The phosphodiesterase-4 inhibitor rolipram reverses Aβ-induced cognitive impairment and neuroinflammatory and apoptotic responses in rats

Abstract

β-amyloid (Aβ) peptides play an important role in cognition deficits, neuroinflammation, and apoptosis observed in Alzheimer's disease (AD). Activation of cyclic AMP (cAMP) signalling enhances memory and inhibits inflammatory and apoptotic responses. However, it is not known whether inhibition of phosphodiesterase-4 (PDE4), a critical controller of intracellular cAMP concentrations, affects AD-associated neuroinflammatory and apoptotic responses and whether these responses contribute to deficits of memory mediated by cAMP signalling. We addressed these issues using memory tests and neurochemical measures. Specifically, rats microinfused with aggregated Aβ25-35 (10 μg/side) into bilateral CA1 subregions displayed deficits in learning ability and memory, as evidenced by decreases in escape latency during acquisition trials and exploratory activities in the probe trial in the water-maze task and 24-h retention in the passive avoidance test. These effects were reversed by rolipram (0.1, 0.25 and 0.5 mg/kg.d i.p.), a prototypic PDE4 inhibitor, in a dose-dependent manner. Interestingly, Aβ25-35-treated rats also displayed decreases in expression of phosphorylated cAMP response-element binding protein (pCREB) and Bcl-2, but increases in expression of NF-κB p65 and Bax in the hippocampus; these effects were also reversed by rolipram in a dose-dependent manner. Similar neurochemical results were observed by replacing Aβ25-35 with Aβ1-42, a full-length amyloid peptide that quickly forms toxic oligomers. These results suggest that PDE4 inhibitors such as rolipram may reverse Aβ-induced memory deficits at least in part via the attenuation of neuronal inflammation and apoptosis mediated by cAMP/CREB signalling. PDE4 could be a target for treatment of memory loss associated with AD.

Phosphodiesterase-4 (PDE4) Molecular Pharmacology and Alzheimer's Disease

“…Thus, treatment with a PDE4 inhibitor may work independently of therapies aimed at lowering Aβ peptide levels in brain. It has also been shown that rolipram reverses memory deficits induced by injection of Aβ 1-40 or 25-35 into rat hippocampus CAI [39,40].…”

Blockade of Tau Hyperphosphorylation and Aβ1–42 Generation by the Aminotetrahydrofuran Derivative ANAVEX2-73, a Mixed Muscarinic and σ1 Receptor Agonist, in a Nontransgenic Mouse Model of Alzheimer’s Disease

“…It is at present widely used to detect the neuroprotective potential of new drugs and natural derivatives (Ruan et al, 2010;Kim et al, 2011;Lu et al, 2012;Wang et al, 2012;Yang et al, 2012). Interestingly, the Ab 25-35 injection resulted not only in an aggressive amyloid toxicity but also in accumulation of endogenous Ab species and Tau hyperphosphorylation, as observed in AD physiopathology.…”

Reducing Neuroinflammation in Psychiatric Disorders: Novel Target of Phosphodiesterase 4 (PDE4) and Developing of the PDE4 Inhibitors

“…Consistent with this hypothesis, the previous studies have demonstrated that rolipram reduces neuroinflammation and promotes axonal regeneration and functional recuperation following spinal cord injury [96][97][98]; [62]. More evidence have shown that PDE4 inhibitor rolipram reduces the production of proinflammatory cytokines and modulates the activity of cAMP-mediated signaling and thus regulates CREB phosphorylation and the downstream efectors [99]; [62,68], showing that potential PDE4 inhibitors may be suitable to antagonize psychiatric disorders. Unfortunately, the development of PDE4 inhibitor rolipram for therapeutic purposes has been hindered by side efects, such as emesis [100,101].…”

“…Speciically, cAMP is a ubiquitous regulator of the inflammatory response and is also a key second messenger that influences glial activity [60,61]. Additionally, recent indings have also suggested that cAMP/cAMP response elementbinding (CREB) signaling is closely involved in antiinflammatory responses [62] by suppressing the activation of glial cells (both microglia and astrocytes), decreasing the production of proinflammatory mediators, including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-12, and nitric oxide, and increasing the expression of antiinflammatory factor IL-10 [63][64][65]. Therefore, previous work has shown that the application of cAMP analogs, adenylyl cyclase (AC) activators, or PDE inhibitors, to increase the levels of intracellular cAMP, antagonizes the changes in microglial cell morphology and their production of proinflammatory cytokines when they are exposed to inflammatory stimuli [66][67].…”