Schizophrenia is a complicated mental disorder. Although multiple hypotheses have been proposed to interpret the molecular mechanisms underlying the pathogenesis of the disease, the key pathological process is yet blurry. Early clinical studies have implicated a role of the histidine triad nucleotide-binding protein-1 (Hint1) in the pathogenesis of schizophrenia. A most recent investigation by Zhang et al has defined the activity of protein PKC gamma (PKC𝛾) in the brain using Hint1-knockout animal model. Their finding that Hint1-deficiency causes a compromised PKC𝛾 signaling in the brain may shed a new light on the glutamate hypothesis of schizophrenia.
{"title":"PKC gamma-mediated signaling and schizophrenia","authors":"Fan Zhang, Q. Qu","doi":"10.14800/TTND.985","DOIUrl":"https://doi.org/10.14800/TTND.985","url":null,"abstract":"Schizophrenia is a complicated mental disorder. Although multiple hypotheses have been proposed to interpret the molecular mechanisms underlying the pathogenesis of the disease, the key pathological process is yet blurry. Early clinical studies have implicated a role of the histidine triad nucleotide-binding protein-1 (Hint1) in the pathogenesis of schizophrenia. A most recent investigation by Zhang et al has defined the activity of protein PKC gamma (PKC𝛾) in the brain using Hint1-knockout animal model. Their finding that Hint1-deficiency causes a compromised PKC𝛾 signaling in the brain may shed a new light on the glutamate hypothesis of schizophrenia.","PeriodicalId":90750,"journal":{"name":"Therapeutic targets for neurological diseases","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66659175","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pericytes are contractile cells that wrap around the endothelial cells of capillaries throughout the body. They play an important role in regulating the blood brain barrier (BBB) and blood spinal cord barrier (BSCB). Our research group is committed to find out the characteristics of pericytes, which directly impact pathophysiological processes in CNSD. We recently reported that the pericytes from brain microvascular and spinal cord microvascular possessed the distinguishable abilities of tube-formation and migration, which provide a better understanding of pericytes in CNS. The awareness of regional microvascular pericytes heterogeneity in CNS obliges consideration that brain and spinal cord microvascular networks might differ in their barrier properties or other capacities. In vivo, our research indicated that pericytes might promote angiogenesis in spinal cord injury C57BL/6 mice. Melatonin ameliorated the loss of blood vessels and disruption of BSCB to exert a protective effect on SCI, which might be mediated by increased pericyte coverage. The upregulation of angiopoietin-1 in pericytes could inhibit inflammation and apoptosis to protect the microvessels. Generally speaking, melatonin could stabilize microvascular barrier function and microcirculation of SCI, whose mechanism was to promote the repair of the damaged BSCB.
{"title":"The pericyte: an important cell type for central nervous system diseases","authors":"Qingbin Wu, Xiaochen Yuan, Hongwei Li, R. Xiu","doi":"10.14800/TTND.900","DOIUrl":"https://doi.org/10.14800/TTND.900","url":null,"abstract":"Pericytes are contractile cells that wrap around the endothelial cells of capillaries throughout the body. They play an important role in regulating the blood brain barrier (BBB) and blood spinal cord barrier (BSCB). Our research group is committed to find out the characteristics of pericytes, which directly impact pathophysiological processes in CNSD. We recently reported that the pericytes from brain microvascular and spinal cord microvascular possessed the distinguishable abilities of tube-formation and migration, which provide a better understanding of pericytes in CNS. The awareness of regional microvascular pericytes heterogeneity in CNS obliges consideration that brain and spinal cord microvascular networks might differ in their barrier properties or other capacities. In vivo, our research indicated that pericytes might promote angiogenesis in spinal cord injury C57BL/6 mice. Melatonin ameliorated the loss of blood vessels and disruption of BSCB to exert a protective effect on SCI, which might be mediated by increased pericyte coverage. The upregulation of angiopoietin-1 in pericytes could inhibit inflammation and apoptosis to protect the microvessels. Generally speaking, melatonin could stabilize microvascular barrier function and microcirculation of SCI, whose mechanism was to promote the repair of the damaged BSCB.","PeriodicalId":90750,"journal":{"name":"Therapeutic targets for neurological diseases","volume":"66 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66659118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Neurosteroids have siginificant neuroprotection for damaged neurocell and may be developed a kind of potential neuroprotectant for treatment of ischemic stroke. In the study, twelve analogues of 5α-androst-3β,5,6β-triol were synthesized by the multiple steps of reaction from dehydroepiandrosterone (DHEA), and their structures were characterized by IR, NMR, MS. Their neuroprotective activities was tested by evaluating survival cells. The results showed that 3β,5α,6β-trihydroxy sterols (3,4a-4e,5a-5e,11) exhibited certain neuroprotective effect on rat cerebellar granule neurons (CGN) against apoptosis induced by glutamic acid in vitro, and compound 5d and 5e exhibited better neuroprotection with the dose-response relationship.
{"title":"Synthesis and neuroprotection of 5α-androst-3β,5,6β-triol derivatives","authors":"Xinhua Li, Xinying Chen, Jiesi Chen, Shujia Zhou, Jin Wen, Yijun Huang, Guangmei Yan, Jingxia Zhang","doi":"10.14800/TTND.831","DOIUrl":"https://doi.org/10.14800/TTND.831","url":null,"abstract":"Neurosteroids have siginificant neuroprotection for damaged neurocell and may be developed a kind of potential neuroprotectant for treatment of ischemic stroke. In the study, twelve analogues of 5α-androst-3β,5,6β-triol were synthesized by the multiple steps of reaction from dehydroepiandrosterone (DHEA), and their structures were characterized by IR, NMR, MS. Their neuroprotective activities was tested by evaluating survival cells. The results showed that 3β,5α,6β-trihydroxy sterols (3,4a-4e,5a-5e,11) exhibited certain neuroprotective effect on rat cerebellar granule neurons (CGN) against apoptosis induced by glutamic acid in vitro, and compound 5d and 5e exhibited better neuroprotection with the dose-response relationship.","PeriodicalId":90750,"journal":{"name":"Therapeutic targets for neurological diseases","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66659071","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Radiation-induced cognitive impairment is one of the late adverse effects of cranial radiation therapy (CRT) for cancer patients with primary and metastatic brain tumors, head and neck cancers etc. It affects approximately 40-50% patients who survive for >6 months and severely reduces the quality of survivors' life. With the advancement of radiation therapy technology, the survival of brain tumor patients is significantly improved, thus understanding the etiology of CRT-induced cognitive impairment and developing the potential strategies of the management of this side-effect have become more important than ever. Some valuable insights have been obtained through extensive preclinical studies. It is suggested that radiation-induced cognitive impairment is due to the dysfunctions of hippocampus-dependent learning, memory and spatial information processing after radiation exposure. Until now, research results have shown that radiation-induced cognitive impairment and neurodegenerative disorders such as Alzheimer disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and aging-related cognitive decline, share some similar pathogenic factors, including chronic oxidative stress and inflammation, impairment in neurogenesis and angiogenesis. Blockade of these factors by antioxidants, anti-inflammatory drugs, transplant of neural stem cells, systemic hypoxia etc. can significantly ameliorate cognitive decline in cranially irradiated experimental animals. These studies shed the light on the pathogenesis of radiation-induced cognitive impairment and may have important implication in developing novel therapeutic interventions for surviving cancer patients who suffer from cognitive decline after CRT.
{"title":"Radiation-induced cognitive impairment","authors":"Liyuan Zhang, Hongying Yang, Ye Tian","doi":"10.14800/TTND.837","DOIUrl":"https://doi.org/10.14800/TTND.837","url":null,"abstract":"Radiation-induced cognitive impairment is one of the late adverse effects of cranial radiation therapy (CRT) for cancer patients with primary and metastatic brain tumors, head and neck cancers etc. It affects approximately 40-50% patients who survive for >6 months and severely reduces the quality of survivors' life. With the advancement of radiation therapy technology, the survival of brain tumor patients is significantly improved, thus understanding the etiology of CRT-induced cognitive impairment and developing the potential strategies of the management of this side-effect have become more important than ever. Some valuable insights have been obtained through extensive preclinical studies. It is suggested that radiation-induced cognitive impairment is due to the dysfunctions of hippocampus-dependent learning, memory and spatial information processing after radiation exposure. Until now, research results have shown that radiation-induced cognitive impairment and neurodegenerative disorders such as Alzheimer disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and aging-related cognitive decline, share some similar pathogenic factors, including chronic oxidative stress and inflammation, impairment in neurogenesis and angiogenesis. Blockade of these factors by antioxidants, anti-inflammatory drugs, transplant of neural stem cells, systemic hypoxia etc. can significantly ameliorate cognitive decline in cranially irradiated experimental animals. These studies shed the light on the pathogenesis of radiation-induced cognitive impairment and may have important implication in developing novel therapeutic interventions for surviving cancer patients who suffer from cognitive decline after CRT.","PeriodicalId":90750,"journal":{"name":"Therapeutic targets for neurological diseases","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66659107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Oxidative stress affects diverse biological processes, including neuron homeostasis, survival and death. Most neurological disorders, such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and stroke, are associated with oxidative stress. It has been extensively investigated that FOXO3a participates in the oxidative stress-induced neuronal apoptosis. However, the function of FOXO3a complexes in oxidative stress processing remains unclear. Recently we identified FOXO3a forms complex with Histone deacetylase 1 (HDAC1) and HDAC2. Under oxidative stress stimuli, the physical interaction between FOXO3a and HDAC1 or HDAC2 was disrupted. Further neuronal apoptosis assay demonstrated that knockdown HDAC2, but not HDAC1, reduced oxidative stress-induced neuronal cell death. Mechanistically, HDAC2 is recruited onto p21 promoter by FOXO3a and deacetylates the surrounding histone at H4K16, hence regulates p21 expression, which inhibits neuronal apoptosis. In addition, we discovered that oxidative stress-mediated HDAC2 Serine 394 (S394) phosphorylation regulated FOXO3a-HDAC2 interaction. Our research suggests that HDAC2 might be therapeutic target for neuron apoptosis-related diseases, including cerebral ischemia and degenerative diseases.
{"title":"HDAC2: A potential target for neurological diseases","authors":"Shengyi Peng, Zengqiang Yuan","doi":"10.14800/TTND.723","DOIUrl":"https://doi.org/10.14800/TTND.723","url":null,"abstract":"Oxidative stress affects diverse biological processes, including neuron homeostasis, survival and death. Most neurological disorders, such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and stroke, are associated with oxidative stress. It has been extensively investigated that FOXO3a participates in the oxidative stress-induced neuronal apoptosis. However, the function of FOXO3a complexes in oxidative stress processing remains unclear. Recently we identified FOXO3a forms complex with Histone deacetylase 1 (HDAC1) and HDAC2. Under oxidative stress stimuli, the physical interaction between FOXO3a and HDAC1 or HDAC2 was disrupted. Further neuronal apoptosis assay demonstrated that knockdown HDAC2, but not HDAC1, reduced oxidative stress-induced neuronal cell death. Mechanistically, HDAC2 is recruited onto p21 promoter by FOXO3a and deacetylates the surrounding histone at H4K16, hence regulates p21 expression, which inhibits neuronal apoptosis. In addition, we discovered that oxidative stress-mediated HDAC2 Serine 394 (S394) phosphorylation regulated FOXO3a-HDAC2 interaction. Our research suggests that HDAC2 might be therapeutic target for neuron apoptosis-related diseases, including cerebral ischemia and degenerative diseases.","PeriodicalId":90750,"journal":{"name":"Therapeutic targets for neurological diseases","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66659001","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
W. Johnson, A. Wilson-Delfosse, Shu G. Chen, J. Mieyal
Parkinson's disease (PD) results from the loss of dopaminergic neurons in the substantia nigra portion of the midbrain, and represents the second most common neurodegenerative disease in the world. Although the etiology of PD is currently unclear, oxidative stress and redox dysfunction are generally understood to play key roles in PD pathogenesis and progression. Aging and environmental factors predispose cells to adverse effects of redox changes. In addition to these factors, genetic mutations linked to PD have been observed to disrupt the redox balance. Mutations in leucine-rich repeat kinase 2 (LRRK2) are associated with autosomal dominant PD, and several of these mutations have also been shown to increase the levels of reactive oxygen species in cells. Anti-oxidant proteins are necessary to restore the redox balance and maintain cell viability. Over the past decade studies have started to demonstrate the critical importance for redox proteins mediating neuronal protection in models of PD. This commentary briefly describes some of the factors hypothesized to contribute to PD, specifically regarding the redox changes that occur in PD. Dysregulation of redox proteins in PD is highlighted by some of the work detailing the roles of peroxiredoxin-3 and thioredoxin-1 in models of PD. In an attempt to generate novel therapies for PD, several potent inhibitors of LRRK2 have been developed. The use of these compounds, both as tools to understand the biology of LRRK2 and as potential therapeutic strategies is also discussed. This mini-review then provides a historical prospective on the discovery and characterization of glutaredoxin (Grx1), and briefly describes current understanding of the role of Grx1 in PD. The review concludes by highlighting our recent publication describing the novel role for Grx1 in mediating dopaminergic neuronal protection both in vitro and in vivo.
{"title":"The roles of redox enzymes in Parkinson's disease: Focus on glutaredoxin.","authors":"W. Johnson, A. Wilson-Delfosse, Shu G. Chen, J. Mieyal","doi":"10.14800/TTND.790","DOIUrl":"https://doi.org/10.14800/TTND.790","url":null,"abstract":"Parkinson's disease (PD) results from the loss of dopaminergic neurons in the substantia nigra portion of the midbrain, and represents the second most common neurodegenerative disease in the world. Although the etiology of PD is currently unclear, oxidative stress and redox dysfunction are generally understood to play key roles in PD pathogenesis and progression. Aging and environmental factors predispose cells to adverse effects of redox changes. In addition to these factors, genetic mutations linked to PD have been observed to disrupt the redox balance. Mutations in leucine-rich repeat kinase 2 (LRRK2) are associated with autosomal dominant PD, and several of these mutations have also been shown to increase the levels of reactive oxygen species in cells. Anti-oxidant proteins are necessary to restore the redox balance and maintain cell viability. Over the past decade studies have started to demonstrate the critical importance for redox proteins mediating neuronal protection in models of PD. This commentary briefly describes some of the factors hypothesized to contribute to PD, specifically regarding the redox changes that occur in PD. Dysregulation of redox proteins in PD is highlighted by some of the work detailing the roles of peroxiredoxin-3 and thioredoxin-1 in models of PD. In an attempt to generate novel therapies for PD, several potent inhibitors of LRRK2 have been developed. The use of these compounds, both as tools to understand the biology of LRRK2 and as potential therapeutic strategies is also discussed. This mini-review then provides a historical prospective on the discovery and characterization of glutaredoxin (Grx1), and briefly describes current understanding of the role of Grx1 in PD. The review concludes by highlighting our recent publication describing the novel role for Grx1 in mediating dopaminergic neuronal protection both in vitro and in vivo.","PeriodicalId":90750,"journal":{"name":"Therapeutic targets for neurological diseases","volume":"2 2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66659059","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
To promote neuroregeneration and angiogenesis is a therapeutic target for the treatment of stroke. Hypoxia-inducible factor-1α (HIF-1α) has pleiotropic effects on neurogenesis, angiogenesis and neuroprotection in central nervous system. In this study we investigated whether HIF-1α can increase the proliferation of ischemia induced neural stem cells in SVZ and neuroregeneration in penumbra. The angiogenesis in penumbra was also investigated. Transient middle cerebral artery occlusion (tMCAO) rat model was used in this study. Rats were divided into 3 groups, NS group, vehicle group and HIF-lα group. In study we found that rats with HIF-1α treatment had better behavioral recovery at day7, 14, 21 and 28 (p<0.05). HIF-lα treatment increased the number of ischemia induced endogenetic NSCs in SVZ obviously (p<0.01). HIF-1α also increased newborn neurons and glial cells in penumbra on the 28 d (p<0.01). Angiogenesis in penumbra was promoted by HIF-lα treatment(p<0.01). In conclusion, our results indicate that modulate HIF-1α after ischemia may be a therapeutic target for the treatment of ischemic stroke through increasing neuroregeneration and angiogenesis.
{"title":"Hypoxia-inducible factor-1α promotes neuroregeneration and angiogenesis after cerebral ischemia","authors":"Hua Ye, Hong Xu, Wan-fu Wu","doi":"10.14800/TTND.719","DOIUrl":"https://doi.org/10.14800/TTND.719","url":null,"abstract":"To promote neuroregeneration and angiogenesis is a therapeutic target for the treatment of stroke. Hypoxia-inducible factor-1α (HIF-1α) has pleiotropic effects on neurogenesis, angiogenesis and neuroprotection in central nervous system. In this study we investigated whether HIF-1α can increase the proliferation of ischemia induced neural stem cells in SVZ and neuroregeneration in penumbra. The angiogenesis in penumbra was also investigated. Transient middle cerebral artery occlusion (tMCAO) rat model was used in this study. Rats were divided into 3 groups, NS group, vehicle group and HIF-lα group. In study we found that rats with HIF-1α treatment had better behavioral recovery at day7, 14, 21 and 28 (p<0.05). HIF-lα treatment increased the number of ischemia induced endogenetic NSCs in SVZ obviously (p<0.01). HIF-1α also increased newborn neurons and glial cells in penumbra on the 28 d (p<0.01). Angiogenesis in penumbra was promoted by HIF-lα treatment(p<0.01). In conclusion, our results indicate that modulate HIF-1α after ischemia may be a therapeutic target for the treatment of ischemic stroke through increasing neuroregeneration and angiogenesis.","PeriodicalId":90750,"journal":{"name":"Therapeutic targets for neurological diseases","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66658965","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
P. Longone, A. Davoli, V. Greco, A. Spalloni, E. Guatteo, C. Nerí, Giada Ricciardo Rizzo, Alberto Cordella, A. Romigi, C. Cortese, S. Bernardini, P. Sarchielli, G. Cardaioli, P. Calabresi, A. Urbani, N. Mercuri
We have recently published a paper in Annals of Neurology entitled “Evidence of Hydrogen Sulphide involvement in Amyotrophic Lateral Sclerosis” [1] where we reported a study performed in patients, and in a genetic model of familial ALS. The outcome of this study is an original finding: the overproduction of hydrogen sulphide (H 2 S) in the human patients and in the animal model. We also show that H 2 S is produced, mainly, by glial cells, is toxic to motor neurons and increases significantly cytosolic Ca 2+ concentration. Altogether, our data introduce H 2 S as a new contestant in the ALS-related toxic pathways, which has potential implications for innovative drug design in ALS.
{"title":"Hydrogen sulphide \"a double-faced Janus\" in amyotrophic lateral sclerosis (ALS)","authors":"P. Longone, A. Davoli, V. Greco, A. Spalloni, E. Guatteo, C. Nerí, Giada Ricciardo Rizzo, Alberto Cordella, A. Romigi, C. Cortese, S. Bernardini, P. Sarchielli, G. Cardaioli, P. Calabresi, A. Urbani, N. Mercuri","doi":"10.14800/TTND.749","DOIUrl":"https://doi.org/10.14800/TTND.749","url":null,"abstract":"We have recently published a paper in Annals of Neurology entitled “Evidence of Hydrogen Sulphide involvement in Amyotrophic Lateral Sclerosis” [1] where we reported a study performed in patients, and in a genetic model of familial ALS. The outcome of this study is an original finding: the overproduction of hydrogen sulphide (H 2 S) in the human patients and in the animal model. We also show that H 2 S is produced, mainly, by glial cells, is toxic to motor neurons and increases significantly cytosolic Ca 2+ concentration. Altogether, our data introduce H 2 S as a new contestant in the ALS-related toxic pathways, which has potential implications for innovative drug design in ALS.","PeriodicalId":90750,"journal":{"name":"Therapeutic targets for neurological diseases","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66659017","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Recently our laboratory has identified many estrogen receptor (ER)α and ERβ coregulators in the brain. This has raised many important issues, more strikingly, regarding the motif specificity, as most of the coregulators reported earlier were from other tissues and related to diseases. It has also aided to the sophistication of transcriptional regulation of genes. Here we have discussed implications of ER coregulators and explored whether they could determine the specificity needed for regulation of estrogen action. Tissue and receptor specificity of coregulators and their motifs might be useful in designing peptide specific agonist and/or antagonist which can regulate specific estrogen action and be used in therapeutics. Keywords : Coregulators; Estrogen receptor; Estrogen action; Specificity; Brain; Peptide agonist/antagonist
{"title":"Estrogen receptor coregulators in brain meet the specificity of estrogen action: a possible roadmap for therapeutics","authors":"V. Paramanik, M. Thakur","doi":"10.14800/TTND.656","DOIUrl":"https://doi.org/10.14800/TTND.656","url":null,"abstract":"Recently our laboratory has identified many estrogen receptor (ER)α and ERβ coregulators in the brain. This has raised many important issues, more strikingly, regarding the motif specificity, as most of the coregulators reported earlier were from other tissues and related to diseases. It has also aided to the sophistication of transcriptional regulation of genes. Here we have discussed implications of ER coregulators and explored whether they could determine the specificity needed for regulation of estrogen action. Tissue and receptor specificity of coregulators and their motifs might be useful in designing peptide specific agonist and/or antagonist which can regulate specific estrogen action and be used in therapeutics. Keywords : Coregulators; Estrogen receptor; Estrogen action; Specificity; Brain; Peptide agonist/antagonist","PeriodicalId":90750,"journal":{"name":"Therapeutic targets for neurological diseases","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66658863","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
H. Funahashi, R. Naono-Nakayama, G. Koganemaru, Yu Miyahara, T. Nishimori, K. Takamiya, Y. Ishida
Substance P (SP) is a member of the tachykinin peptide family. Hemokinin-1 (HK-1) was recently identified as a new mammalian tachykinin peptide. SP and HK-1 consist of undecapeptides and share a common carboxyl-terminal (C-terminal), Phe-Xaa-Gly-Leu-Met-amide motif, and more varied amino-terminals (N-terminal). The function of SP in the pain system of the spinal cord has been examined in detail, whereas that of HK-1 remains unclear. Therefore, the effects of [Leu 11 ]-HK-1 on the induction of scratching behavior by the intrathecal administration of HK-1 or SP and scratching behavior by a subcutaneous injection of histamine and serotonin were examined in order to elucidate the function of HK-1. The pretreatment with [Leu 11 ]-HK-1 decreased the induction of scratching behavior by HK-1, but not by SP, while the pretreatment with [Leu 11 ]-SP decreased the induction of scratching behavior by SP, but not by HK-1. Furthermore, the pretreatments with [Leu 11 ]-HK-1 and [Leu 11 ]-SP decreased the frequency of scratching following an intradermal injection of pruritogens, such as serotonin (5-HT) and histamine, into the nape of the neck. The effects of the pretreatment with HK-1 (1-5), an N-terminal fragment peptide, were also examined to determine the function of HK-1. The pretreatment with HK-1 (1-5) attenuated the induction of scratching behavior by HK-1 and SP. In addition, the pretreatment with HK-1 (1-5) attenuated the induction of scratching behavior by a subcutaneous injection of histamine and 5-HT, while the pretreatment with SP (1-5) had a negligible effect on the scratching behavior induced by these compounds. Collectively, these results indicated that HK-1 was involved in pruritic processing because the pretreatment with [Leu 11 ]-HK-1 and HK-1 (1-5) attenuated the induction of scratching behavior by an injection of histamine and 5-HT. Peptide-derived antagonists, such as [Leu 11 ]-HK-1 and HK-1 (1-5), may be unsuitable for the treatment of pruritus because of the difficulties associated with penetrating the blood brain barrier. Therefore, the discovery of chemical compounds that function as antagonists to the HK-1-preferred receptor will become more important in the treatment of pruritic diseases.
{"title":"Hemokinin-1-derived peptides have antipruritic effects in rats","authors":"H. Funahashi, R. Naono-Nakayama, G. Koganemaru, Yu Miyahara, T. Nishimori, K. Takamiya, Y. Ishida","doi":"10.14800/TTND.704","DOIUrl":"https://doi.org/10.14800/TTND.704","url":null,"abstract":"Substance P (SP) is a member of the tachykinin peptide family. Hemokinin-1 (HK-1) was recently identified as a new mammalian tachykinin peptide. SP and HK-1 consist of undecapeptides and share a common carboxyl-terminal (C-terminal), Phe-Xaa-Gly-Leu-Met-amide motif, and more varied amino-terminals (N-terminal). The function of SP in the pain system of the spinal cord has been examined in detail, whereas that of HK-1 remains unclear. Therefore, the effects of [Leu 11 ]-HK-1 on the induction of scratching behavior by the intrathecal administration of HK-1 or SP and scratching behavior by a subcutaneous injection of histamine and serotonin were examined in order to elucidate the function of HK-1. The pretreatment with [Leu 11 ]-HK-1 decreased the induction of scratching behavior by HK-1, but not by SP, while the pretreatment with [Leu 11 ]-SP decreased the induction of scratching behavior by SP, but not by HK-1. Furthermore, the pretreatments with [Leu 11 ]-HK-1 and [Leu 11 ]-SP decreased the frequency of scratching following an intradermal injection of pruritogens, such as serotonin (5-HT) and histamine, into the nape of the neck. The effects of the pretreatment with HK-1 (1-5), an N-terminal fragment peptide, were also examined to determine the function of HK-1. The pretreatment with HK-1 (1-5) attenuated the induction of scratching behavior by HK-1 and SP. In addition, the pretreatment with HK-1 (1-5) attenuated the induction of scratching behavior by a subcutaneous injection of histamine and 5-HT, while the pretreatment with SP (1-5) had a negligible effect on the scratching behavior induced by these compounds. Collectively, these results indicated that HK-1 was involved in pruritic processing because the pretreatment with [Leu 11 ]-HK-1 and HK-1 (1-5) attenuated the induction of scratching behavior by an injection of histamine and 5-HT. Peptide-derived antagonists, such as [Leu 11 ]-HK-1 and HK-1 (1-5), may be unsuitable for the treatment of pruritus because of the difficulties associated with penetrating the blood brain barrier. Therefore, the discovery of chemical compounds that function as antagonists to the HK-1-preferred receptor will become more important in the treatment of pruritic diseases.","PeriodicalId":90750,"journal":{"name":"Therapeutic targets for neurological diseases","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66658954","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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