Phosphodiesterase inhibition and modulation of corticostriatal and hippocampal circuits: Clinical overview and translational considerations


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Abstract

HighlightsCorticostriatal and hippocampal circuits constitute the neurobiological basis for many neuropsychiatric disorders.PDE1, 4 and 10 inhibitors seem interesting for corticostriatal disorders due to their modulation of DAergic system.PDE3, 4 and 9 inhibitors are currently most promising for hippocampal disorders.So far, the wealth of positive preclinical data has not been able to be translated to convincing clinical efficacy.The local net amount of cAMP and/or cGMP will eventually determine the cellular and functional fate.The corticostriatal and hippocampal circuits contribute to the neurobiological underpinnings of several neuropsychiatric disorders, including Alzheimer's disease, Parkinson's disease and schizophrenia. Based on biological function, these circuits can be clustered into motor circuits, associative/cognitive circuits and limbic circuits. Together, dysfunctions in these circuits produce the wide range of symptoms observed in related neuropsychiatric disorders. Intracellular signaling in these circuits is largely mediated through the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway with an additional role for the cyclic guanosine monophosphate (cGMP)/ protein kinase G (PKG) pathway, both of which can be regulated by phosphodiesterase inhibitors (PDE inhibitors). Through their effects on cAMP response element-binding protein (CREB) and Dopamine- and cAMP-Regulated PhosphoProtein MR 32 kDa (DARPP-32), cyclic nucleotide pathways are involved in synaptic transmission, neuron excitability, neuroplasticity and neuroprotection. In this clinical review, we provide an overview of the current clinical status, discuss the general mechanism of action of PDE inhibitors in relation to the corticostriatal and hippocampal circuits and consider several translational challenges.

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