Use of statins in PD: further comments on Ghosh et al.

The paper by Ghosh et al. represents an interesting contribution, elegantly executed as highlighted by Ben Wolozin in his comments. I entirely share Ben Wolozin’s views on the relevance of statins to PD and his call for caution.

Translation of findings from experimental to clinical stage is indeed challenging. The vast majority of the previous experimental “neuroprotective” studies have not been investigated in what we proposed to call a clinically driven design (Bezard, 2003; Meissner et al., 2004). In our view, such a design should ideally satisfy the following three criteria. First, the chosen animal model should recapitulate most, if not all, features of sporadic PD, including its progressiveness (all acute models should thus be excluded though useful for initial screening) and its pathological landmark, i.e. the replication of Lewy body-like inclusions. Second, administration of the drug candidate should begin once neurodegeneration has started or from a pre-defined level of DA neuronal loss in order to mimic the clinical setting. Third, final proof of efficacy should be obtained from non-human primate models and not limited to rodents because it is likely that complex cell death mechanisms may differ in rodents and primates.

Ghosh et al. are among the few to fulfill the second criteria (delayed administration of the candidate), which in our mind is the main issue faced by most previous neuroprotective candidates that failed “protecting” DA neurons in such “delayed” designs. In addition, the authors have been very cautious in their use of the MPTP paradigm. Although acute, they do not exclude the need for testing the approach in more chronic models as they present their data as a first step.

As an aside note, it should noted that statins might in fact be useful at different stages of the disease. Indeed, statins offer potential as anti-dyskinetic drugs (Schuster et al., 2008). The MJFF sponsors the currently ongoing clinical trial (Clinical Intervention Award 2008) that tests the ability of simvastatin to diminish drug-induced dyskinesia in PD patients. The rationale behind the use of statin for dyskinesia is very comparable, i.e. inhibiting the isoprenylation of ras, as dyskinesia have been associated with an elevated activation of the ras-ERK signaling cascade. One difference, still, might be in the identity of the Ras subtype as, in the striatum, RasGRF1 seems the predominant species, which functional inhibition (by use of dominant-negative forms) also results in dyskinesia improvement. Would statins eventually be harmful to PD patients as in AD patients (see Wolozin’s comment), specific inhibitors of RasGRF1 would still be a candidate for dyskinesia while statins on their own would be disqualified. In that respect, the current clinical trial will bring important insights both on the potential against dyskinesia and on the safety.