A neuroinflammatory response is commonly involved in the progression of many neurodegenerative diseases. Potassium 2-(1-hydroxypentyl)-benzoate(PHPB), a novel neuroprotective compound, has shown promising effects in t...A neuroinflammatory response is commonly involved in the progression of many neurodegenerative diseases. Potassium 2-(1-hydroxypentyl)-benzoate(PHPB), a novel neuroprotective compound, has shown promising effects in the treatment of ischemic stroke and Alzheimer's disease(AD). In the present study, the anti-inflammatory effects of PHPB were investigated in the plasma and brain of C57BL/6 mice administered a single intraperitoneal(i.p.) injection of lipopolysaccharide(LPS). Levels of i NOS and the cytokines TNFα, IL-1β and IL-10 were elevated in plasma, cerebral cortex and hippocampus after LPS injection and the number of microglia and astrocytes in cortex and hippocampus were increased. LPS also upregulated the expression of heme oxygenase-1(HO-1) in the cortex and hippocampus. PHPB reduced the levels of i NOS and cytokines in the plasma and brain, decreased the number of microglia and astrocytes and further enhanced the upregulation of HO-1. In addition, PHPB inhibited the LPS-induced phosphorylation of ERK, P38 and JNK. These results suggest that PHPB is a potential candidate in the treatment of neurodegenerative diseases through inhibiting neuroinflammation.展开更多
Potassium 2-(1-hydroxypentyl)-benzoate(PHPB) is a novel drug candidate for acute ischemic stroke. PHPB has been also shown to be beneficial for some neurodegenerative diseases. In this study, we demonstrated that PHPB...Potassium 2-(1-hydroxypentyl)-benzoate(PHPB) is a novel drug candidate for acute ischemic stroke. PHPB has been also shown to be beneficial for some neurodegenerative diseases. In this study, we demonstrated that PHPB improved depressive-like behaviors induced by chronic unpredictable mild stress(CUMS) in rats. Male SD rats were subjected to the stress for five weeks. PHPB(30 and 100 mg/kg) or fluoxetine(FLX 10 mg/kg, as positive control) was administered orally from the third week in CUMS procedure. The behavioral tests were applied and then the biochemical studies were carried out. PHPB or FLX treatment rescued the behavioral deficiency in CUMS-exposed rats. Meanwhile, PHPB normalized the enhanced level of serum corticosterone, improved hippocampal and serum BDNF levels, as well as p-CREB level in hippocampus. In addition, PHPB could reverse the reduced level of extracellular 5-HT and its metabolite 5-HIAA in prefrontal cortex(PFC) of depressed rats. In summary, our results showed that PHPB improved depression-like behaviors in CUMS-exposed rats. The mechanisms might relate to the reverse of neurotrophic disturbance in the brain, reducing excessive HPA axis response and facilitating the release of 5-HT.展开更多
Potassium 2-(1-hydroxypentyl)-benzoate(D,L-PHPB), a new drug candidate for ischemic stroke at the phase II clinic trial, has been shown to protect neurons by inhibiting oxidative injury and reducing neuron apoptosis i...Potassium 2-(1-hydroxypentyl)-benzoate(D,L-PHPB), a new drug candidate for ischemic stroke at the phase II clinic trial, has been shown to protect neurons by inhibiting oxidative injury and reducing neuron apoptosis in previous studies. But the mechanisms of D,L-PHPB remain to be studied.In this study, a neuron–astrocytes co-culture system was used to elucidate the roles of astrocytes in neuroprotection of D,L-PHPB under oxygen-glucose deprivation/reoxygenation(OGD/R) condition. Our data showed that D,L-PHPB reduced neuronal apoptosis in mono-culture system and this effect was enhanced in neuron–astrocyte co-culture system under the OGD/R condition. Meanwhile, D,L-PHPB obviously increased the levels of brain-derived neurotrophic factor(BDNF) and nerve growth factor(NGF), which were mainly secreted from astrocytes, in the co-culture system after OGD/R. The PI3K/AKT and ERK signaling pathways as well as the p-TRKA/B receptors were involved in the process. In addition, the levels of TNF-α and IL-1β secreted from astrocytes after OGD/R were markedly reduced after D,L-PHPB treatment, which was mainly due to the suppression of phosphorylated p38. In conclusion, the present study demonstrates that the neuroprotective effects of D,L-PHPB were improved by astrocytes, mainly mediated by increasing the release of BDNF/NGF and attenuating inflammatory cytokines.展开更多
基金supported by grants from the National Natural Science Foundation of China (No. 81373387)the Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Studies (BZ0150).
文摘A neuroinflammatory response is commonly involved in the progression of many neurodegenerative diseases. Potassium 2-(1-hydroxypentyl)-benzoate(PHPB), a novel neuroprotective compound, has shown promising effects in the treatment of ischemic stroke and Alzheimer's disease(AD). In the present study, the anti-inflammatory effects of PHPB were investigated in the plasma and brain of C57BL/6 mice administered a single intraperitoneal(i.p.) injection of lipopolysaccharide(LPS). Levels of i NOS and the cytokines TNFα, IL-1β and IL-10 were elevated in plasma, cerebral cortex and hippocampus after LPS injection and the number of microglia and astrocytes in cortex and hippocampus were increased. LPS also upregulated the expression of heme oxygenase-1(HO-1) in the cortex and hippocampus. PHPB reduced the levels of i NOS and cytokines in the plasma and brain, decreased the number of microglia and astrocytes and further enhanced the upregulation of HO-1. In addition, PHPB inhibited the LPS-induced phosphorylation of ERK, P38 and JNK. These results suggest that PHPB is a potential candidate in the treatment of neurodegenerative diseases through inhibiting neuroinflammation.
基金supported by grants of National Nature Science Foundation of China (No. 81573417)the CAMS Initiative for Innovative Medicine (CAMS-I2M-1-010, China)the Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study (BZ0150, China)
文摘Potassium 2-(1-hydroxypentyl)-benzoate(PHPB) is a novel drug candidate for acute ischemic stroke. PHPB has been also shown to be beneficial for some neurodegenerative diseases. In this study, we demonstrated that PHPB improved depressive-like behaviors induced by chronic unpredictable mild stress(CUMS) in rats. Male SD rats were subjected to the stress for five weeks. PHPB(30 and 100 mg/kg) or fluoxetine(FLX 10 mg/kg, as positive control) was administered orally from the third week in CUMS procedure. The behavioral tests were applied and then the biochemical studies were carried out. PHPB or FLX treatment rescued the behavioral deficiency in CUMS-exposed rats. Meanwhile, PHPB normalized the enhanced level of serum corticosterone, improved hippocampal and serum BDNF levels, as well as p-CREB level in hippocampus. In addition, PHPB could reverse the reduced level of extracellular 5-HT and its metabolite 5-HIAA in prefrontal cortex(PFC) of depressed rats. In summary, our results showed that PHPB improved depression-like behaviors in CUMS-exposed rats. The mechanisms might relate to the reverse of neurotrophic disturbance in the brain, reducing excessive HPA axis response and facilitating the release of 5-HT.
文摘Potassium 2-(1-hydroxypentyl)-benzoate(D,L-PHPB), a new drug candidate for ischemic stroke at the phase II clinic trial, has been shown to protect neurons by inhibiting oxidative injury and reducing neuron apoptosis in previous studies. But the mechanisms of D,L-PHPB remain to be studied.In this study, a neuron–astrocytes co-culture system was used to elucidate the roles of astrocytes in neuroprotection of D,L-PHPB under oxygen-glucose deprivation/reoxygenation(OGD/R) condition. Our data showed that D,L-PHPB reduced neuronal apoptosis in mono-culture system and this effect was enhanced in neuron–astrocyte co-culture system under the OGD/R condition. Meanwhile, D,L-PHPB obviously increased the levels of brain-derived neurotrophic factor(BDNF) and nerve growth factor(NGF), which were mainly secreted from astrocytes, in the co-culture system after OGD/R. The PI3K/AKT and ERK signaling pathways as well as the p-TRKA/B receptors were involved in the process. In addition, the levels of TNF-α and IL-1β secreted from astrocytes after OGD/R were markedly reduced after D,L-PHPB treatment, which was mainly due to the suppression of phosphorylated p38. In conclusion, the present study demonstrates that the neuroprotective effects of D,L-PHPB were improved by astrocytes, mainly mediated by increasing the release of BDNF/NGF and attenuating inflammatory cytokines.
