Phosphodiesterases as Therapeutic Targets for Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is the most common form of dementia among the elderly. In AD patients, memory loss is accompanied by the formation of beta-amyloid plaques and the appearance of tau in a pathological form. Given the lack of effective treatments for AD, the development of new management strategies for these patients is critical. The continued failure to find effective therapies using molecules aimed at addressing the anti-beta amyloid pathology has led researchers to focus on other non-amyloid-based approaches to restore memory function. Promising non-amyloid related candidate targets include phosphosdiesterases (PDEs), and indeed, Rolipram, a specific PDE4 inhibitor, was the first compound found to effectively restore cognitive deficits in animal models of AD. More recently, PDE5 inhibitors have also been shown to effectively restore memory function. Accordingly, inhibitors of other members of the PDE family may also improve memory performance in AD and non-AD animal models. Hence, in this review, we will summarize the data supporting the use of PDE inhibitors as cognitive enhancers and we will discuss the possible mechanisms of action underlying these effects. We shall also adopt a medicinal chemistry perspective that leads us to propose the most promising PDE candidates on the basis of inhibitor selectivity, brain distribution, and mechanism of action.

Drug Repositioning Approaches for the Discovery of New Therapeutics for Alzheimer's Disease

“…Puzzo et al [130] first demonstrated the preclinical efficacy of PDE5 inhibitors in AD mouse models and the findings were later confirmed by other groups [131][132][133]. Among reported PDE5 inhibitors, tadalafil and sildenafil can penetrate into the brain and ameliorate synaptic, learning, and memory deficits by modulating the cyclic guanosine monophosphate intracellular signaling pathway [130,134].…”

Roles of roflumilast, a selective phosphodiesterase 4 inhibitor, in airway diseases

“…Since cAMP response element-binding (CREB) may be modulator of processes required for memory formation (96). Rolipram was the first compound found to effectively restore cognitive defect in Alzheimer's disease animal models (97). Furthermore, roflumilast and rolipram ameliorate hypertension-induced impairment of learning and memory functions in rats (98).…”

Cyclic Adenosine Monophosphate Signalling in Inflammatory Skin Disease

“…predicted to have anti-inflammatory effects [6]. Due to their presence in immune cells, the PDE4 family of enzymes represents a potential therapeutic target to induce immune suppression [105][106][107][108]. Thus, the PDE4 family of enzymes represents a promising target in the treatment of cutaneous inflammatory conditions [109].…”