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Edward J. Calabrese - One of the best experts on this subject based on the ideXlab platform.
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U-Shaped Dose Response in Behavioral Pharmacology: Historical Foundations
Critical reviews in toxicology, 2008Co-Authors: Edward J. CalabreseAbstract:This article assesses the historical foundations of U-Shaped Dose-Responses in behavioral pharmacology and toxicology with particular emphasis on schedules of reinforcement. Quantitative features of the drug Dose Response, which are consistent with the hormetic Dose Response model, are detailed along with possible mechanistic foundations to account for low-Dose stimulation and high-Dose inhibition Responses. The article provides a reinterpretation of the biphasic Dose Response in the fixed interval (FI) schedule of reinforcement.
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Alzheimer's Disease Drugs: An Application of the Hormetic Dose-Response Model
Critical reviews in toxicology, 2008Co-Authors: Edward J. CalabreseAbstract:This article provides an evaluation of the Dose-Response features of drugs that are intended to improve memory, some of which have been used in the treatment of Alzheimer's disease (AD). A common feature of these drugs is that they act via an inverted U-Shaped Dose Response, consistent with the hormetic Dose Response model. This article assesses historical foundations that lead to the development of AD drugs, their Dose-Response features and how the quantitative features of such Dose Responses affected drug discovery and development, and the successes and possible failures of such agents in preclinical and clinical settings. This story begins about 150 years ago with the discovery of an active agent in the Calabar bean plant called physostigmine, its unfolding medical applications, and its implications for Dose-Response relationships, memory enhancement, and improved drug discovery activities. The article also demonstrates the occurrence of U-Shaped Dose Responses for memory with numerous endogenous agonists including neurosteroids, various peptides (e.g., vasopressin, CCK-8, neuropeptide Y), and other agents (e.g., epinephrine, antagonists for platelet activity factor and nicotinic receptors), supporting the generalizability of the hormetic biphasic Dose Response. Finally, the significance of the U-Shaped Dose Response is critical for successful clinical application, since it defines the therapeutic window.
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Pharmacological enhancement of neuronal survival.
Critical reviews in toxicology, 2008Co-Authors: Edward J. CalabreseAbstract:This article is a comprehensive assessment of the quantitative features of the Dose Response for neuroprotective agents and their underlying mechanistic foundations. The data were derived from published studies using numerous primary neuronal cell cultures and neuronal cell lines. These biological models assessed normal developmental and aging processes, preconditioning adaptive Responses, and various neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and Huntington's disease. The nature of the Dose Response was generally U-Shaped with quantitative features similar to the hormetic Dose-Response model and independent of biological model, endpoint measured, and chemical class. The agents displaying the U-Shaped Dose Response for neuronal survival include numerous endogenous agonists, plant-derived agents, synthetic drugs, and widely used chemicals including potent neurotoxins. That neuroprotective agents display similar Dose-Response relationships regardless of experimental system, potency, and endpoint is an important observation with widespread biomedical and clinical implications.
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U-Shaped Dose-Responses in biology, toxicology, and public health.
Annual review of public health, 2001Co-Authors: Edward J. Calabrese, Linda A. BaldwinAbstract:The occurrence of U-Shaped Dose-Response relationships (often termed hormesis) has been documented in numerous biological, toxicological, and pharmacological investigations. Many of the endpoints studied are of considerable significance to public health (e.g. body weight, cholesterol levels, ethanol consumption, longevity, cancer incidence, etc). Despite the fact that U-Shaped Dose-Responses are widely and independently observed, little attempt has been made to assess this phenomenon in an integrative manner. This review provides an overview of the historical foundations of hormesis and a discussion of its definition within a mechanistic framework. The occurrence, generalizability, and biological significance of U-Shaped Dose-Response relationships along with the concept of biological optimality are addressed.
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A general classification of U-Shaped Dose-Response relationships in toxicology and their mechanistic foundations
Human & experimental toxicology, 1998Co-Authors: Edward J. Calabrese, Linda A. BaldwinAbstract:The development of a comprehensive database of chemical hormetic Responses (i.e., U-or inverted U-Shaped Dose-Response relationships) using objective a priori study design, statistical and study replication criteria has recently been reported.1 An assessment of this database reveals the existence of a wide range of hormetic Dose-reponse relationships including those demonstrating a direct stimulation or an overcompensation Response to a disruption of homeostasis. These two broad types of hormetic Responses are affected by temporal factors and display unique patterns of Dose-range stimulation, magnitude of stimulatory Response and relationship of the maximum stimulatory Response to the NOAEL. A general classification of U-Shaped Dose-Response relationships is proposed to provide a more organized framework to evaluate the highly distinctive and diverse hormetic Responses within the context of establishing underlying biological mechanisms and exploring risk assessment implications.
G.b. Janssen - One of the best experts on this subject based on the ideXlab platform.
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subacute toxicity of α ergocryptine in sprague dawley rats 1 general toxicological effects
Food and Chemical Toxicology, 2000Co-Authors: G.b. Janssen, Rudolf B. Beems, G. J. A. Speijers, Hans P. Van EgmondAbstract:The dietary subacute toxicity of the ergot alkaloid α-ergocryptine was studied in Sprague–Dawley rats. Rats were fed 0, 4, 20, 100 or 500 mg ergocryptine/kg diet for 28–32 days (equal to 0, 0.36, 1.7, 8.9 and 60 mg ergocryptine/kg body weight/day for females and 0, 0.34, 1.4, 6.6 and 44 mg ergocryptine/kg body weight/day for males). The present study describes the general toxicological effects; the effects on metabolic and hormonal parameters will be reported separately. Body weight, body weight gain, food intake and food efficiency were all decreased with a U-Shaped Dose–Response curve, as in both sexes the ranking severity of effects was in the order 100–20–500 and 4 mg/kg diet. Other changes with a U-Shaped Dose–Response relationship included: hematological parameters (decreased MCV and MCH), serum enzyme activities (slightly increased/decreased ALAT, ASAT, GGT), increased serum urea concentrations, decreased glomular filtration (creatinine and urea clearances), decreased absolute organ weights, increased and decreased relative organ weights, atrophy of thymus and in females atrophy of ovary and uterus with in the mid-Dose groups no detectable morphological features of an oestric cycle in the uterus. Other parameters, including increased relative liver, heart and ovarian weights and necrosis of the tail, were influenced in a Dose-related manner or only in the high Dose group. The U-Shaped changes for the parameters mentioned above might be caused by the U-Shaped Dose–Response relationship for food intake, which may be explained by the dopaminergic properties of α-ergocryptine. It is concluded that in rats fed ergocryptine for 28 days the Dose–effect curve is rather steep and that the NOAEL is 4 mg/kg diet.
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Subacute toxicity of α-ergocryptine in Sprague–Dawley rats. 1: general toxicological effects
Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association, 2000Co-Authors: G.b. Janssen, Rudolf B. Beems, G. J. A. Speijers, H.p Van EgmondAbstract:The dietary subacute toxicity of the ergot alkaloid α-ergocryptine was studied in Sprague–Dawley rats. Rats were fed 0, 4, 20, 100 or 500 mg ergocryptine/kg diet for 28–32 days (equal to 0, 0.36, 1.7, 8.9 and 60 mg ergocryptine/kg body weight/day for females and 0, 0.34, 1.4, 6.6 and 44 mg ergocryptine/kg body weight/day for males). The present study describes the general toxicological effects; the effects on metabolic and hormonal parameters will be reported separately. Body weight, body weight gain, food intake and food efficiency were all decreased with a U-Shaped Dose–Response curve, as in both sexes the ranking severity of effects was in the order 100–20–500 and 4 mg/kg diet. Other changes with a U-Shaped Dose–Response relationship included: hematological parameters (decreased MCV and MCH), serum enzyme activities (slightly increased/decreased ALAT, ASAT, GGT), increased serum urea concentrations, decreased glomular filtration (creatinine and urea clearances), decreased absolute organ weights, increased and decreased relative organ weights, atrophy of thymus and in females atrophy of ovary and uterus with in the mid-Dose groups no detectable morphological features of an oestric cycle in the uterus. Other parameters, including increased relative liver, heart and ovarian weights and necrosis of the tail, were influenced in a Dose-related manner or only in the high Dose group. The U-Shaped changes for the parameters mentioned above might be caused by the U-Shaped Dose–Response relationship for food intake, which may be explained by the dopaminergic properties of α-ergocryptine. It is concluded that in rats fed ergocryptine for 28 days the Dose–effect curve is rather steep and that the NOAEL is 4 mg/kg diet.
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the u shaped Dose Response curve of alpha ergocryptine risk assessment ergot alkaloids
1998Co-Authors: G.b. Janssen, Rudolf B. Beems, Boink Abtj, P K Beekhof, Te Biesebeek Jd, Van Egmond Hp, L H Elvers, Jansen Van T Land C, Van Loenen Ha, C SchotAbstract:In een voorgaand subacuut toxiciteits experiment met alpha- ergocryptine werd een U-vormige dosis respons relatie waargenomen voor voedselinname en enkele andere parameters. Weer andere parameters waren beinvloed op een dosis afhankelijke wijze. Een kwalitatieve risico beoordeling voor ergot alkaloiden kan niet uitgevoerd worden zolang het mechanisme van deze U-vorminge dosis-respons curve niet uitgezocht is. Het doel van dit onderzoek is het testen van de hypothese dat de U-vormige dosis respons curve voor voedselinname primair verantwoordelijk is voor de U-vormige dosis respons curve van de andere parameters. Een tweede doel is het verklaren van de U-vormige dosis respons curve voor voedselinname, veroorzaakt door alpha-ergocryptine. In de huidige toxiciteits experimenten (subacuut en biotelemetrie systeem), uitgevoerd met beperkt gevoerde dieren, werd aangetoond dat de U-vormige dosis respons curve voor voedselinname primair verantwoordelijk is voor de U-vormige dosis respons curve van de andere parameters. Op basis van literatuur onderzoek, statistische analyse van de data-set van het vorige toxiciteits experiment en de resultaten van de huidige studies werd geconcludeerd dat de dopaminerge eigenschappen van ergocryptine verantwoordelijk zijn voor de U-vormige dosis respons curve voor voedselinname. Na combinatie van alle toxiciteits data en op basis van de in Nederland gemeten maximale concentraties aan totaal ergot alkaloiden in granen kan er geconcludeerd worden dat de minimale veiligheidsmarge tussen inname door de mens t.o.v. de NOAEL 145 bedraagt en dat er geen reden tot bezorgdheid voor de volksgezondheid lijkt te zijn.
Hans P. Van Egmond - One of the best experts on this subject based on the ideXlab platform.
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subacute toxicity of α ergocryptine in sprague dawley rats 1 general toxicological effects
Food and Chemical Toxicology, 2000Co-Authors: G.b. Janssen, Rudolf B. Beems, G. J. A. Speijers, Hans P. Van EgmondAbstract:The dietary subacute toxicity of the ergot alkaloid α-ergocryptine was studied in Sprague–Dawley rats. Rats were fed 0, 4, 20, 100 or 500 mg ergocryptine/kg diet for 28–32 days (equal to 0, 0.36, 1.7, 8.9 and 60 mg ergocryptine/kg body weight/day for females and 0, 0.34, 1.4, 6.6 and 44 mg ergocryptine/kg body weight/day for males). The present study describes the general toxicological effects; the effects on metabolic and hormonal parameters will be reported separately. Body weight, body weight gain, food intake and food efficiency were all decreased with a U-Shaped Dose–Response curve, as in both sexes the ranking severity of effects was in the order 100–20–500 and 4 mg/kg diet. Other changes with a U-Shaped Dose–Response relationship included: hematological parameters (decreased MCV and MCH), serum enzyme activities (slightly increased/decreased ALAT, ASAT, GGT), increased serum urea concentrations, decreased glomular filtration (creatinine and urea clearances), decreased absolute organ weights, increased and decreased relative organ weights, atrophy of thymus and in females atrophy of ovary and uterus with in the mid-Dose groups no detectable morphological features of an oestric cycle in the uterus. Other parameters, including increased relative liver, heart and ovarian weights and necrosis of the tail, were influenced in a Dose-related manner or only in the high Dose group. The U-Shaped changes for the parameters mentioned above might be caused by the U-Shaped Dose–Response relationship for food intake, which may be explained by the dopaminergic properties of α-ergocryptine. It is concluded that in rats fed ergocryptine for 28 days the Dose–effect curve is rather steep and that the NOAEL is 4 mg/kg diet.
Thomas E Johnson - One of the best experts on this subject based on the ideXlab platform.
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the u shaped Response of initial mortality in caenorhabditis elegans to mild heat shock does it explain recent trends in human mortality
Journals of Gerontology Series A-biological Sciences and Medical Sciences, 2008Co-Authors: Deqing Wu, James R Cypser, Anatoli I Yashin, Thomas E JohnsonAbstract:U-Shaped Dose-Response relationships (hormesis) have been documented in numerous biological, toxicological, and pharmacological investigations. For example, in Response to a mild 35°C heat shock, the longevity of Caenorhabditis elegans exhibits an inverted U-Shaped Dose-Response. By applying the demographic concept of heterogeneity, we find that this U-Shaped curve for longevity Response is driven by a U-Shaped Dose-Response of initial mortality. When worms are subjected to mild heat shock, the initial mortality decreases compared to the control. This initial mortality benefit increases with moderate increases in the length of heat shock, peaking at a point that coincides with the induction of damage to the worms. The Dose of heat shock that coincided with this benefit in initial mortality did not affect the rate of increase in mortality.
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The U-Shaped Response of Initial Mortality in Caenorhabditis elegans to Mild Heat Shock: Does It Explain Recent Trends in Human Mortality?
The journals of gerontology. Series A Biological sciences and medical sciences, 2008Co-Authors: James R Cypser, Anatoli I Yashin, Thomas E JohnsonAbstract:U-Shaped Dose-Response relationships (hormesis) have been documented in numerous biological, toxicological, and pharmacological investigations. For example, in Response to a mild 35 degrees C heat shock, the longevity of Caenorhabditis elegans exhibits an inverted U-Shaped Dose-Response. By applying the demographic concept of heterogeneity, we find that this U-Shaped curve for longevity Response is driven by a U-Shaped Dose-Response of initial mortality. When worms are subjected to mild heat shock, the initial mortality decreases compared to the control. This initial mortality benefit increases with moderate increases in the length of heat shock, peaking at a point that coincides with the induction of damage to the worms. The Dose of heat shock that coincided with this benefit in initial mortality did not affect the rate of increase in mortality.
M. Sala - One of the best experts on this subject based on the ideXlab platform.
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Behavioural and pharmacological profiles of zebrafish administrated pyrrolidinyl benzodioxanes and prolinol aryl ethers with high affinity for heteromeric nicotinic acetylcholine receptors
'Springer Science and Business Media LLC', 2020Co-Authors: D. Braida, L. Ponzoni, M. Moretti, P. Viani, M. Pallavicini, C. Bolchi, R. Appiani, F. Bavo, C. Gotti, M. SalaAbstract:Rationale Prolinol aryl ethers and their rigidified analogues pyrrolidinyl benzodioxanes have a high affinity for mammalian a4β2 nicotinic acetylcholine receptors (nAChRs). Electrophysiological studies have shown that the former are full agonists and the latter partial agonists or antagonists of human a4β2 receptors, but their in vivo effects are unkown. Objectives and Methods As a4b2 nAChRs play an important role in cognition and the rewarding effects of nicotine we tested the effects of two full agonists and one antagonist on spatial learning, memory and attention in zebrafish using a T-maze task and virtual object recognition test (VORT).The effect of a partial agonist in reducing nicotine-induced conditioned place preference (CPP), was also investigated. Results In comparison with the vehicle alone, the full agonists MCL-11 and MCL-28 induced a significant cognitive enhancement as measured by the reduced running time in the T-maze and increased attention as measured by the increased discrimination index in the VORT. MCL-11 was 882 times more potent than nicotine. The two compounds were characterised by an inverted U-Shaped Dose– Response curve, and their effects were blocked by the co-administration of the antagonist MCL117, which alone had no effect. The partial agonist MCL-54 induced CPP and had an inverted U-Shaped Dose–Response curve similar to that of nicotine, but blocked the reinforcing effect of co-administered nicotine. Binding studies showed that all of the compounds have a higher affinity for heteromeric [3H]- epibatidine receptors than [125I]-aBungarotoxin receptors. MCL-11 was the most selective of heteromeric receptors. Conclusions. These behavioural studies indicate that full-agonist prolinol aryl ethers, are very active in increasing spatial learning, memory and attention in zebrafish. The benzodioxane partial agonist MCL-54 reduced nicotine-induced CPP, and the benzodioxane antagonist MCL-117 blocked all agonistinduced activities
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Behavioural and pharmacological profiles of zebrafish administrated pyrrolidinyl benzodioxanes and prolinol aryl ethers with high affinity for heteromeric nicotinic acetylcholine receptors
Psychopharmacology, 2020Co-Authors: D. Braida, L. Ponzoni, M. Moretti, P. Viani, M. Pallavicini, C. Bolchi, R. Appiani, F. Bavo, C. Gotti, M. SalaAbstract:Rationale Prolinol aryl ethers and their rigidified analogues pyrrolidinyl benzodioxanes have a high affinity for mammalian α4β2 nicotinic acetylcholine receptors (nAChRs). Electrophysiological studies have shown that the former are full agonists and the latter partial agonists or antagonists of human α4β2 receptors, but their in vivo effects are unknown. Objectives and methods As α4β2 nAChRs play an important role in the cognition and the rewarding effects of nicotine, we tested the effects of two full agonists and one antagonist on spatial learning, memory and attention in zebrafish using a T-maze task and virtual object recognition test (VORT). The effect of a partial agonist in reducing nicotine-induced conditioned place preference (CPP) was also investigated. Results In comparison with the vehicle alone, the full agonists MCL-11 and MCL-28 induced a significant cognitive enhancement as measured by the reduced running time in the T-maze and increased attention as measured by the increased discrimination index in the VORT. MCL-11 was 882 times more potent than nicotine. The two compounds were characterised by an inverted U-Shaped Dose-Response curve, and their effects were blocked by the co-administration of the antagonist MCL-117, which alone had no effect. The partial agonist MCL-54 induced CPP and had an inverted U-Shaped Dose-Response curve similar to that of nicotine but blocked the reinforcing effect of co-administered nicotine. Binding studies showed that all of the compounds have a higher affinity for heteromeric [^3H]-epibatidine receptors than [^125I]-αBungarotoxin receptors. MCL-11 was the most selective of heteromeric receptors. Conclusions These behavioural studies indicate that full agonist prolinol aryl ethers are very active in increasing spatial learning, memory and attention in zebrafish. The benzodioxane partial agonist MCL-54 reduced nicotine-induced CPP, and the benzodioxane antagonist MCL-117 blocked all agonist-induced activities.
