more importantly to design assessments that identify clinically-meaningful improvements in function.
B. Banwelln, G. Giovannoni, C.H. Hawkes, F. Lublin University of Pennsylvania, Division of Neurology, Department of Pediatrics, Children's Hospital of Philadelphia, Rm 10018, Colket Research Building, 3501 Civic Center Boulevard, Philadelphia 19104, PA, United States E-mail address: [email protected] (B. Banwell)
n
Corresponding author. Tel.: +1 215 590 1710; fax: +1 215 590 2950.
