The immediate early gene c-fos is rapidly and transiently induced in response to a variety of extracellular stimuli and codes for a protein, Fos, that regulates transcription of target genes in neurons. Detection of Fos can serve as a marker of neuronal activation at the individual cell level. Thus, localization of Fos provides investigators with a widely applicable tool for assessment of neuronal activation during age-related changes in brain function. This article describes a method for the immunocytochemical localization of Fos in neurons of the aging brain using free-floating sections and the avidin-biotin detection system. This technique is particularly useful when Fos expression is cobcalized with other neuropeptides, permitting the assessment of age-related changes in discrete neuronal populations. Application of this method to studies of age-associated changes in hypothalamic neurons involved in reproductive cyclicity is described.
{"title":"Use of Fos as an Index of Altered Neuronal Activation in Aging Animals","authors":"Lloyd Jonathan M.","doi":"10.1006/ncmn.1994.1024","DOIUrl":"https://doi.org/10.1006/ncmn.1994.1024","url":null,"abstract":"<div><p>The immediate early gene c-<em>fos</em> is rapidly and transiently induced in response to a variety of extracellular stimuli and codes for a protein, Fos, that regulates transcription of target genes in neurons. Detection of Fos can serve as a marker of neuronal activation at the individual cell level. Thus, localization of Fos provides investigators with a widely applicable tool for assessment of neuronal activation during age-related changes in brain function. This article describes a method for the immunocytochemical localization of Fos in neurons of the aging brain using free-floating sections and the avidin-biotin detection system. This technique is particularly useful when Fos expression is cobcalized with other neuropeptides, permitting the assessment of age-related changes in discrete neuronal populations. Application of this method to studies of age-associated changes in hypothalamic neurons involved in reproductive cyclicity is described.</p></div>","PeriodicalId":100951,"journal":{"name":"Neuroprotocols","volume":"4 3","pages":"Pages 182-187"},"PeriodicalIF":0.0,"publicationDate":"1994-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1006/ncmn.1994.1024","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72111971","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}
Abstract A thorough understanding of the nature of age-related changes at the hypothalamic level would be greatly enhanced by the ability to directly measure neuropeptide release. In vivo measurement of neurosecretion is a demanding undertaking in young animals and increases in difficulty in aging animals due to additional considerations that must be acknowledged. Push-pull perfusion and in vivo microdialysis are two methods currently being used to directly measure neuropeptide output. The advantages and disadvantages of each are discussed. Moreover, special concerns regarding their use in aging animals are addressed, including the potential for: (1) differences in the response of the aging brain to insult; (2)age-related differences in levels of degradative enzymes; and (3) confounding effects of age-related differences in the stress response. Push-pull perfusion was used to compare the pattern of luteinizing hormone-releasing hormone output in middle-aged and young female rats during a steroid-induced LH surge. The data revealed age-related differences in the overall pattern and the mean levels of LHRH output. When used with the proper precautions, these in vivo protocols enable characterization of the patterns of release of neuroactive substances in a single animal over time. They eliminate the need to sacrifice large numbers of animals to obtain measurements for a single time point, a feature particularly important for aging studies due to the heterogeneity of the population and the expense of the animals. Moreover, use of these methods is essential if alterations in the patterns of neuropeptide release play an important role in the changes that accompany aging.
{"title":"The Use of Push-Pull Perfusion and in Vivo Microdialysis to Assess Changing Patterns of Hypothalamic Releasing Hormone Output in Aging Animals","authors":"Rubin Beverly S.","doi":"10.1006/ncmn.1994.1027","DOIUrl":"https://doi.org/10.1006/ncmn.1994.1027","url":null,"abstract":"Abstract A thorough understanding of the nature of age-related changes at the hypothalamic level would be greatly enhanced by the ability to directly measure neuropeptide release. In vivo measurement of neurosecretion is a demanding undertaking in young animals and increases in difficulty in aging animals due to additional considerations that must be acknowledged. Push-pull perfusion and in vivo microdialysis are two methods currently being used to directly measure neuropeptide output. The advantages and disadvantages of each are discussed. Moreover, special concerns regarding their use in aging animals are addressed, including the potential for: (1) differences in the response of the aging brain to insult; (2)age-related differences in levels of degradative enzymes; and (3) confounding effects of age-related differences in the stress response. Push-pull perfusion was used to compare the pattern of luteinizing hormone-releasing hormone output in middle-aged and young female rats during a steroid-induced LH surge. The data revealed age-related differences in the overall pattern and the mean levels of LHRH output. When used with the proper precautions, these in vivo protocols enable characterization of the patterns of release of neuroactive substances in a single animal over time. They eliminate the need to sacrifice large numbers of animals to obtain measurements for a single time point, a feature particularly important for aging studies due to the heterogeneity of the population and the expense of the animals. Moreover, use of these methods is essential if alterations in the patterns of neuropeptide release play an important role in the changes that accompany aging.","PeriodicalId":100951,"journal":{"name":"Neuroprotocols","volume":"4 3","pages":"Pages 210-220"},"PeriodicalIF":0.0,"publicationDate":"1994-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1006/ncmn.1994.1027","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72111972","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}
The notions that age-related changes in the neuroendocrine system partly account for hormonal changes during aging and that the neuroendocrine system thereby contributes to the development of the senescent phenotype are widely accepted. Less attention has been given to the possibility that the neuroendocrine system can play a role in the retardation of aging. The objective of this paper is to present evidence that the neuroendocrine system contributes to the retardation of aging by food restriction by orchestrating the hormonal changes that are associated with chronic caloric restriction. Relatively little is known about the characteristics of the neuroendocrine system of the chronically food-restricted organism. The evidence that this system may play a central role in mediating the life-extending action of food restriction argues for further study of neuroendocrine function in the food-restricted animal.
{"title":"Calorie Restriction as a Probe for Understanding Neuroendocrine Involvement in the Aging Processes","authors":"Nelson James F.","doi":"10.1006/ncmn.1994.1026","DOIUrl":"https://doi.org/10.1006/ncmn.1994.1026","url":null,"abstract":"<div><p>The notions that age-related changes in the neuroendocrine system partly account for hormonal changes during aging and that the neuroendocrine system thereby contributes to the development of the senescent phenotype are widely accepted. Less attention has been given to the possibility that the neuroendocrine system can play a role in the retardation of aging. The objective of this paper is to present evidence that the neuroendocrine system contributes to the retardation of aging by food restriction by orchestrating the hormonal changes that are associated with chronic caloric restriction. Relatively little is known about the characteristics of the neuroendocrine system of the chronically food-restricted organism. The evidence that this system may play a central role in mediating the life-extending action of food restriction argues for further study of neuroendocrine function in the food-restricted animal.</p></div>","PeriodicalId":100951,"journal":{"name":"Neuroprotocols","volume":"4 3","pages":"Pages 204-209"},"PeriodicalIF":0.0,"publicationDate":"1994-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1006/ncmn.1994.1026","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72111973","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}
Abstract A thorough understanding of the nature of age-related changes at the hypothalamic level would be greatly enhanced by the ability to directly measure neuropeptide release. In vivo measurement of neurosecretion is a demanding undertaking in young animals and increases in difficulty in aging animals due to additional considerations that must be acknowledged. Push-pull perfusion and in vivo microdialysis are two methods currently being used to directly measure neuropeptide output. The advantages and disadvantages of each are discussed. Moreover, special concerns regarding their use in aging animals are addressed, including the potential for: (1) differences in the response of the aging brain to insult; (2)age-related differences in levels of degradative enzymes; and (3) confounding effects of age-related differences in the stress response. Push-pull perfusion was used to compare the pattern of luteinizing hormone-releasing hormone output in middle-aged and young female rats during a steroid-induced LH surge. The data revealed age-related differences in the overall pattern and the mean levels of LHRH output. When used with the proper precautions, these in vivo protocols enable characterization of the patterns of release of neuroactive substances in a single animal over time. They eliminate the need to sacrifice large numbers of animals to obtain measurements for a single time point, a feature particularly important for aging studies due to the heterogeneity of the population and the expense of the animals. Moreover, use of these methods is essential if alterations in the patterns of neuropeptide release play an important role in the changes that accompany aging.
{"title":"The Use of Push-Pull Perfusion and in Vivo Microdialysis to Assess Changing Patterns of Hypothalamic Releasing Hormone Output in Aging Animals","authors":"B. Rubin","doi":"10.1006/NCMN.1994.1027","DOIUrl":"https://doi.org/10.1006/NCMN.1994.1027","url":null,"abstract":"Abstract A thorough understanding of the nature of age-related changes at the hypothalamic level would be greatly enhanced by the ability to directly measure neuropeptide release. In vivo measurement of neurosecretion is a demanding undertaking in young animals and increases in difficulty in aging animals due to additional considerations that must be acknowledged. Push-pull perfusion and in vivo microdialysis are two methods currently being used to directly measure neuropeptide output. The advantages and disadvantages of each are discussed. Moreover, special concerns regarding their use in aging animals are addressed, including the potential for: (1) differences in the response of the aging brain to insult; (2)age-related differences in levels of degradative enzymes; and (3) confounding effects of age-related differences in the stress response. Push-pull perfusion was used to compare the pattern of luteinizing hormone-releasing hormone output in middle-aged and young female rats during a steroid-induced LH surge. The data revealed age-related differences in the overall pattern and the mean levels of LHRH output. When used with the proper precautions, these in vivo protocols enable characterization of the patterns of release of neuroactive substances in a single animal over time. They eliminate the need to sacrifice large numbers of animals to obtain measurements for a single time point, a feature particularly important for aging studies due to the heterogeneity of the population and the expense of the animals. Moreover, use of these methods is essential if alterations in the patterns of neuropeptide release play an important role in the changes that accompany aging.","PeriodicalId":100951,"journal":{"name":"Neuroprotocols","volume":"108 1","pages":"210-220"},"PeriodicalIF":0.0,"publicationDate":"1994-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79335726","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}
Abstract One of the difficulties in the field of the neurobiology of aging is that many of the studies are necessarily correlative in nature. Investigators interested in the neurotransmitter or neuropeptide control of a given brain function often describe the situation in young animals and compare these observations with findings for groups of aged animals. However, ascribing causation with such studies is difficult at best. The use of antisense oligodeoxynucleotides described in this article allows the investigator to target one or more neuropeptides expressed in a confined area of the brain for selective abiation. The assessment of cause and effect on the physiological endpoint of Interest then becomes more tractable. Having previously identified age-related changes in neuropeptide dynamics that may underlie certain aspects of endocrine aging, we used this method to determine whether specific antisense oligodeoxynucleotide treatment of young animals mimicked the effect of age on the endocrine system. The theoretical background and practical aspects of the method are presented in sufficient detail to allow investigators not familiar with the technique to design appropriate oligodeoxynucleotides and use them in their research.
{"title":"Use of Antisense Oligodeoxynucleotides in the Study of Neuroendocrine Aging","authors":"K. Scarbrough","doi":"10.1006/NCMN.1994.1028","DOIUrl":"https://doi.org/10.1006/NCMN.1994.1028","url":null,"abstract":"Abstract One of the difficulties in the field of the neurobiology of aging is that many of the studies are necessarily correlative in nature. Investigators interested in the neurotransmitter or neuropeptide control of a given brain function often describe the situation in young animals and compare these observations with findings for groups of aged animals. However, ascribing causation with such studies is difficult at best. The use of antisense oligodeoxynucleotides described in this article allows the investigator to target one or more neuropeptides expressed in a confined area of the brain for selective abiation. The assessment of cause and effect on the physiological endpoint of Interest then becomes more tractable. Having previously identified age-related changes in neuropeptide dynamics that may underlie certain aspects of endocrine aging, we used this method to determine whether specific antisense oligodeoxynucleotide treatment of young animals mimicked the effect of age on the endocrine system. The theoretical background and practical aspects of the method are presented in sufficient detail to allow investigators not familiar with the technique to design appropriate oligodeoxynucleotides and use them in their research.","PeriodicalId":100951,"journal":{"name":"Neuroprotocols","volume":"30 1","pages":"221-224"},"PeriodicalIF":0.0,"publicationDate":"1994-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83421592","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}
Changes in the synaptic input to aging neurons can best be evaluated using electron microscopy (EM). Immunocytochemistry is used to identify neuronal populations and to distinguish the chemical identity of their synaptic input, using a double-label protocol (e.g., diaminobenzidine for the sites of the first antigen/antibody complexes and tetramethylbenzidine for the second). In preparing tissue for EM examination, neurons are sectioned in the plane of the nucleus at 70 nm and sections collected on slot hole grids. Photographic montages of neurons are made at a minimum of 3 depths of section, with about 1 μm intervening. The original micrographs are taken at 10,000× and printed at 25,000×. Morphometric analyses are performed using the Bloquant program (R&M Biometrics) and an IBM computer. The perikaryal membrane is outlined on an X-Y digitizing pad, and regions along which there is synaptic modification are measured. These synaptic regions are expressed as a percentage of the perikaryal membrane measured. Data are tested using a non-parametric statistic (Mann-Whitney U, P < 0.05). In some cases, the entire neuronal soma is serially sectioned in order to determine whether synapses are randomly distributed over the neuronal surface.
老化神经元突触输入的变化可以用电子显微镜(EM)来最好地评估。免疫细胞化学用于识别神经元群并区分其突触输入的化学特性，使用双标签协议(例如，二氨基联苯胺用于第一个抗原/抗体复合物的位点，四甲基联苯胺用于第二个)。在准备组织进行EM检查时，神经元在70 nm的核平面上切片，并在槽孔网格上收集切片。神经元的摄影蒙太奇至少在3个深度的切片，中间约1 μm。原始的显微照片是在10000倍的分辨率下拍摄的，在25000倍的分辨率下打印的。使用Bloquant程序(R&M生物计量学)和IBM计算机执行形态计量学分析。在X-Y数字化垫上勾勒出核周膜，并测量突触修饰的区域。这些突触区域以所测量的核周膜的百分比表示。数据使用非参数统计量进行检验(Mann-Whitney U, P < 0.05)。在某些情况下，为了确定突触是否随机分布在神经元表面，整个神经元体被连续切片。
{"title":"Electron Microscopic Methods for Determining Changes in the Density of Synaptic Input to Neurons in the Aging Brain","authors":"J. Witkin","doi":"10.1006/NCMN.1994.1030","DOIUrl":"https://doi.org/10.1006/NCMN.1994.1030","url":null,"abstract":"Changes in the synaptic input to aging neurons can best be evaluated using electron microscopy (EM). Immunocytochemistry is used to identify neuronal populations and to distinguish the chemical identity of their synaptic input, using a double-label protocol (e.g., diaminobenzidine for the sites of the first antigen/antibody complexes and tetramethylbenzidine for the second). In preparing tissue for EM examination, neurons are sectioned in the plane of the nucleus at 70 nm and sections collected on slot hole grids. Photographic montages of neurons are made at a minimum of 3 depths of section, with about 1 μm intervening. The original micrographs are taken at 10,000× and printed at 25,000×. Morphometric analyses are performed using the Bloquant program (R&M Biometrics) and an IBM computer. The perikaryal membrane is outlined on an X-Y digitizing pad, and regions along which there is synaptic modification are measured. These synaptic regions are expressed as a percentage of the perikaryal membrane measured. Data are tested using a non-parametric statistic (Mann-Whitney U, P < 0.05). In some cases, the entire neuronal soma is serially sectioned in order to determine whether synapses are randomly distributed over the neuronal surface.","PeriodicalId":100951,"journal":{"name":"Neuroprotocols","volume":"55 1","pages":"235-239"},"PeriodicalIF":0.0,"publicationDate":"1994-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83926893","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}
We describe the methods and rationale for using rats with a partial unilateral lesion of the nigrostriatal system as an animal model for studying neural plasticity in both young and aged brains. The rats are lesioned with 6-hydroxydopamine injected into the substantia nigra or the medial forebrain bundle. Amphetamine- and apomorphine-induced rotational behaviors are tested 3 and 4 weeks following the lesion. Based on the rotational responses to amphetamine and apomorphine administration, animals can be classified into one of three groups: unaffected, partially lesioned, or severely lesioned. Animals classified as displaying unaffected rotational behavior are those that do not respond to either amphetamine or apomorphine stimulation. Partially lesioned animals rotate ipsilateral to the lesioned side upon amphetamine injection, but do not display a significant number of rotations in response to apomorphine administration. In contrast, severely lesioned rats rotate after both amphetamine and apomorphine injections. Cell counts reveal that the mean number of dopamine neurons in the ventral mesencephalon of partially lesioned animals is reduced to 40% of that of the intact side. Also in partially lesioned animals, dopamine concentrations on the lesion side are even more severely depleted, averaging about 20% of levels in the contralateral intact striatum. Striatal dopamine concentrations correlate well with the number of surviving dopamine neurons in the ventral mesencephalon (r2 = 0.66, P < 0.05). Amphetamine-induced rotation rates also show a moderate correlation with both striatal dopamine concentrations and mesencephalic dopamine neuron cell counts. Therefore, rotational behavior induced by amphetamine and apomorphine stimulation can be used to identify partially lesioned rats following unilateral 6-hydroxydopamine lesions. It is also possible to estimate the extent of nigrostriatal system damage from the rate of amphetamine-induced rotation.
我们描述了使用单侧黑质纹状体部分损伤的大鼠作为研究年轻和老年大脑神经可塑性的动物模型的方法和原理。将6-羟多巴胺注入黑质或内侧前脑束损伤大鼠。在病变后3周和4周检测安非他明和阿帕吗啡诱导的旋转行为。根据对安非他明和阿波啡的轮流反应，动物可分为三组:未受影响、部分受损或严重受损。被归类为显示未受影响的旋转行为的动物是那些对安非他明或阿波啡刺激没有反应的动物。部分损伤的动物在注射安非他明后向损伤侧旋转，但在阿波啡给药后没有明显的旋转。相比之下，严重损伤的大鼠在注射安非他明和阿波啡后都旋转。细胞计数显示，部分损伤动物腹侧中脑多巴胺神经元的平均数量减少到完好侧的40%。同样，在部分受损的动物中，受损侧的多巴胺浓度甚至更为严重，平均约为对侧完整纹状体水平的20%。纹状体多巴胺浓度与中脑腹侧多巴胺神经元存活数呈正相关(r2 = 0.66, P < 0.05)。安非他明诱导的旋转速率也显示出纹状体多巴胺浓度和中脑多巴胺神经元细胞计数的适度相关性。因此，安非他明和阿波啡刺激诱导的旋转行为可用于识别单侧6-羟多巴胺损伤后部分损伤的大鼠。也可以从安非他明引起的旋转速率来估计黑质纹状体系统损伤的程度。
{"title":"Rats with Partial Unilateral Nigrostriatal Lesions as a Model for Studying CNS Plasticity","authors":"F. Junn, T. Collier, S. Felten, D. Gash","doi":"10.1006/NCMN.1994.1022","DOIUrl":"https://doi.org/10.1006/NCMN.1994.1022","url":null,"abstract":"We describe the methods and rationale for using rats with a partial unilateral lesion of the nigrostriatal system as an animal model for studying neural plasticity in both young and aged brains. The rats are lesioned with 6-hydroxydopamine injected into the substantia nigra or the medial forebrain bundle. Amphetamine- and apomorphine-induced rotational behaviors are tested 3 and 4 weeks following the lesion. Based on the rotational responses to amphetamine and apomorphine administration, animals can be classified into one of three groups: unaffected, partially lesioned, or severely lesioned. Animals classified as displaying unaffected rotational behavior are those that do not respond to either amphetamine or apomorphine stimulation. Partially lesioned animals rotate ipsilateral to the lesioned side upon amphetamine injection, but do not display a significant number of rotations in response to apomorphine administration. In contrast, severely lesioned rats rotate after both amphetamine and apomorphine injections. Cell counts reveal that the mean number of dopamine neurons in the ventral mesencephalon of partially lesioned animals is reduced to 40% of that of the intact side. Also in partially lesioned animals, dopamine concentrations on the lesion side are even more severely depleted, averaging about 20% of levels in the contralateral intact striatum. Striatal dopamine concentrations correlate well with the number of surviving dopamine neurons in the ventral mesencephalon (r2 = 0.66, P < 0.05). Amphetamine-induced rotation rates also show a moderate correlation with both striatal dopamine concentrations and mesencephalic dopamine neuron cell counts. Therefore, rotational behavior induced by amphetamine and apomorphine stimulation can be used to identify partially lesioned rats following unilateral 6-hydroxydopamine lesions. It is also possible to estimate the extent of nigrostriatal system damage from the rate of amphetamine-induced rotation.","PeriodicalId":100951,"journal":{"name":"Neuroprotocols","volume":"23 1","pages":"168-176"},"PeriodicalIF":0.0,"publicationDate":"1994-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78974013","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}
Simpkins James W., Ouyang Xudong, Prokai Laszlo, Bodor Nicholas
The major obstacle to the use of neuropeptides in the pharmacotherapy of brain diseases is their delivery to the CNS. This report presents a novel method for the in vitro molecular packaging of peptides that allows their delivery across the blood-brain barrier (BBB) following systemic administration. The molecular packaging is intended both to disguise the peptide nature of the molecule, thus protecting it from a plethora of vascular and BBB peptidases, and to "lock in" the peptide precursor. The delivered peptide-precursor complex is designed to undergo sequential metabolism, resulting in the release of the active peptide. The proposed method for the CNS delivery of neuroactive peptides results in the brain delivery of the intact peptide sequence, and the delivered peptides exhibit appropriate pharmacological activity. This method may be applicable to delivery of a variety of peptides to the CNS and hence opens the possibility of peptide therapy for CNS diseases that are particularly common in the elderly.
{"title":"Delivery of Peptides into the Central Nervous System by Molecular Packaging and Sequential Metabolism as a Method of Altering Neuropeptide Activity during Aging","authors":"Simpkins James W., Ouyang Xudong, Prokai Laszlo, Bodor Nicholas","doi":"10.1006/ncmn.1994.1029","DOIUrl":"https://doi.org/10.1006/ncmn.1994.1029","url":null,"abstract":"<div><p>The major obstacle to the use of neuropeptides in the pharmacotherapy of brain diseases is their delivery to the CNS. This report presents a novel method for the <em>in vitro</em> molecular packaging of peptides that allows their delivery across the blood-brain barrier (BBB) following systemic administration. The molecular packaging is intended both to disguise the peptide nature of the molecule, thus protecting it from a plethora of vascular and BBB peptidases, and to \"lock in\" the peptide precursor. The delivered peptide-precursor complex is designed to undergo sequential metabolism, resulting in the release of the active peptide. The proposed method for the CNS delivery of neuroactive peptides results in the brain delivery of the intact peptide sequence, and the delivered peptides exhibit appropriate pharmacological activity. This method may be applicable to delivery of a variety of peptides to the CNS and hence opens the possibility of peptide therapy for CNS diseases that are particularly common in the elderly.</p></div>","PeriodicalId":100951,"journal":{"name":"Neuroprotocols","volume":"4 3","pages":"Pages 225-234"},"PeriodicalIF":0.0,"publicationDate":"1994-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1006/ncmn.1994.1029","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72111368","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}
Abstract The notions that age-related changes in the neuroendocrine system partly account for hormonal changes during aging and that the neuroendocrine system thereby contributes to the development of the senescent phenotype are widely accepted. Less attention has been given to the possibility that the neuroendocrine system can play a role in the retardation of aging. The objective of this paper is to present evidence that the neuroendocrine system contributes to the retardation of aging by food restriction by orchestrating the hormonal changes that are associated with chronic caloric restriction. Relatively little is known about the characteristics of the neuroendocrine system of the chronically food-restricted organism. The evidence that this system may play a central role in mediating the life-extending action of food restriction argues for further study of neuroendocrine function in the food-restricted animal.
{"title":"Calorie Restriction as a Probe for Understanding Neuroendocrine Involvement in the Aging Processes","authors":"J. Nelson","doi":"10.1006/NCMN.1994.1026","DOIUrl":"https://doi.org/10.1006/NCMN.1994.1026","url":null,"abstract":"Abstract The notions that age-related changes in the neuroendocrine system partly account for hormonal changes during aging and that the neuroendocrine system thereby contributes to the development of the senescent phenotype are widely accepted. Less attention has been given to the possibility that the neuroendocrine system can play a role in the retardation of aging. The objective of this paper is to present evidence that the neuroendocrine system contributes to the retardation of aging by food restriction by orchestrating the hormonal changes that are associated with chronic caloric restriction. Relatively little is known about the characteristics of the neuroendocrine system of the chronically food-restricted organism. The evidence that this system may play a central role in mediating the life-extending action of food restriction argues for further study of neuroendocrine function in the food-restricted animal.","PeriodicalId":100951,"journal":{"name":"Neuroprotocols","volume":"26 1","pages":"204-209"},"PeriodicalIF":0.0,"publicationDate":"1994-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82072843","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}
Abstract The major obstacle to the use of neuropeptides in the pharmacotherapy of brain diseases is their delivery to the CNS. This report presents a novel method for the in vitro molecular packaging of peptides that allows their delivery across the blood-brain barrier (BBB) following systemic administration. The molecular packaging is intended both to disguise the peptide nature of the molecule, thus protecting it from a plethora of vascular and BBB peptidases, and to "lock in" the peptide precursor. The delivered peptide-precursor complex is designed to undergo sequential metabolism, resulting in the release of the active peptide. The proposed method for the CNS delivery of neuroactive peptides results in the brain delivery of the intact peptide sequence, and the delivered peptides exhibit appropriate pharmacological activity. This method may be applicable to delivery of a variety of peptides to the CNS and hence opens the possibility of peptide therapy for CNS diseases that are particularly common in the elderly.
{"title":"Delivery of Peptides into the Central Nervous System by Molecular Packaging and Sequential Metabolism as a Method of Altering Neuropeptide Activity during Aging","authors":"J. Simpkins, X. Ouyang, L. Prokai, N. Bodor","doi":"10.1006/NCMN.1994.1029","DOIUrl":"https://doi.org/10.1006/NCMN.1994.1029","url":null,"abstract":"Abstract The major obstacle to the use of neuropeptides in the pharmacotherapy of brain diseases is their delivery to the CNS. This report presents a novel method for the in vitro molecular packaging of peptides that allows their delivery across the blood-brain barrier (BBB) following systemic administration. The molecular packaging is intended both to disguise the peptide nature of the molecule, thus protecting it from a plethora of vascular and BBB peptidases, and to \"lock in\" the peptide precursor. The delivered peptide-precursor complex is designed to undergo sequential metabolism, resulting in the release of the active peptide. The proposed method for the CNS delivery of neuroactive peptides results in the brain delivery of the intact peptide sequence, and the delivered peptides exhibit appropriate pharmacological activity. This method may be applicable to delivery of a variety of peptides to the CNS and hence opens the possibility of peptide therapy for CNS diseases that are particularly common in the elderly.","PeriodicalId":100951,"journal":{"name":"Neuroprotocols","volume":"5 1","pages":"225-234"},"PeriodicalIF":0.0,"publicationDate":"1994-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88095815","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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