Neuroprotection for Parkinson's disease: Prospects and promises

Despite the many advantages of modern therapy for Parkinson’s disease (PD), most patients eventually experience intolerable disability. Accordingly, there has been an intensive search for neuroprotective therapies that can slow, stop, or reverse the degenerative process. Indeed, advances in our understanding of the cause and pathogenesis of PD offer the promise that these insights can be translated into new treatments and treatment strategies that can modify the course of PD. Major advances have been made in the genetics of PD, and, at the time of this writing, linkage to several chromosomal loci and identification of five gene mutations have been demonstrated in familial forms of PD. The identification of gene mutations in familial PD has enhanced our understanding of mechanisms that can lead to neurodegeneration of nigral neurons and facilitated the development of transgenic animals. The contribution of the environment to PD remains largely undefined. Specific environmental toxins might be responsible for a relatively small proportion of individual PD cases, although twin studies suggest that environmental factors play a major role in late-onset sporadic PD. It is also possible that sporadic forms of PD result from a complex interaction between a variety of environmental factors and specific susceptibility genes. Thus, it appears likely that a PD syndrome can develop as a result of several causes, making it unlikely that a treatment aimed at a specific cause will have widespread application. Factors that appear to be involved in the pathogenetic cascade leading to cell death in PD include mitochondrial dysfunction, oxidative stress, excitotoxicity, and inflammatory changes, but each of these is not found in the brain of every PD patient. This suggests that their role and contribution varies from patient to patient and may differ depending on the specific gene mutation and/or environmental factor that triggers the degenerative process. A body of information also indicates that cell death in PD occurs, at least in part, by way of a signal-mediated apoptotic process. Finally, recent studies suggest that a defect in the handling and degradation of abnormal intracellular proteins is common to all of the various familial and sporadic forms of PD. There thus are many factors that have been implicated in the pathogenesis of cell death in PD, and that offer targets for the development of neuroprotective agents. However, here too, a therapy that is neuroprotective or restores function in one type of PD may not necessarily be effective in another, and targets for neuroprotective therapies that are common to the various types of PD need to be sought. Attempts to modify the course of PD are not new. The DATATOP study demonstrated that deprenyl (selegiline) can delay the introduction of L-dopa by 9 to 12 months, although the basis for the mechanism responsible for this benefit remains uncertain. Interestingly, attention has more recently been focused on the metabolite of selegiline, desmethylselegiline and other propargylamines, which have been shown to have powerful neuroprotective actions in vitro possibly through interactions with GAPDH and its potential to interfere with intrinsic protective programs. Clinical trials of such agents are under way. A recent small-scale study using treatment with high-dose coenzyme Q10 has shown that this bioenergetic compound may delay clinical progression when given to newly diagnosed patients, but this result needs to be confirmed in a larger trial. A recent large-scale study of the antiglutamatergic agent riluzole was discontinued based on a futility analysis. Dopamine agonists have emerged as important candidates for disease modification in PD based on laboratory studies demonstrating their capacity to protect dopaminergic and nondopaminergic neurons in a variety of in vitro and in vivo models. The mechanisms responsible for these benefits is not known but may involve their capacity to provide antioxidant effects through decreased dopamine turnover and free radical scavenging activity as well as their potential to interfere with proapoptotic intracellular signals. Alternative forms of disease modification primarily based on cell-based therapies and/or gene therapies are also being developed for PD. Recent trials using transplanted fetal mesencephalic tissue have demonstrated that implanted cells can survive, form connections with host neurons, and manufacture dopamine. However, double-blind studies have failed to demonstrate meaningful clinical benefits after transplantation, and offmedication dyskinesia present in as many as 50% of patients may severely limit the potential value of transplantation and other cell-based therapies. Growth factors such as GDNF delivered into the striatum by direct infusion or by gene therapy have shown striking benefits in laboratory models and are now beginning to be tested clinically. Stem cells also are being actively explored as a potential treatment for PD. Preliminary studies have shown that embryonic stem cells can be