scholarly journals The Phosphodiesterase-4 Inhibitor Roflumilast, a Potential Treatment for the Comorbidity of Memory Loss and Depression in Alzheimer’s Disease: A Preclinical Study in APP/PS1 Transgenic Mice

2020 ◽  
Vol 23 (10) ◽  
pp. 700-711 ◽  
Author(s):  
Hao Wang ◽  
Fang-fang Zhang ◽  
Yong Xu ◽  
Hua-rong Fu ◽  
Xiao-dan Wang ◽  
...  
Keyword(s):  
Forced Swimming Test ◽  
Memory Loss ◽  
Tail Suspension Test ◽  
Camp Response Element Binding ◽  
Novel Object Recognition ◽  
The Novel ◽  
Camp Response Element ◽  
Phosphodiesterase 4 ◽  
Element Binding Protein ◽  
Swimming Test

Abstract Background Depression is highly related to Alzheimer’s disease (AD), yet no effective treatment is available. Phosphodiesterase-4 (PDE4) has been considered a promising target for treatment of AD and depression. Roflumilast, the first PDE4 inhibitor approved for clinical use, improves cognition at doses that do not cause side effects such as emesis. Methods Here we examined the effects of roflumilast on behavioral dysfunction and the related mechanisms in APPswe/PS1dE9 transgenic mice, a widely used model of AD. Mice at 10 months of age were examined for memory in the novel object recognition and Morris water-maze tests and depression-like behavior in the tail-suspension test and forced swimming test before killing for neurochemical assays. Results In the novel object recognition and Morris water-maze, APPswe/PS1dE9 mice showed significant cognitive declines, which were reversed by roflumilast at 5 and 10 mg/kg orally once per day. In the tail-suspension test and forced swimming test, the AD mice showed prolonged immobility time, which was also reversed by roflumilast. In addition, the staining of hematoxylin–eosin and Nissl showed that roflumilast relieved the neuronal cell injuries, while terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labelling analysis indicated that roflumilast ameliorated cell apoptosis in AD mice. Further, roflumilast reversed the decreased ratio of B-cell lymphoma-2/Bcl-2-associated X protein and the increased expression of PDE4B and PDE4D in the cerebral cortex and hippocampus of AD mice. Finally, roflumilast reversed the decreased levels of cyclic AMP (cAMP) and expression of phosphorylated cAMP response element-binding protein and brain derived neurotrophic factor in AD mice. Conclusions Together, these results suggest that roflumilast not only improves learning and memory but also attenuates depression-like behavior in AD mice, likely via PDE4B/PDE4D-mediated cAMP/cAMP response element-binding protein/brain derived neurotrophic factor signaling. Roflumilast can be a therapeutic agent for AD, in particular the comorbidity of memory loss and depression.

scholarly journals Antidepressant-Like Effects of Gyejibokryeong-hwan in a Mouse Model of Reserpine-Induced Depression

2018 ◽  
Vol 2018 ◽  
pp. 1-12 ◽  
Author(s):  
Bo-Kyung Park ◽  
Yu Ri Kim ◽  
Young Hwa Kim ◽  
Changsop Yang ◽  
Chang-Seob Seo ◽  
...  
Keyword(s):  
Mouse Model ◽  
Forced Swim Test ◽  
Treatment Protocol ◽  
Tail Suspension Test ◽  
Plasma Corticosterone ◽  
Camp Response Element Binding ◽  
Camp Response Element ◽  
Reserpine Treatment ◽  
Immobility Time ◽  
Element Binding Protein

Treatment with the antihypertensive agent reserpine depletes monoamine levels, resulting in depression. In the present study, we evaluated the antidepressant effects of Gyejibokryeong-hwan (GBH), a traditional Korean medicine, in a mouse model of reserpine-induced depression. Mice were treated with reserpine (0.5 mg·kg−1, i.p.) or phosphate-buffered saline (PBS, i.p., normal) once daily for 10 days. GBH (50, 100, 300, and 500 mg·kg−1), PBS (normal, control), fluoxetine (FXT, 20 mg·kg−1), or amitriptyline (AMT, 30 mg·kg−1) was administered orally 1 h prior to reserpine treatment. Mouse behavior was examined in the forced swim test (FST), tail suspension test (TST), and open-field test (OFT) following completion of the treatment protocol. Administration of GBH reduced immobility time in the FST and TST and significantly increased the total distance traveled in the OFT. Plasma serotonin levels were significantly lower in control mice than in normal mice, although these decreases were significantly attenuated to a similar extent by treatment with GBH, FXT, or AMT. Reserpine-induced increases in plasma corticosterone were also attenuated by GBH treatment. Moreover, GBH attenuated reserpine-induced increases in interleukin- (IL-) 1β, IL-6, and tumor necrosis factor- (TNF-) α mRNA expression in the hippocampus. In addition, GBH mice exhibited increased levels of brain-derived neurotrophic factor (BDNF) and a higher ratio of phosphorylated cAMP response element-binding protein (p-CREB) to CREB (p-CREB/CREB) in the hippocampus. Our results indicated that GBH can ameliorate depressive-like behaviors, affect the concentration of mood-related hormones, and help to regulate immune/endocrine dysfunction in mice with reserpine-induced depression, likely via activation of the BDNF-CREB pathway. Taken together, these findings indicate that GBH may be effective in treating patients with depression.

scholarly journals Dammarane Sapogenins Improving Simulated Weightlessness-Induced Depressive-Like Behaviors and Cognitive Dysfunction in Rats

2021 ◽  
Vol 12 ◽  
Author(s):  
Qiong Wang ◽  
Li Dong ◽  
Mengdi Wang ◽  
Shanguang Chen ◽  
Shanshan Li ◽  
...  
Keyword(s):  
Brain Function ◽  
Forced Swimming Test ◽  
Open Field Test ◽  
Space Environment ◽  
Novel Object Recognition ◽  
The Novel ◽  
Simulated Weightlessness ◽  
Object Recognition Test ◽  
Novel Object ◽  
Swimming Test

Background: Our studies demonstrated that the space environment has an impact on the brain function of astronauts. Numerous ground-based microgravity and social isolation showed that the space environment can induce brain function damages in humans and animals. Dammarane sapogenins (DS), an active fraction from oriental ginseng, possesses neuropsychic protective effects and has been shown to improve depression and memory. This study aimed to explore the effects and mechanisms of DS in attenuating depressive-like behaviors and cognitive deficiency induced by simulated weightlessness and isolation [hindlimb suspension and isolation (HLSI)] in rats.Methods: Male rats were orally administered with two different doses of DS (37.5, 75 mg/kg) for 14 days, and huperzine-A (1 mg/kg) served as positive control. Rats were subjected to HLSI for 14 days except the control group during drug administration. The depressive-like behaviors were then evaluated by the open-field test, the novel object recognition test, and the forced swimming test. The spatial memory and working memory were evaluated by the Morris water maze (MWM) test, and the related mechanism was further explored by analyzing the activity of choline acetyltransferase (ChAT), acetylcholinesterase (AChE), and superoxide dismutase (SOD) in the hippocampus of rats.Results: The results showed that DS treatment significantly reversed the HLSI-induced depressive-like behaviors in the open-field test, the novel object recognition test, and the forced swimming test and improved the HLSI-induced cognitive impairment in the MWM test. Furthermore, after DS treatment, the ChAT and SOD activities of HLSI rats were increased while AChE activity was significantly suppressed.Conclusions: These findings clearly demonstrated that DS might exert a significant neuropsychic protective effect induced by spaceflight environment, driven in part by the modulation of cholinergic system and anti-oxidation in the hippocampus.

Scutellarin Mitigates Cancer-Induced Bone Pain by Suppressing CaMKII/CREB Pathway in Rat Models

2019 ◽  
Vol 17 (3) ◽  
pp. 249-253
Author(s):  
Liu Chenglong ◽  
Liu Haihua ◽  
Zhang Fei ◽  
Zheng Jie ◽  
Wei Fang
Keyword(s):  
Protein Kinase ◽  
Bone Pain ◽  
Binding Protein ◽  
Camp Response Element Binding ◽  
Camp Response Element ◽  
Dependent Protein Kinase ◽  
Response Element ◽  
Protein Kinase Ii ◽  
Element Binding Protein ◽  
Dependent Protein

Cancer-induced bone pain is a severe and complex pain caused by metastases to bone in cancer patients. The aim of this study was to investigate the analgesic effect of scutellarin on cancer-induced bone pain in rat models by intrathecal injection of Walker 256 carcinoma cells. Mechanical allodynia was determined by paw withdrawal threshold in response to mechanical stimulus, and thermal hyperalgesia was indicated by paw withdrawal latency in response to noxious thermal stimulus. The paw withdrawal threshold and paw withdrawal latencies were significantly decreased after inoculation of tumor cells, whereas administration of scutellarin significantly attenuated tumor cell inoculation-induced mechanical and heat hyperalgesia. Tumor cell inoculation-induced tumor growth was also significantly abrogated by scutellarin. Ca2+/calmodulin-dependent protein kinase II is a multifunctional kinase with up-regulated activity in bone pain models. The activation of Ca2+/calmodulin-dependent protein kinase II triggers phosphorylation of cAMP-response element binding protein. Scutellarin significantly reduced the expression of phosphorylated-Ca2+/calmodulin-dependent protein kinase II and phosphorylated-cAMP-response element binding protein in cancer-induced bone pain rats. Collectively, our study demonstrated that scutellarin attenuated tumor cell inoculation-induced bone pain by down-regulating the expression of phosphorylated-Ca2+/calmodulin-dependent protein kinase II and phosphorylated-cAMP-response element binding protein. The suppressive effect of scutellarin on phosphorylated-Ca2+/calmodulin-dependent protein kinase II/phosphorylated-cAMP-response element binding protein activation may serve as a novel therapeutic strategy for CIBP management.

cAMP Response Element Binding Protein Is Expressed and Phosphorylated in the Human Heart

Circulation ◽  
1995 ◽  
Vol 92 (8) ◽  
pp. 2041-2043 ◽  
Author(s):  
Frank Ulrich Müller ◽  
Peter Bokník ◽  
Andreas Horst ◽  
Jörg Knapp ◽  
Bettina Linck ◽  
...  
Keyword(s):  
Human Heart ◽  
Binding Protein ◽  
Camp Response Element Binding ◽  
Camp Response Element ◽  
Response Element ◽  
Element Binding Protein
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