The application of PDE-Is in studies of animal cognition enhancement has been fruitful. These studies have extended our fundamental knowledge about the possible underlying cellular and molecular mechanisms of learning, memory, and other cognitive functions. However, to predict which classes of PDE-Is are possibly the most effective cognition enhancers, in either preclinical or clinical studies, depends on various factors.
First, it is important to know the exact localization of specific PDE enzymes in the normal brain (see also Table ). The localization of the enzymes might predict that certain cognitive functions that are primarily located in specific brain structures may be enhanced by some PDE-Is, but not by others. For example, PDE10 is predominantly expressed in striatal areas (Schmidt et al. 2008
) and is, therefore, a target for schizophrenia. In contrast, PDE4 is highly expressed in the hippocampus and cortex (Perez-Torres et al. 2000
) and is, therefore, considered a better target for cognition enhancement. Of note, the development of a specific antibody against a selective PDE, preferentially of the level of isoform type, will more specifically target a PDE for a certain cognitive function (Fujita et al. 2007
Secondly, it must be taken into account that the constitution of the brain changes with age and the distribution of PDEs can be modified by the aging process As a consequence, a PDE-I can improve cognition in young subjects, but impair cognition in old subjects. Likewise, Ramos et al. (2003
) demonstrated that rolipram had a positive effect on prefrontal cortex-dependent working memory in young rhesus monkeys, but had a negative effect on working memory in aged rhesus monkeys. However, rolipram improved performance in the passive avoidance task, a test of hippocampus-dependent memory, in both young and aged mice (Barad et al. 1998
). With advancing age, opposite profiles between the function of PKA in the hippocampus and prefrontal cortex were suggested to explain the results of Ramos et al. (2003
), i.e., the prefrontal cortex showed indices of increased PKA activity, while the hippocampus exhibited evidence of decreased PKA activity (Ramos et al. 2003
). In addition, is has been shown that expression of PDE5 is strongly reduced in brains of Alzheimer’s disease patients (Reyes-Irisarri et al. 2007
). However, PDE2 and PDE9 do not show this Alzheimer-related reduction in expression patterns, but show the same distribution as in healthy age-matched controls (Reyes-Irisarri et al. 2007
). Along similar lines, PDE5 inhibition did not improve object memory in aged rats (Domek-Lopacinska and Strosznajder 2008
). Consequently, when developing a PDE-I for the treatment of cognitive decline resulting from Alzheimer’s disease, PDE2-Is and PDE9-Is may be better targets in this population than PDE5-Is.
Thirdly, since most PDEs are transcribed by several genes, which give rise to multiple PDE splice variants and isoforms, further investigation into possible isoform-specific effects of PDE-Is is a field of great interest. For example, four isoforms of PDE4 mRNA have been found; PDE4A, PDE4B, PDE4C, and PDE4D. Indirect evidence suggests that PDE4A and PDE4B are involved in signaling pathways related to affective (Ye et al. 2000
) and memory (Ahmed and Frey 2003
) processes, respectively. Recently, the antidepressant potential of PDE4A in the hippocampus has been found to be related to specific splice variants of this PDE4 isoform (D’Sa et al. 2005
). The same probably holds for PDE4B and memory (Ahmed and Frey 2005
) or schizophrenia (Siuciak et al. 2008a
). PDE4D KO mice have already been generated and these animals display both an antidepressant and procognitive profile (Zhang et al. 2002
). Furthermore, it has been observed that the expression of the majority of PDE4D isoforms (1–9) was reduced in the hippocampus of patients with Alzheimer’s disease compared to healthy adults. Interestingly, PDE4D1 and PDE4D2 were increased in the brains Alzheimer’s patients (McLachlan et al. 2007
). These findings underscore the relevance of further investigations into the role of isoform-specific PDEs in cognition enhancement.
Furthermore, the most widely used PDE4-I in behavioral studies, rolipram, produces severe dose-limiting emetic side effects including headache, gastric hypersecretion, and severe emesis (e.g., nausea) in humans (Zhu et al. 2001
). Novel PDE4-Is are thought to produce less emetic side effects, but thus far no human cognition studies have been reported using these second-generation PDE4-Is. Thus far, only PDE5-Is can be prescribed to humans. However, particularly cardiovascular effects limit their usefulness as a general treatment for cognitive disorders, since patients with cardiovascular indications cannot be included. In addition, central effects including visual disturbances and headache limit the use of PDE5-I such as sildenafil (Kruuse et al. 2002
). Especially chronic treatment with these drugs could be disadvantageous. Again, an isoform-specific PDE-I could circumvent the abovementioned side effects.