Misoprostol Reverse Hippocampal Neuron Cyclooxygenase-2 Downstream Signaling Imbalance in Aluminum-Overload Rats

Guo, Yuanxin; Lei, Wenjuan; Wang, Jianfeng; Hu, Xinyue; Wei, Yue; Ji, Chaonan; Yang, Junqing

doi:10.2174/1567205013666160401114601

Cited by 6 publications

(8 citation statements)

References 45 publications

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“…24,25 Our previous study showed that the four different receptor subtypes of PGE2 participated in brain injury caused by aluminum overload. 26 On the basis of these reports, we hypothesized that COX2 and its downstream signaling pathway may participate in cognitive impairment in diabetic rats, and that a COX2 inhibitor will have a protective effect on diabetic cognitive impairment. In this study, we investigated the protection of meloxicam on cognitive impairment in diabetic rats as well as the alterations of COX2, PGE2, and its downstream pathway.…”

Section: ■ Introductionmentioning

confidence: 99%

Meloxicam Improves Cognitive Impairment of Diabetic Rats through COX2-PGE2-EPs-cAMP/pPKA Pathway

Luo

et al. 2018

Mol. Pharmaceutics

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Diabetics often face greater risk of cognitive impairment than nondiabetics. However, how to prevent this disease is still unconfirmed. In this study, we investigated the potential protection and mechanism of meloxicam on cognitive impairment in diabetic rats. The diabetic rat model was established with a high-fat diet and a small dose of streptozotocin (40 mg/kg). The changes of spatial learning and memory, histopathology, and the protein expressions of amyloid protein precursor (APP) and β-amyloid (Aβ) indicated that diabetic rats had neuronal injury and cognitive impairment. Tumor necrosis factor α (TNFα), interleukin 6 (IL-6), C reactive protein (CRP) and prostaglandin E2 (PGE2) levels, and microglial cell number were significantly increased in the diabetic rat brain. Meanwhile, the protein expressions of APP, Aβ, cyclooxygenases2 (COX2), E-type prostanoid recptors 1 (EP1) and EP2, and the level of cyclic adenosine monophosphate (cAMP) were significantly increased, while the protein expressions of EP3 and phosphorylated protein kinase A (pPKA) were significantly decreased in the diabetic rat hippocampus and cortex. However, the EP4 protein expression had no significant changes. Meloxicam significantly improved neuronal injury and cognitive impairment, and significantly decreased inflammatory cytokines levels. Meloxicam also significantly decreased the protein expressions of APP, Aβ, COX2, EP1 and EP2, and the level of cAMP and significantly increased the EP3 and pPKA protein expressions in rat hippocampus and cortex. However, meloxicam did not significantly influence the levels of blood glucose, lipids, and insulin of rats. Our results suggest that meloxicam could significantly protect diabetic rats from cognitive impairment via a mechanism that may be associated with rebalancing the COX2-PGE2-EPs-cAMP/PKA pathway.

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Section: ■ Introductionmentioning

confidence: 99%

Meloxicam Improves Cognitive Impairment of Diabetic Rats through COX2-PGE2-EPs-cAMP/pPKA Pathway

Luo

et al. 2018

Mol. Pharmaceutics

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“…Liang reported that EP4 agonist reduces infarct volume and ameliorates long term behavioral deficits after ischemia, whereas genetic inactivation of EP4 worsened stroke outcome [ 69 ]. Contrary to the studies, our previous study demonstrated that PGES-PGE2-EP4 signaling pathway disorders might related to cerebral injury and neuronal degeneration rats caused by chronic aluminum overload [ 66 ]. In present study, the expression EP4 mRNA in aluminum overload group significantly increased compared with control group.…”

Section: Discussionmentioning

confidence: 82%

“…McCullough reported that activation of EP2 receptor can protect against toxicity in ischemia, hypoxia and excitotoxic models in a cAMP dependent manner, while genetic deletion of EP2 receptor can exacerbate infarction of cerebral cortex and subcortical structures [ 65 ]. Our previous study demonstrated that PGES-PGE2-EP2 signaling pathway disorders might have a vital role in cerebral injury and neuronal degeneration rats caused by chronic aluminum overload, while the mechanism of which is still unknown [ 66 ]. In the present study, EP2 was highly expressed in aluminum overload primary hippocampal neurons, whereas treatment with EP2 antagonist (AH6809) aggravated the aluminum-overload damage.…”

Section: Discussionmentioning

confidence: 99%

“…found that stimulation of EP3 receptor by sulprostone resulted in a significant rescue of CA1 neurons in the hippocampal slices treated with NMDA [ 9 ]. Previous study indicate that the activation of PGE2-EP3 signaling contribute to neuroprotective effect on neurodegeneration of APP/PS1 mice [ 66 , 72 ]. However, some investigator state that EP3 aggravates neurotoxicity.…”

Section: Discussionmentioning

confidence: 99%

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Effect of PGE2-EPs pathway on primary cultured rat neuron injury caused by aluminum

et al. 2017

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To observe the characteristic changes of PGE2-EPs pathway and divergent functions of PGE2 receptor subtypes on neuronal injury. The primary cultured rat hippocampus neuron injury model was established via aluminum maltolate (100 μM). The aluminum-overload neurons were treated with the agonists of EP1 (17-phenyl trinor Prostaglandin E2 ethyl amide), EP2 (Butaprost), EP3 (Sulprostone) and EP4 (CAY10598) and antagonists of EP1 (SC-19220), EP2 (AH6809) and EP4 (L-161982) at different concentrations, respectively. The neuronal viability, lactate dehydrogenase leakage rate and PGE2 content were detected by MTT assay, lactate dehydrogenase assay kit and enzyme-linked immunosorbent assay, respectively. The mRNA and protein expressions of mPGES-1 and EPs were determined by RT-PCR and western blot, respectively. The pathomorphology was identified by hematoxylin-eosin staining. In the model group, neuronal viability significantly decreased, while lactate dehydrogenase leakage rate and PGE2 content increased. The mPGES-1, EP1, EP2 and EP4 mRNA expression, and the mPGES-1, EP1 and EP2 protein expression increased, while EP3 level decreased. EP3 agonist exerted protective function in neuronal viability and lactate dehydrogenase leakage rate, while EP1 agonist, EP2 and EP4 antagonist exerted an opposite effect. In conclusion, aluminum-overload caused an imbalance of PGE2-EP1-4 pathway and activation of EP receptor may provide a viable therapeutic target in neuronal injury.

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“…Proceed as follows: dewaxing in xylen, hydration in alcohols, HE staining, dehydration in alcohols, transparent in xylen and mounting with neutral resins. Ten consecutive fields were selected randomly from the hippocampal and cortical neurons, and the morphological changes were observed under an optical microscope (Olympus, Japan) at 400× magnification ( Guo et al, 2016 ).…”

Section: Methodsmentioning

confidence: 99%

Adapentpronitrile, a New Dipeptidyl Peptidase-IV Inhibitor, Ameliorates Diabetic Neuronal Injury Through Inhibiting Mitochondria-Related Oxidative Stress and Apoptosis

Lü

Han

Luo

et al. 2018

Front. Cell. Neurosci.

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Our previous studies indicated that adapentpronitrile, a new adamantane-based dipeptidyl peptidase-IV (DPP-IV) inhibitor, has a hypoglycemic effect and ameliorates rat pancreatic β cell dysfunction in type 2 diabetes mellitus through inhibiting DPP-IV activity. However, the effect of adapentpronitrile on the neurodegenerative diseases has not been studied. In the present study, we first found that adapentpronitrile significantly ameliorated neuronal injury and decreased amyloid precursor protein (APP) and amyloid beta (Aβ) expression in the hippocampus and cortex in the high fat diet/STZ rat model of diabetes. Furthermore, adapentpronitrile significantly attenuated oxidative stress, downregulated expression of the pro-apoptotic proteins BAX, cytochrome c, caspase-9, and caspase-3, and upregulated expression of the anti-apoptotic protein Bcl-2, although there was no effect on GLP-1R expression. At 30 min post-injection of adapentpronitrile (50 mg/kg) via the tail vein, its concentration in normal rat brain was 0.2034 ± 0.0094 μg/g. Subsequently, we further confirmed the neuroprotective effects and mechanism of adapentpronitrile in HT22 cells treated with high glucose (HG) and aluminum maltolate [Al(mal)3] overload, respectively. Our results showed significant decreases in mitochondrial membrane potential (MTP) and Bcl-2 expression, accompanied by a significant increase in apoptosis, reactive oxygen species (ROS) generation, and the expression of pro-apoptotic proteins in HT22 cells exposed to these stimuli. Adapentpronitrile treatment protected against neuronal injury, suppressed ROS generation, and reduced MTP and mitochondrial apoptosis in HT22 cells; however, DPP-IV activity was not detected. Our results suggest that adapentpronitrile protects against diabetic neuronal injury, at least partially, by inhibiting mitochondrial oxidative stress and the apoptotic pathway in a DPP-IV-independent manner.

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Misoprostol Reverse Hippocampal Neuron Cyclooxygenase-2 Downstream Signaling Imbalance in Aluminum-Overload Rats

Cited by 6 publications

References 45 publications

Meloxicam Improves Cognitive Impairment of Diabetic Rats through COX2-PGE2-EPs-cAMP/pPKA Pathway

Meloxicam Improves Cognitive Impairment of Diabetic Rats through COX2-PGE2-EPs-cAMP/pPKA Pathway

Effect of PGE2-EPs pathway on primary cultured rat neuron injury caused by aluminum

Adapentpronitrile, a New Dipeptidyl Peptidase-IV Inhibitor, Ameliorates Diabetic Neuronal Injury Through Inhibiting Mitochondria-Related Oxidative Stress and Apoptosis

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