Inhibition of phosphodiesterase-4 reverses the cognitive dysfunction and oxidative stress induced by Aβ25–35 in rats

Abstract

Phosphodiesterase-4 (PDE4) inhibitors prevent the breakdown of the second messenger cAMP and have been demonstrated to improve learning in several animal models of cognition. In this study, we explored the antioxidative effects of rolipram in Alzheimer's disease (AD) by using bilateral Aβ25-35 injection into the hippocampus of rats, which were used as an AD model. Rats received 3 intraperitoneal (i.p.) doses of rolipram (0.1, 0.5 and 1.25 mg/kg) daily after the injection of Aβ25-35 for 25 days. Chronic administration of rolipram prevented the memory impairments induced by Aβ25-35, as assessed using the passive avoidance test and the Morris water maze test. Furthermore, rolipram significantly reduced the oxidative stress induced by Aβ25-35, as evidenced by the decrease in the levels of reactive oxygen species (ROS) and malondialdehyde (MDA), and restored the reduced GSH levels and superoxide dismutase (SOD) activity. Moreover, western blotting and real-time reverse transcription polymerase chain reaction (RT-PCR) analysis showed that rolipram remarkably upregulated thioredoxin (Trx) and inhibited the inducible nitric oxide synthase/nitric oxide (iNOS/NO) pathway in the hippocampus. These results demonstrated that rolipram improved the learning and memory abilities in an Aβ25-35-induced AD rat model. The mechanism underlying these effects may be due to the noticeable antioxidative effects of rolipram.

The phosphodiesterase type 2 inhibitor BAY 60‐7550 reverses functional impairments induced by brain ischemia by decreasing hippocampal neurodegeneration and enhancing hippocampal neuronal plasticity

“…Growing attention has been given to the potential of PDEs as therapeutic targets for affective disorders and/or diseases affecting cognitive functions (Wang et al ., ). The utility of blocking cyclic nucleotide hydrolysis by selective PDE inhibitors (PDE‐I) has been recognized in several brain conditions, including depression (Berton & Nestler, ; Li et al ., ), schizophrenia (Soares et al ., ; Heckman et al ., ; Shim et al ., ), Alzheimer's disease (Sallustio & Studer, ; Su et al ., ; Zhuo et al ., ) and ischemia (Hu et al ., ; Kim et al ., ; Moretti et al ., ; Soares et al ., ; Takagi & Hara, ). Moreover, PDE‐Is have been considered therapeutic tools for the treatment of cognitive decline (Heckman et al ., ) and affective disorders (Zhu et al ., ) often impaired in these brain conditions.…”

Inhibition of phosphodiesterase 4 by FCPR16 protects SH-SY5Y cells against MPP+-induced decline of mitochondrial membrane potential and oxidative stress

“…Phosphodiesterase 4 (PDE4) inhibitors are potent and promising neuroprotectants against neurodegenrative diseases, mental disorders and acute brain injuries [15] , [16] , [17] . Our previous studies showed that inhibition of PDE4 by rolipram is effective to reverse Aβ-induced cognitive impairment and neuronal apoptosis in rats [18] , and the neuroprotective effect of rolipram may be due to the antioxidative effects, as evidenced by the decreased level of ROS, and increased activity of antioxidant enzymes in mice treated with rolipram [19] . As for PD, PDE4 is highly expressed in the basal ganglia in the brain [20] , and administration of PDE4 selective inhibitors has been shown to have protective effects against MPP + -induced neuronal loss in nigral neurons [21] .…”

Roflumilast promotes memory recovery and attenuates white matter injury in aged rats subjected to chronic cerebral hypoperfusion

“…PDE4 inhibition has also been shown to play an important role in cognitive function (Bender & Beavo, 2006). For example, the prototypical PDE4 inhibitor (PDE4-I) rolipram improved memory in healthy rats (Rutten et al, 2006) and reversed memory deficits that were induced by scopolamine (Imanishi et al, 1997), MK-801 (Zhang and O'Donnell, 2000;Rutten et al, 2007), and Aβ protein (Gong et al, 2004;Zhuo et al, 2016) in rodents. Rolipram also improved spatial memory in aged rats that presented hypertension (Jabaris et al, 2015a).…”