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Deprenyl and the Issue of Neuroprotection F. Vingerhoets, MD, Neurodegenerative Disorders Centre, University Hospital, UBC Site, Purdy Pavilion, 2211 Wesbrook Mall, Vancouver, BC V6T 2B5 (Canada) The Parkinson Disease Study Group (PDSG) recently published its findings concerning antioxidant drug therapy for early Parkinson’s disease [1] (idiopathic parkinsonism (IP)) as follow-up to an earlier report published in 1989 [2]. After almost 4 years of controversy [3, 4], the sole firm conclusion that could be drawn concerning the use of deprenyl, a monoamine oxidase (MAO) type B inhibitor was that it allowed the introduction of levodopa treatment to be postponed by somewhat less than 1 year. For this reason, the authors argue, deprenyl should be considered among the available therapeutic options for the initial treatment of early Parkinson’s disease. A discussion of when and how symptomatic treatment of early Parkinson’s disease should be carried out is beyond the scope of this editorial and has recently been addressed elsewhere [5]. Our discussion here will be restricted to the issue of neuroprotection as illustrated by the DATATOP experience. Few would argue against neuroprotection being a goal worth pursuing. However, for the concept to be meaningfully assessed a specific definition is required. On the cellular level, the definition of neuroprotection is relatively straightforward. Most would accept an agent as neuroprotective if it reduced the death rate in a population of cells. In this context, visual examination of cells surviving in culture, following a toxic stressor, would allow conclusions regarding the neuroprotective effect of an agent. In experiments where neuropathological studies can be performed serially, for example in an experimental group of animals, comments concerning cellular neuroprotection can likewise be made. In this context, experimental models can be constructed, based on knowledge of a given deleterious phenomenon, including its mechanisms and natural evolution, and potential neuroprotective influences proposed (e.g. MPTP-induced parkinsonism – oxidative stress/excitotoxicity – MAO inhibitors). Similarly, when the cause of a human disease is known, as in the case of Wilson’s disease or subacute combined degeneration of the cord, chelation and vitamin therapy may be regarded as providing a kind of neuroprotection. By contrast, in the distinctly human condition of IP, the mechanism and natural evolution of the disorder are not known or quantifi-ably defined. Furthermore, practical access to visualizing neuronal populations from the brains of living patients is impossible. Consequently, it is difficult to define neuroprotection in this context. This difficulty has been recognized by the PDSG. The DATATOP design [1,2, 6] is representative of the framework for several human neuroprotective studies and therefore worthy of further consideration. Information from three sources seems essential for establishing a convincing neuroprotective story: (1) An ongoing pathogenic mechanism must be identified. In IP, some evidence suggests a disturbance in oxidative pathways in the substantia nigra. This has been taken, in the DATATOP study, as indicating a primary role for free radical/oxidative stress in the development of parkinsonism [6]. However, others speak with equal conviction and evidence against the oxidative stress hypothesis [7]. Alternatively, or perhaps additionally, it has been postulated that continuous exposure to an environmental pro-toxin may contribute to the demise of nigral neuronal function [6]. However, to date no relevant protoxin has been identified in the environment. Furthermore, it has been shown that, at least in some other forms of parkinsonism, a transient exposure to a toxic agent such as manganese [8] or MPTP [9] may lead to a chronically pro-gresssive condition. One can only speculate as to whether the cause(s) of IP is (are) an event or process [10]. © 1994 S.Karger AG, Basel 0014-3022/94/0341-0001 $5.00/0 The neuroprotective agent must have a predominant effect on the identified pathogenic mechanism. De-prenyl was thought to afford cellular neuroprotection by decreasing the propensity of MAO B to produce free radical compounds resulting from deamination of catecholamines [6]. However, as has been subsequently pointed out by others, including the PDSG [1], the termination of dopamine synaptic action is primarily mediated by reuptake and MAO type A is actually the isoform which predominates in striatal neurons (rather than type B). Consequently, inhibitors of MAO A have been postulated as potentially superior neuroprotective agents. Another confounding factor in the literature is the recent report that deprenyl may also rescue neurons through a neuro-trophic-like effect [11]. Neuroprotection must be operationally defined in a way that allows experimental study and, more specifically, measurement. The DAT ATOP study relied on clinical assessment for quantifying neuroprotection. Unfortunately, there is a major gap in our knowledge concerning the pathological evolution of IP and its clinical progression. Clinical features seem to appear only when some half of the normal complement of nigro-striatal dopaminergic neurons remain; from that point onward the relationship becomes uncharted. However, even if this relationship were known, it would be an impossible task to distinguish symptomatic from neuroprotective effects if clinical indices were the sole measuring instrument. The theoretical possibility of differentiating the two mechanisms by wash-in and wash-out examinations [4] is saddled with the problem of separating a delayed (post wash-in) or prolonged (post wash-out) symptomatic effect from neuroprotection. A good example of this complication was provided by the DATATOP study which demonstrated, by an extended wash-out [1], that part of the symptomatic effect had initially been missed [2]. Using clinical assessment as the sole yardstick, the DATATOP study showed that the symptomatic effect of deprenyl may have been sufficient to explain the difference in outcome for the patients treated with