Selective phosphodiesterase inhibitors improve performance on the ED/ID cognitive task in rats

Introduction: Phosphodiesterase (PDE) inhibitors improve signaling pathways in brain circuits by increasing intracellular cyclic adenosine monophosphate (cAMP) and/or cyclic guanosine monophosphate (cGMP). In the last decade, the first clinical studies investigating selective PDE inhibitors in Alzheimer's disease (AD) have been initiated, based on their positive effects on cognitive processes and neuroprotection in numerous animal studies. Areas covered: This article reviews the clinical studies investigating the pro-cognitive/neuroprotective effects of PDE inhibitors in patients with AD, as well as in age-associated memory impaired elderly and patients with mild cognitive impairment (MCI), the prodromal stage of AD. PDE inhibitors will also be discussed with respect to adverse effects including safety and tolerability. Expert opinion: The limited available data of clinical studies with PDE inhibitors tested in different populations of AD patients do not allow the drawing of any concrete conclusion yet. Currently, studies with a PDE3 (cilostazol) or PDE9 inhibitor (BI 409,306) are still ongoing in patients with MCI or AD, respectively. Studies with PDE4 inhibitors (HT-0712, roflumilast and BPN14770) in healthy elderly and elderly with age-associated memory impairments indicate that the optimum dose and/or inhibiting the most relevant PDE isoform hold great promise when tested in the appropriate population of patients with MCI or AD eventually. ARTICLE HISTORY

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“…[101][102][103]). Until now no PDE10 inhibitors have been tested in clinical trials of aging and AD.…”

Section: Phosphodiesterase 10mentioning

confidence: 99%

Investigational phosphodiesterase inhibitors in phase I and phase II clinical trials for Alzheimer’s disease

Prickaerts

Heckman

Blokland

2017

Expert Opinion on Investigational Drugs

133

168

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“…Selective PDE10A inhibitors decrease psychomotor activity, reverse deficits in prepulse inhibition, and inhibit conditioned avoidance responding in rodents, models that are predictive of antipsychotic activity in the clinic (17)(18)(19)(20)(21). PDE10A inhibitors are also efficacious in preclinical assays that test cognitive domains impaired in schizophrenia (17,20,22,23) and models of negative symptoms (17).…”

mentioning

confidence: 99%

Genetic Deletion and Pharmacological Inhibition of Phosphodiesterase 10A Protects Mice From Diet-Induced Obesity and Insulin Resistance

et al. 2013

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Phosphodiesterase 10A (PDE10A) is a novel therapeutic target for the treatment of schizophrenia. Here we report a novel role of PDE10A in the regulation of caloric intake and energy homeostasis. PDE10A-deficient mice are resistant to diet-induced obesity (DIO) and associated metabolic disturbances. Inhibition of weight gain is due to hypophagia after mice are fed a highly palatable diet rich in fats and sugar but not a standard diet. PDE10A deficiency produces a decrease in caloric intake without affecting meal frequency, daytime versus nighttime feeding behavior, or locomotor activity. We tested THPP-6, a small molecule PDE10A inhibitor, in DIO mice. THPP-6 treatment resulted in decreased food intake, body weight loss, and reduced adiposity at doses that produced antipsychotic efficacy in behavioral models. We show that PDE10A inhibition increased whole-body energy expenditure in DIO mice fed a Western-style diet, achieving weight loss and reducing adiposity beyond the extent seen with food restriction alone. Therefore, chronic THPP-6 treatment conferred improved insulin sensitivity and reversed hyperinsulinemia. These data demonstrate that PDE10A inhibition represents a novel antipsychotic target that may have additional metabolic benefits over current medications for schizophrenia by suppressing food intake, alleviating weight gain, and reducing the risk for the development of diabetes.

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“…Rolipram, the PDE4 inhibitor, improved memory consolidation, working memory and information processing in rodent species subject to a variety of cognitive tasks: radial arm maze, passive avoidance, delayed arm water and visual -spatial tasks, working memory and information [25][26][27][28]. In the macaque monkey species, rolipram improved object retrieval performance suggesting positive interaction with executive function [26].…”

Section: Disc-1 Gene and Pde: Role In Schizophreniamentioning

confidence: 97%

Exploring Standardized Zembrin® Extracts from the South African plant Sceletium tortuosum in Dual Targeting Phosphodiesterase-4 (PDE-4) and Serotonin Reuptake Inhibition as potential treatment in Schizophrenia

Chiu¹

2017

IJCAM

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Selective phosphodiesterase inhibitors improve performance on the ED/ID cognitive task in rats

Cited by 67 publications

References 89 publications

Investigational phosphodiesterase inhibitors in phase I and phase II clinical trials for Alzheimer’s disease

Investigational phosphodiesterase inhibitors in phase I and phase II clinical trials for Alzheimer’s disease

Genetic Deletion and Pharmacological Inhibition of Phosphodiesterase 10A Protects Mice From Diet-Induced Obesity and Insulin Resistance

Exploring Standardized Zembrin® Extracts from the South African plant Sceletium tortuosum in Dual Targeting Phosphodiesterase-4 (PDE-4) and Serotonin Reuptake Inhibition as potential treatment in Schizophrenia

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