Current Drug Targets - Immune, Endocrine & Metabolic Disorders, 2005, 5, 11-26 11 1568-0088/05 $50.00+.00 © 2005 Bentham Science Publishers Ltd. Therapeutic Strategies To Prevent Neurodegeneration And Promote Regeneration In Multiple Sclerosis T. Chitnis*, J. Imitola and S.J. Khoury Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School Boston, Massachusetts, 02115, USA Abstract: Multiple sclerosis (MS) is an immune-mediated demyelinating and degenerative disease of the central nervous system (CNS), with lesions predominantly occurring in the CNS white matter. The current treatment for MS relies on therapies that primarily target the peripheral immune response. However, it is clear that these strategies alone are insufficient for treating the chronic progressive disability that is the ultimate outcome of the disease. Axonal degeneration may be the primary determinant of fixed neurological deficits in MS. Here, we will discuss the contribution of axonal damage to MS pathogenesis, and potential cellular and molecular targets in the prevention of neurodegeneration. In addition, we will discuss potential molecular approaches to promote repair of CNS components in multiple sclerosis. Key Words: Multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE), T cell, macrophage, axon, neural progenitor cell, neural stem cell, regeneration. INTRODUCTION Multiple sclerosis (MS) is the leading cause of neurological disability in young adults [1]. It is an immune- mediated demyelinating and degenerative disease of the central nervous system (CNS), with lesions predominantly occurring in the CNS white matter. The majority of patients experience a relapsing-remitting form of disease with transient symptoms followed by a secondary progressive phase characterized by irreversible deficits. The current treatment for MS relies on therapies that primarily target the peripheral immune response. However, it is clear that these strategies alone are insufficient for treating the chronic progressive disability, which is the ultimate outcome of the disease [2]. Therefore, rational therapies for MS should target the underlying mechanisms of chronic disability, and should promote repair and regeneration in the CNS, with the goal of preventing and potentially improving fixed deficits. Oligodendrocyte cell death, axonal degeneration, and neuronal dysfunction [3,4] are key features in MS pathology, and form the basis for irreversible deficits. In particular, axonal degeneration may be the primary determinant of fixed neurological deficits in MS [5,6]. Therefore, an understanding of the mechanisms of axonal damage, and the design of strategies to promote axon survival are critical in the prevention of irreversible chronic disability in MS. In addition to the prevention of permanent neuronal and oligodendroglial degeneration, future therapies in MS should promote repair and regeneration of damaged cells, thereby potentially reversing disability. Studies in EAE have *Address correspondence to this author at the 77 Avenue Louis Pasteur, Room 710, Center for Neurologic Diseases, Brigham and Women’s Hospital, Boston, Massachusetts, 02115, USA; Tel: (617)525-5374; Fax: (617)525-5252; E-mail:tchitnis@rics.bwh.harvard.edu indicated that regeneration of CNS components is feasible [7,8], but may be limited by ongoing immune-mediated damage. As the mechanisms of remyelination and cell renewal in the CNS begin to be better understood, optimization of current treatments and discovery of novel molecular therapeutic targets can be entertained. Here, we will discuss the contribution of axonal damage to MS pathogenesis, and potential cellular and molecular targets in the prevention of neurodegeneration. In addition, we will discuss potential molecular approaches to promote repair of CNS components in multiple sclerosis. A. NEURODEGENERATION Challenges in the Prevention of Neuronal and Axonal Degeneration in MS Ideal neuroprotective strategies should target the initial site of injury to the neuron. The majority of the current literature on neurodegeneration in both MS and EAE has focused on injury to the axon [9-13]. The axon is the longest portion of the neuron, it is primarily located in the white matter where the majority of damage in MS occurs, and is therefore the most likely initial target of injury. However, the question of whether it is the primary target of neuronal injury in MS, has not been fully explored. We will discuss the evidence for axonal and neuronal damage in MS, and pathological processes involved. The hallmark of MS is an enhanced immune response in the CNS. It is likely that both axonal damage and demyelination are, in part, a result of local inflammation. One of the challenges in the study of neurodegeneration in MS, is to definitively identify its cellular and molecular mediators. Several cytokines produced in MS have clear neurotoxic potential, while others may have beneficial effects. Thus, novel immunomodulatory approaches should take this into account, and exploit the immunosuppressive as well as the neuroprotective properties of various factors.