Jiangping Xu

The Nerve Growth Factor Signaling and Its Potential as Therapeutic Target for Glaucoma

Neuroprotective therapies which focus on factors leading to retinal ganglion cells (RGCs) degeneration have been drawing more and more attention. The beneficial effects of nerve growth factor (NGF) on the glaucoma have been recently suggested, but its effects on eye tissue are complex and controversial in various studies. Recent clinical trials of systemically and topically administrated NGF demonstrate that NGF is effective in treating several ocular diseases, including glaucoma. NGF has two receptors named high affinity NGF tyrosine kinase receptor TrkA and low affinity receptor p75NTR. Both receptors exist in cells in retina like RGC (expressing TrkA) and glia cells (expressing p75NTR). NGF functions by binding to TrkA or p75NTR alone or both together. The binding of NGF to TrkA alone in RGC promotes RGCs survival and proliferation through activation of TrkA and several prosurvival pathways. In contrast, the binding of NGF to p75NTR leads to apoptosis although it also promotes survival in some cases. Binding of NGF to both TrkA and p75NTR at the same time leads to survival in which p75NTR functions as a TrkA helping receptor. This review discusses the current understanding of the NGF signaling in retina and the therapeutic implications in the treatment of glaucoma.

FOXO signaling pathways as therapeutic targets in cancer

Many transcription factors play a key role in cellular differentiation and the delineation of cell phenotype. Transcription factors are regulated by phosphorylation, ubiquitination, acetylation/deacetylation and interactions between two or more proteins controlling multiple signaling pathways. These pathways regulate different physiological processes and pathological events, such as cancer and other diseases. The Forkhead box O (FOXO) is one subfamily of the fork head transcription factor family with important roles in cell fate decisions and this subfamily is also suggested to play a pivotal functional role as a tumor suppressor in a wide range of cancers. During apoptosis, FOXOs are involved in mitochondria-dependent and -independent processes triggering the expression of death receptor ligands like Fas ligand, TNF apoptosis ligand and Bcl‑XL, bNIP3, Bim from Bcl-2 family members. Different types of growth factors like insulin play a vital role in the regulation of FOXOs. The most important pathway interacting with FOXO in different types of cancers is the PI3K/AKT pathway. Some other important pathways such as the Ras-MEK-ERK, IKK and AMPK pathways are also associated with FOXOs in tumorigenesis. Therapeutically targeting the FOXO signaling pathway(s) could lead to the discovery and development of efficacious agents against some cancers, but this requires an enhanced understanding and knowledge of FOXO transcription factors and their regulation and functioning. This review focused on the current understanding of cell biology of FOXO transcription factors which relates to their potential role as targets for the treatment and prevention of human cancers. We also discuss drugs which are currently being used for cancer treatment along with their target pathways and also point out some potential drawbacks of those drugs, which further signifies the need for development of new drug strategies in the field of cancer treatment.

RNA Interference-Mediated Knockdown of Long-Form Phosphodiesterase-4D (PDE4D) Enzyme Reverses Amyloid-β42-Induced Memory Deficits in Mice

Phosphodiesterase-4 (PDE4) inhibitors enhance memory, increase hippocampal neurogenesis, and reverse amyloid-β (Aβ)-induced memory deficits. Here, we examined whether long-form PDE4D knockdown by lentiviral RNA construct containing a specific microRNA/miRNA-mir hairpin structure (4DmiRNA) reversed memory impairment caused by amyloid-β1-42 (Aβ42) in mice using the Morris water maze (MWM) and novelty object recognition tests. Western blotting analysis was used to assess protein levels of cAMP response element-binding protein (CREB, unphosphorylated and phosphorylated [pCREB]), brain-derived neurotrophic factor (BDNF), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and nuclear factor-κB (NF-κB) to explore the neurochemical mechanisms. Aggregated Aβ42 (0.5 μg/side) bilaterally infused in dentate gyrus decreased cAMP levels (p < 0.01) and produced memory deficits in the MWM (p < 0.01) and object recognition tests (p < 0.01). Microinfusions of lentiviruses resulted in downregulated expression of PDE4D4 and 4D5 proteins and reversed Aβ42-induced cAMP decline (p < 0.05) and memory deficits. Treatment also concomitantly increased pCREB (p < 0.05) and BDNF (p < 0.01) and reduced IL-1β (p < 0.05), TNF-α (p < 0.01), and NF-κB (p65) (p < 0.05) in the hippocampus of Aβ42-challenged mice. These results suggest that long-form PDE4D knockdown may offer a promising treatment for memory loss associated with Alzheimers disease.

Forkhead box O transcription factors as possible mediators in the development of major depression

Forkhead box O (FoxO) transcription factors play important roles in cellular physiology and biology. Recent findings indicate that FoxOs are also involved in the development of major depressive disorder. Alterations in the upstream molecules of FoxOs, such as brain derived neurotrophic factor or protein kinase B, have been linked to depression. Antidepressants, such as imipramine and venlafaxine, modify the FoxOs phosphorylation. Furthermore, FoxOs could be regulated by serotonin and norepinephrine receptor signaling as well as the hypothalamic-pituitary-adrenal axis, all of which are involved in the pathogenesis of depression. FoxOs also regulate neuronal morphology, synaptogenesis and adult hippocampal neurogenesis, which are viewed as candidate mechanisms for the etiology of depression. In this review, we emphasize the possible roles of FoxOs during the development of depression and make some strategic recommendations for future research. We propose that FoxOs and its signaling pathways may constitute potential therapeutic targets in the treatment of depression.

FFPM, a PDE4 inhibitor, reverses learning and memory deficits in APP/PS1 transgenic mice via cAMP/PKA/CREB signaling and anti-inflammatory effects.

&NA; Thus far, phosphodiesterase‐4 (PDE4) inhibitors have not been approved for application in Alzheimers disease (AD) in a clinical setting due to severe side effects, such as nausea and vomiting. In this study, we investigated the effect of FFPM, a novel PDE4 inhibitor, on learning and memory abilities, as well as the underlying mechanism in the APP/PS1 mouse model of AD. Pharmacokinetic studies have revealed that FFPM efficiently permeates into the brain, and reached peak values in plasma 2 h after orally dosing. A 3‐week treatment with FFPM, at doses of 0.25 mg/kg and 0.5 mg/kg, significantly improved the learning and memory abilities of APP/PS1 transgenic mice in the Morris water maze and the Step‐down passive avoidance task. Interestingly, we found that while rolipram (0.5 mg/kg) reduced the duration of the &agr;2 adrenergic receptor‐mediated anesthesia induced by xylazine/ketamine, FFPM (0.5 mg/kg) or the vehicle did not have an evident effect. FFPM increased the cAMP, PKA and CREB phosphorylation and BDNF levels, and reduced the NF‐&kgr;B p65, iNOS, TNF‐&agr; and IL‐1&bgr; levels in the hippocampi of APP/PS1 trangenic mice, as observed by ELISA and Western blot analysis. Taken together, our data demonstrated that the reversal effect of FFPM on cognitive deficits in APP/PS1 transgenic mice might be related to stimulation of the cAMP/PKA/CREB/BDNF pathway and anti‐inflammatory effects. Moreover, FFPM appears to have potential as an effective PDE4 inhibitor in AD treatment with little emetic potential. HighlightsFFPM reversed the learning and memory deficits in APP/PS1 transgenic mice.FFPM activated cAMP/PKA/CREB/BDNF signaling in the hippocampi of APP/PS1 mice.FFPM inhibited nuclear NF‐&kgr;B expression and attenuated the levels of inflammatory factors.FFPM showed a low emetic potency in mice.

Neuroprotection, learning and memory improvement of a standardized extract from Renshen Shouwu against neuronal injury and vascular dementia in rats with brain ischemia

ETHNOPHARMACOLOGICAL RELEVANCE The Renshen Shouwu capsule (RSSW) is a patented Traditional Chinese Medicine (TCM), that has been proven to improve memory and is widely used in China to apoplexy syndrome and memory deficits. To investigate the neuroprotective and therapeutic effect of the Renshen Shouwu standardized extract (RSSW) on ischemic brain neuronal injury and impairment of learning and memory related to Vascular Dementia (VD) induced by a focal and global cerebral ischemia-reperfusion injury in rats. MATERIAL AND METHODS Using in vivo rat models of both focal ischemia/reperfusion (I/R) injuries induced by a middle cerebral artery occlusion (MCAO), and VD with transient global brain I/R neuronal injuries induced by a four-vessel occlusion (4-VO) in Sprague-Dawley (SD) rats, RSSW (50,100, and 200 mg kg(-1) body weights) and Egb761® (80 mg kg(-1)) were administered orally for 20 days (preventively 6 days+therapeutically 14 days) in 4-VO rats, and for 7 days (3 days preventively+4 days therapeutically) in MCAO rats. Learning and memory behavioral performance was assayed using a Morris water maze test including a place navigation trial and a spatial probe trial. Brain histochemical morphology and hippocampal neuron survival was quantified using microscope assay of a puffin brain/hippocampus slice with cresyl violet staining. RESULTS MCAO ischemia/reperfusion caused infarct damage in rat brain tissue. 4-VO ischemia/reperfusion caused a hippocampal neuronal lesion and learning and memory deficits in rats. Administration of RSSW (50, 100, and 200mg/kg) or EGb761 significantly reduced the size of the insulted brain hemisphere lesion and improved the neurological behavior of MCAO rats. In addition, RSSW markedly reduced an increase in the brain infarct volume from an I/R-induced MCAO and reduced the cerebral water content in a dose-dependent way. Administration of RSSW also increased the pyramidal neuronal density in the hippocampus of surviving rats after transient global brain ischemia and improved the learning and memory ability of rats with 4-VO induced vascular dementia in a dose-dependent manner. CONCLUSIONS The in vivo results suggested that RSSW has significant neuroprotective effects against MCAO and 4-VO I/R injury and a therapeutic effect on cognitive disorders in VD rats. RSSW also improved the learning and memory ability of VD rats. These results convincingly demonstrated that RSSW may be useful to prevent and treat ischemia/reperfusion injury and vascular dementia disease.

Systematic correlation between spine plasticity and the anxiety/depression-like phenotype induced by corticosterone in mice.

Unraveling the pathophysiological basis for the development of and recovery from depression is a unique challenge. Dendritic plasticity has been reported to be involved in the development of depression. We modeled an anxiety/depression-like phenotype by chronic corticosterone exposure in mice and reversed this anxiety/depression-like phenotype by long-term treatment with fluoxetine (FLX). Spine density in the hippocampus was detected by Golgi–Cox staining at five time points. The data showed that 35 days of corticosterone exposure led to a decrease in spine density in CA1, concomitant with the onset of depression. Following 25 days of treatment with FLX, the decrease in both the dendritic spine density in the hippocampus and the anxiety/depression-like phenotype induced by chronic corticosterone recovered to normal levels concomitantly. Interestingly, the total spine density changes are all mainly driven by changes in thin and stubby spines, not mushroom spines, following chronic corticosterone or FLX treatment. Our results suggest that the changes in dendritic spine density in the hippocampus may be one of the pathophysiological mechanisms underlying the development of and recovery from depression, and the neuronal plasticity of CA1 is first impaired during the development of depression.

cAMP/PKA/CREB/GLT1 signaling involved in the antidepressant-like effects of phosphodiesterase 4D inhibitor (GEBR-7b) in rats

Objectives GEBR-7b, a potential phosphodiesterase 4D inhibitor, has been shown to have memory-enhancing effects in rodents. However, it is still unknown whether GEBR-7b also has the antidepressant-like effects in rats. Herein, we examined the potential of GEBR-7b to attenuate depression-like behaviors in the rat model of depression induced by chronic unpredictable stress (CUS). Next, we also investigated the alterations of cyclic adenosine monophosphate (cAMP), protein kinase A (PKA) catalytic subunit (PKAca), cAMP response element-binding (CREB), and glutamate transporter 1 (GLT1) levels produced by GEBR-7b in the rats model of depression. Methods Effects of GEBR-7b on CUS (35 days)-induced depression-like behaviors were examined by measuring immobility time in the forced swimming test (FST). Hippocampal cAMP levels were examined by enzyme-linked immunosorbent assay, whereas PKAca, phosphorylation of CREB (pCREB), CREB, and GLT1 in the hippocampus of rats were subjected to Western blot analysis. Results CUS exposure caused a depression-like behavior evidenced by the increased immobility time in FST. Depression-like behavior induced by CUS was accompanied by a significant increased GLT, decreased cAMP, PKAca, pCREB activities in hippocampus. However, repeated GEBR-7b administration significantly reversed CUS-induced depression-like behavior and changes of cAMP/PKA/CREB/GLT1 signaling. No alteration was observed in locomotor activity in open field test. Conclusion These findings indicate that GEBR-7b reversed the depression-like behaviors induced by CUS in rats, which is at least in part mediated by modulating cAMP, PKAca, pCREB, and GLT1 levels in the hippocampus of rats, supporting its neuroprotective potential against behavioral and biochemical dysfunctions induced by CUS.

Development of highly potent phosphodiesterase 4 inhibitors with anti-neuroinflammation potential: Design, synthesis, and structure-activity relationship study of catecholamides bearing aromatic rings.

In this study, catecholamides (7a-l) bearing different aromatic rings (such as pyridine-2-yl, pyridine-3-yl, phenyl, and 2-chlorophenyl groups) were synthesized as potent phosphodiesterase (PDE) 4 inhibitors. The inhibitory activities of these compounds were evaluated against the core catalytic domains of human PDE4 (PDE4CAT), full-length PDE4A4, PDE4B1, PDE4C1, and PDE4D7 enzymes, and other PDE family members. Eight of the synthesized compounds were identified as having submicromolar IC50 values in the mid-to low-nanomolar range. Careful analysis on the structure-activity relationship of compounds 7a-l revealed that the replacement of the 4-methoxy group with the difluoromethoxy group improved inhibitory activities. More interesting, 4-difluoromethoxybenzamides 7i and 7j exhibited preference for PDE4 with higher selectivities of about 3333 and 1111-fold over other PDEs, respectively. In addition, compound 7j with wonderful PDE4D7 inhibitory activities inhibited LPS-induced TNF-α production in microglia.

Involvement of norepinephrine and serotonin system in antidepressant-like effects of hederagenin in the rat model of unpredictable chronic mild stress-induced depression

Abstract Context: Previous studies from our laboratory indicated that both acute and subchronic administration of Fructus Akebiae (FAE) [the fruit of Akebiae quinata (Thunb.) Decne, (Lardizabalaceae)] produce antidepressant-like effects in animal depressive behavior tests. FAE contains approximately 70% of hederagenin (HG) as its main chemical component. Objective: This study compared the antidepressant ability of FAE with that of HG in mice and further investigated the antidepressant-like effects and potential mechanisms of HG in rats subjected to unpredictable chronic mild stress (UCMS). Materials and methods: Mice received FAE (50 mg/kg) and HG (20 mg/kg) once a day via intragastric administration (i.g.) for 3 weeks. The anxiolytic and antidepressant activities of FAE and HG were compared using elevated plus maze (EPM) and behavioral despair tests including tail suspension test (TST) and forced swimming test (FST), respectively. Antidepressant effects of HG (5 mg/kg) were assessed using the UCMS depressive rat model. Moreover, the levels of monoamine neurotransmitters and relevant gene expression in UCMS rats’ hippocampi were determined through high-performance liquid chromatography with electrochemical detection and real-time polymerase chain reaction techniques. Results: The results of our preliminary screening test suggest that HG at 20 mg/kg, while not FAE at 50 mg/kg, significantly decreased the immobility in both TST and FST compared with the vehicle group when administered chronically; however, there were no significant differences observed between the HG and the FAE group. Chronic administration of HG failed to significantly reverse the altered crossing and rearing behavioral performance, time spent in the open arm and closed entries in the EPM, even if they showed an increased tendency, but HG significantly increased the percent of sucrose preference in the sucrose preference test (SPT) and decreased the immobility time in the FST. HG showed that significant increases of norepinephrine and serotonin levels and exhibited a tendency to increase the expression of 5-hydroxytryptamine (serotonin) 1A receptor mRNA, and to significantly decrease the expression of the mRNA for the serotonin transporter (5-HTT). However, there were no significant differences in the expression of the brain-derived neurotrophic factor. Conclusion: These findings confirm the antidepressant-like effects of HG in a behavioral despair test and UCMS rat model, which may be associated with monoamine neurotransmitters and 5-HTT mRNA expression.