Introduction The pathological substrate of permanent disability in multiple sclerosis (MS) is neuronal injury and axonal loss. While axonal loss is initiated early in the disease process, the mechanisms for axonal damage likely vary at different stages of the disease. In this chapter, we review the mechanisms for both inflammatory and non-inflammatory mediated neural degeneration in MS and discuss potential therapeutic targets for neuroprotection. While this is a convenient manner in which to divide these topics, it should be recognized that there is likely a continuum of inflammatory and non-inflammatory neurodegenerative mechanisms occurring simultaneously in most patients. Therefore, treatment strategies need to address both aspects of the disease. Effect of immunomodulatory drugs on cerebral atrophy and black holes The interferon-beta (IFNβ) trials revealed that the most potent effect of this class of drugs is at the blood–brain barrier as evidenced by reductions in new T2 weighted lesions and gadolinium (Gd)-enhancing lesions. Further, IFNβ may offer some neuroprotective effect by reducing inflammation and thereby preventing the formation of new black holes. IFNβ-1a was shown to reduce the rate of brain atrophy significantly between the first and second year of the trial but not between baseline and year 1 suggesting that the reduction of inflammation in year 1 might result in fewer damaging plaques that evolve into black holes in year 2. Importantly, another MRI-based trial found that IFNβ had no effect on the likelihood of T1 hole formation after a Gd-enhancing lesion has already occurred providing further evidence that IFNβs act systemically and are probably not neuroprotective within the central nervous system (CNS). Alternatively, glatiramer acetate (GA) has a more modest effect on reducing Gd-enhancing lesions than IFNβ drugs but seems to have equal efficacy in reducing relapse rate. An MRI-based study of GA suggested that fewer of the Gd-enhancing lesions that occurred on GA became permanent T1 black holes, which raises the possibility that GA may have neuroprotective effects within the CNS. This supports data from experimental autoimmune encephalomyelitis (EAE) studies and in vitro where GA-reactive T-cells can be found within the CNS and secrete brain-derived neurotrophic factor (BDNF). Natalizumab reduced the rate of brain atrophy in year 2 of the Phase 3 trials., Interestingly, fingolimod was also shown to reduce the rate of brain atrophy, but unlike other drugs, its effect was seen in the first six-month epoch of treatment. Whether the earlier reduction in the rate of atrophy reflects the known CNS penetration of this lipophilic drug or possibly bioactivity on neural and or glial cells, which express sphingosine 1-phosphate receptors, is unknown.
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