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Title: Functional observational battery and motor activity in rats after single administration of two NHE 1 inhibitors

Abstract

Two tests, a functional observational battery (FOB) and measurement of motor activity, have been used to screen the two NHE inhibitors EMD 96785 and EMD 125021 for neurobehavioral effects. These two NHE inhibitors, which exhibit a marked selectivity for the NHE 1 isoform, are under development in the research laboratories of Merck KGaA. NHE inhibitors are developed for the treatment of acute myocardial infarction and chronic heart failure. In prior studies with EMD 96785 and EMD 125021, clinical symptoms, such as uncoordinated movements and weakness of the hindlimbs, were detected in rats. The aim of this study was the evaluation of clinical findings in more detail using a FOB and measurement of motor activity in 96 female rats. The time course and reversibility of the adverse effects were investigated. The animals were treated with EMD 96785 or EMD 125021 by intravenous injection at a single dose of 100 mg/kg and four different time points (2 h, 1 day, 7 days and 21 days after treatment) were chosen for the clinical examination. This neurobehavioral test battery clearly detected neurological activity and defined time-course characteristics after treatment with EMD 96785 or EMD 125021. The various clinical parameters were grouped into functional-related domainsmore » and most alterations were seen in the domains of central nervous system and neuromuscular system. The most prominent clinical findings were seen with the pharmacologically more potent NHE inhibitor EMD 125021 when compared to EMD 96785. The clinical symptoms were proven to be reversible by 7 days after the single treatment for both compounds.« less

Authors:
 [1];  [2];  [1];  [1];  [3]
  1. Merck KGaA, Institute of Toxicology, Frankfurter Strasse 250, Darmstadt, 64293 (Germany)
  2. Merck KGaA, Institute of Toxicology, Frankfurter Strasse 250, Darmstadt, 64293 (Germany). E-mail: barbara.gottschling@merck.de
  3. Tieraerztliche Hochschule Hannover, Institute of Pathology, Buenteweg 17, D-30559 Hannover (Germany)
Publication Date:
OSTI Identifier:
20722027
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 208; Journal Issue: 3; Other Information: DOI: 10.1016/j.taap.2005.02.017; PII: S0041-008X(05)00112-2; Copyright (c) 2005 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; CENTRAL NERVOUS SYSTEM; ENZYME INHIBITORS; EVALUATION; HEART FAILURE; INHIBITION; INTRAVENOUS INJECTION; MYOCARDIAL INFARCTION; RATS; SINGLE INTAKE

Citation Formats

Huebler, Nicole, Gottschling, Barbara, Jacobs, Maren, Landenberg, Friedrich von, and Hewicker-Trautwein, Marion. Functional observational battery and motor activity in rats after single administration of two NHE 1 inhibitors. United States: N. p., 2005. Web. doi:10.1016/j.taap.2005.02.017.
Huebler, Nicole, Gottschling, Barbara, Jacobs, Maren, Landenberg, Friedrich von, & Hewicker-Trautwein, Marion. Functional observational battery and motor activity in rats after single administration of two NHE 1 inhibitors. United States. doi:10.1016/j.taap.2005.02.017.
Huebler, Nicole, Gottschling, Barbara, Jacobs, Maren, Landenberg, Friedrich von, and Hewicker-Trautwein, Marion. Tue . "Functional observational battery and motor activity in rats after single administration of two NHE 1 inhibitors". United States. doi:10.1016/j.taap.2005.02.017.
@article{osti_20722027,
title = {Functional observational battery and motor activity in rats after single administration of two NHE 1 inhibitors},
author = {Huebler, Nicole and Gottschling, Barbara and Jacobs, Maren and Landenberg, Friedrich von and Hewicker-Trautwein, Marion},
abstractNote = {Two tests, a functional observational battery (FOB) and measurement of motor activity, have been used to screen the two NHE inhibitors EMD 96785 and EMD 125021 for neurobehavioral effects. These two NHE inhibitors, which exhibit a marked selectivity for the NHE 1 isoform, are under development in the research laboratories of Merck KGaA. NHE inhibitors are developed for the treatment of acute myocardial infarction and chronic heart failure. In prior studies with EMD 96785 and EMD 125021, clinical symptoms, such as uncoordinated movements and weakness of the hindlimbs, were detected in rats. The aim of this study was the evaluation of clinical findings in more detail using a FOB and measurement of motor activity in 96 female rats. The time course and reversibility of the adverse effects were investigated. The animals were treated with EMD 96785 or EMD 125021 by intravenous injection at a single dose of 100 mg/kg and four different time points (2 h, 1 day, 7 days and 21 days after treatment) were chosen for the clinical examination. This neurobehavioral test battery clearly detected neurological activity and defined time-course characteristics after treatment with EMD 96785 or EMD 125021. The various clinical parameters were grouped into functional-related domains and most alterations were seen in the domains of central nervous system and neuromuscular system. The most prominent clinical findings were seen with the pharmacologically more potent NHE inhibitor EMD 125021 when compared to EMD 96785. The clinical symptoms were proven to be reversible by 7 days after the single treatment for both compounds.},
doi = {10.1016/j.taap.2005.02.017},
journal = {Toxicology and Applied Pharmacology},
number = 3,
volume = 208,
place = {United States},
year = {Tue Nov 01 00:00:00 EST 2005},
month = {Tue Nov 01 00:00:00 EST 2005}
}
  • Activity of acetylcholinesterase (AChE) and specific binding of [{sup 3}H]quinuclidinyl benzilate (QNB), [{sup 3}H]pirenzepine (PZP) and [{sup 3}H]AF-DX 384 to muscarinic acetylcholine receptor (mAChR) preparations in the striatum, hippocampus and cortex of rats were determined 1, 6 and 11 days after the last treatment with an organophosphate DDVP, a carbamate propoxur or a muscarinic agonist oxotremorine as a reference for 7 and 14 days. AChE activity was markedly decreased in the three regions 1 day after the treatment with DDVP for 7 and 14 days with a gradual recovery 6 to 11 days, and much less decreased 1, 6 andmore » 11 days after the treatment with propoxur for 7 days but not for 14 days in the hippocampus and cortex. The binding of [{sup 3}H]-QNB, PZP and AF-DX 384 in the three regions was generally decreased by the treatment with DDVP for 7 and 14 days. Such down-regulations were generally restored 6 or 11 days after the treatment for 7 but not for 14 days. The down-regulation or up-regulation as measured by [{sup 3}H]-QNB, PZP and AF-DX 384 was observed 1, 6 or 11 days after treatment with propoxur for 7 days and/or 14 days. Repeated treatment with oxotremorine produced similar effects except AChE activity to DDVP. These results suggest that repeated inhibition of AChE activity may usually cause down-regulation of mAChRs with some exception in the hippocampus when a reversible antiChE propoxur is injected.« less
  • The leucocyte count and blood formula were determined at 3, 9, 16, 21, 30, 90, l80, 270, and 360 days after the irradiation of rats with a dose of 500 r. At 30 days the per cent and absolute number of segmented neutrophils was twice the initial level, and the per cent of lymphocytes was 68.3%, compared to 81.7% before irradiation. At 90 day's the per cent of polymorphonuclear neutrophils was 1.9%, compared to 0.9% before irradiation, while the per cent of segmented neutrophils increased from 14 to 22.4%. At 180 days a shift to the left was observed inmore » the blood formula. The per cent of polymorphonuclear neutrophils rose to 5.4%. The number of mature neutrophils was twice the initial level. The per cent and absolute number of lymphocytes was significantly lower than in unirradiated rats. At 270 days the number of leucocytes in the irradiated rats exceeded that of the controls by a factor of 1.5. The shift to the left was more pronounced with the number of polymorphonuclear neutrophils exceeding that of the controls by a factor of 5. At this time hyperplasia of the bone marrow occurred (36.3 mg vs. 16 mg for the weight of bone marrow in the control rats). At 360 days a further increase in the weight of the bone marrow and the number of nucleated cells was observed. (TTT)« less
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