The diffuse nature of the lesions in neurodegenerative parkinsonian syndromes explains the inefficacy of symptomatic treatments and the potential interest of neuroprotector treatments that could slow down or even prevent neuron degeneration in structures involved in the degenerative processes. As these syndromes share preferential degeneration of the substantia nigra with Parkinson's disease it is logical to hypothesize that the same mechanisms of neuron death are involved. The responsibility of an exotoxin, with a mechanism of action that would be similar to that of MPTP and/or rotenone, appears to be implicated only in progressive supranuclear palsy (PSP): this is suggested by the "guadeloupean parkinsonean" syndrome. There is no evidence demonstrating an exotoxin in corticobasal degeneration (CBD), which might play an anecdotal role in rare cases of multiple system atrophy (MSA). There are rare cases of PSP, sometimes with autopsy proof, generally with autosomal dominant inheritance, but in the much larger number of sporadic cases there is an undeniable genetic susceptibility linked with certain polymorphisms of the tau protein gene. Genetic susceptibility plays a much less pronounced role in CBD. There is no argument however in favor of a genetic factor in MSA. A few arguments suggest that oxidative stress is involved in PSP and MSA, or even CBD, but no evidence of a primary effect. Perturbed mitochondrial metabolism is possible in PSP. Undeniable proof of the effect of inflammation, excitotoxicity, and apoptosis remains to be presented. We now have several compounds which could affect different phases of neurodegeneration. Identifying the precise cause of neuronal death is needed to properly choose the most effective therapeutic approach (single drug or multiple drug regimens). Therapeutic assessment should be conducted in patients with certain diagnosis. This apparently evident prerequisite does not however appear to be easy to satisfy as has been demonstrated by anatomoclinical series in PSP and MSA, and even more so in CBD. Use of international criteria does not alleviate the difficulty. Satisfactory criteria of efficacy remain to be identified. Assuming that such trials would be conclusive, there remains the question of how to implement neuroprotection in routine practice. The difficulties encountered are well known: late intervention after development of the disease in sporadic cases, ethical issues concerning preclinical screening in familial forms of the disease or in patients exposed to an exotoxin.
