Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder that involves progressive cognitive, psychiatric and motor symptoms. HD is caused by an expanded CAG/glutamine repeat and is the most common of at least nine brain diseases involving such dynamic mutations, leading to neurotoxic polyglutamine expansion in different proteins. There are a range of molecular and cellular mechanisms that have been implicated in the pathogenesis of HD (reviewed by Gil & Rego, 2008), leading to various therapeutic approaches in animal models. In this issue, Giampàet al. (2009) have administered rolipram, a phosphodiesterase type IV (PDE4) inhibitor, to R6/2 transgenic HD mice and their wild-type controls. The authors have provided evidence, using two behavioural tests, that chronic rolipram administration significantly ameliorated motor signs. Giampàet al. (2009) have also shown in the same mice that rolipram inhibits sequestration of CREB-binding protein (CBP) into intranuclear inclusions (protein aggregates) and ameliorates the reduction of parvalbumin immunopositive neurons in the striatum. While there are plenty of other molecular and cellular correlates of pathogenesis that could be examined, some of which have been investigated by this group (DeMarch et al., 2008), as well as other implicated brain areas such as the cerebral cortex, this study suggests that rolipram, and possibly other PDE4 inhibitors may be worth progressing towards clinical trials. Rolipram is thought to mediate its neuroprotective effects at least partly via activation of CREB and subsequent enhancement of brain-derived neurotrophic factor (BDNF) expression (DeMarch et al., 2008). Therefore rolipram can be added to the list of drugs that enhance BDNF expression and are beneficial in mouse models of HD, emphasising the importance of BDNF both in pathogenesis and the development of novel therapeutics (reviewed by Zuccato & Cattaneo, 2007).
This interesting study leads to some new questions, which need to be answered before rolipram could be progressed to clinical trials. Giampàet al. (2009) only look at a single late stage in their open field and rotarod motor tests. Examining earlier stages would determine whether rolipram delayed onset of behavioural signs and/or slowed progression. Furthermore, the authors did not assess the cognitive or affective abnormalities which have been reported in R6 lines of HD mice (e.g. Murphy et al., 2000; Grote et al., 2005) and which are of great clinical relevance. Associated with the issue of assessing cognitive, affective and motor behaviours, it would be of interest to repeat the rolipram study with drug administration commencing after onset of specific behavioural signs, so as to have relevance to clinical trials which would initially attempt to slow progression in cohorts of symptomatic patients (clinical trials aimed at delaying onset will also eventually be possible for HD, but currently face a number of practical challenges). Furthermore, as there is some prior evidence for neuroprotective effects of rolipram in other models, including transgenic Alzheimer’s disease mice (Gong et al., 2004), it will be interesting to establish whether rolipram is beneficial in models of other neurodegenerative diseases. Finally, it will be important to establish whether other PDE inhibitors with minimal side-effect profiles exert equivalent, or superior, effects to that of rolipram.
There are a number of other compounds which have shown promise in preclinical studies on mouse models of HD, such as histone deacetylase (HDAC) inhibitors, selective serotonin reuptake inhibitors (SSRIs) and a range of neuroprotective agents (reviewed by Wright & Barker, 2007). Therefore, with limited large cohorts available for clinical trials the prioritisation of these candidate compounds for clinical trials is absolutely crucial. Key selection criteria should include the quality of preclinical studies and their replicability across multiple models possessing construct validity, as well as key experimental parameters such as genetic and environmental factors, which optimise face validity of the respective models. In this way, the work of Giampàet al. (2009), and many others, can be critically evaluated, so as to lead to successful translation in clinical trials as soon as possible.