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Inhibition of phosphodiesterase-4 reverses the cognitive dysfunction and oxidative stress induced by Aβ25-35 in rats
Yeye Zhuo1,2, Haibiao Guo1, Yufang Cheng1
1Department of Pharmacology, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, China.
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.
Insights
Rolipram, a phosphodiesterase-4 (PDE4) inhibitor, improved learning and memory in an Alzheimer's disease (AD) rat model. It demonstrated significant antioxidative effects, reducing oxidative stress and restoring key antioxidant levels in the hippocampus.
Area of Science:
- Neuroscience
- Pharmacology
- Biochemistry
Background:
- Phosphodiesterase-4 (PDE4) inhibitors increase cAMP levels, enhancing cognition.
- Alzheimer's disease (AD) is characterized by cognitive decline and oxidative stress.
- Amyloid-beta (Aβ) peptide is implicated in AD pathogenesis and induces oxidative damage.
Purpose of the Study:
- To investigate the antioxidative effects and therapeutic potential of rolipram in an Aβ25-35-induced rat model of Alzheimer's disease.
- To evaluate rolipram's impact on learning, memory, and oxidative stress markers in the hippocampus.
Main Methods:
- Rats were administered Aβ25-35 to induce an AD-like state.
- Rolipram was administered intraperitoneally at varying doses (0.1, 0.5, 1.25 mg/kg) daily for 25 days.
- Cognitive function was assessed using the passive avoidance and Morris water maze tests.
- Oxidative stress markers (ROS, MDA, GSH, SOD) and molecular pathways (Trx, iNOS/NO) were analyzed in hippocampal tissue.
Main Results:
- Chronic rolipram administration prevented memory impairments in the Aβ25-35-treated rats.
- Rolipram significantly reduced reactive oxygen species (ROS) and malondialdehyde (MDA) levels.
- It restored glutathione (GSH) levels and superoxide dismutase (SOD) activity.
- Rolipram upregulated thioredoxin (Trx) and inhibited the inducible nitric oxide synthase/nitric oxide (iNOS/NO) pathway.
Conclusions:
- Rolipram ameliorates cognitive deficits in an Aβ25-35-induced AD rat model.
- The therapeutic effects of rolipram are attributed to its potent antioxidative properties.
- Rolipram modulates key molecular pathways involved in oxidative stress and neuronal function in the hippocampus.
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