pathway” that can be modulated by neurotransmitters and that underlies axonal degeneration after various insults.13,25,26,91,92 Neuroprotective interventions can preserve axonal function and integrity after acute insult in two ways. Axons can be protected either by agents that block or modulate the various injurious ion fluxes that occur during this molecular death cascade or by agents that interfere with “downstream” degenerative events, such as activation of calpains and other destructive enzymes.24,32,92
It is well established that axonal transection can trigger dramatic changes in the neuronal cell body, but with a few exceptions, the effects of demyelination on the neuronal cell body have not been examined. The available evidence suggests that demyelination may produce significant molecular changes in the neuronal cell body, including changes in gene activation.9 Since these changes are likely to interfere with neuronal function, they should be studied.
Details of the molecular mechanisms underlying various pathological changes in neurons in MS remain to be elucidated. Rather than reflecting a pessimistic scenario, recognition of neuronal changes in the “demyelinating” diseases presents new therapeutic targets and opportunities. We know a lot about injured neurons, including injured axons, and about how to alter their behavior. Neuronal injury in demyelinating diseases is therefore not necessarily bad news. More information about neuronal dysfunction in MS and related disorders might provide inroads in the search for more effective therapies that will preserve function in people with MS.
Demyelination is the hallmark of multiple sclerosis, and it is also known that oligodendrocytes degenerate in this disorder. Yet we still do not understand the primary target of MS. Is it the oligodendrocyte or the myelin sheath it forms? Much is known about the “death cascade” in neurons, which leads from initial insults, via a series of molecular steps, to the ultimate death of the cell. Less is known about the degenerative cascade in oligodendrocytes. Recent evidence suggests that excitotoxic mechanisms, possibly involving glutamate acting via AMPA/kainate receptors, may injure oligodendrocytes (Figure 5.2).47 (The AMPA/kainate receptor is one of several glutamate receptors in the brain; it also binds to kainic acid and AMPA.) If the details of mechanisms that injure oligodendrocytes and axons were better understood, it might be possible to protect oligodendrocytes, or their myelin sheaths, so that they are not injured in MS.
There is also the important question of whether oligodendrocyte progenitors (stemlike cells that can give rise to oligodendrocytes with the potential to form new myelin) are present within the adult brain. If they are, can these cells be awakened or activated, so that they will, in fact, form new myelin in multiple sclerosis? Evidence from animal models indicates that it is, in fact, possible to promote remyelination by endogenous cells by exposing oligodendrocytes to