The neurochemical and behavioral effects of the novel cholinesterase–monoamine oxidase inhibitor, ladostigil, in response to L‐dopa and L‐tryptophan, in rats

The novel drugs, ladostigil (TV3326) and TV3279, are R and S isomers, respectively, derived from a combination of the carbamate cholinesterase (ChE) inhibitor, rivastigmine, and the pharmacophore of the monoamine oxidase (MAO) B inhibitor, rasagiline. They were developed for the treatment of comorbi...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:British journal of pharmacology 2005-10, Vol.146 (4), p.553-560
Hauptverfasser: Sagi, Yotam, Driguès, Noam, Youdim, Moussa B H
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page 560
container_issue 4
container_start_page 553
container_title British journal of pharmacology
container_volume 146
creator Sagi, Yotam
Driguès, Noam
Youdim, Moussa B H
description The novel drugs, ladostigil (TV3326) and TV3279, are R and S isomers, respectively, derived from a combination of the carbamate cholinesterase (ChE) inhibitor, rivastigmine, and the pharmacophore of the monoamine oxidase (MAO) B inhibitor, rasagiline. They were developed for the treatment of comorbidity of dementia with Parkinsonism. In the present study, we determined the effects of these drugs on both aminergic neurotransmitter levels and motor behavioral activity in naïve and in L‐dopa‐ or L‐tryptophan‐induced rats. Chronic treatment of rats with ladostigil (52 mg kg−1 for 21 days) inhibited hippocampal and striatal MAO A and B activities by >90%, increased striatal levels of dopamine and serotonin, and inhibited striatal ChE activity by ∼50%. Chronic TV3279 (26 mg kg−1 for 21 days) similarly inhibited ∼50% of striatal ChE activity, but did not affect MAO activity or amine levels. In sharp contrast to the inductive effect of the MAO A/B inhibitor, tranylcypromine (TCP), on stereotyped hyperactivity in response to L‐dopa (50 mg kg−1) or L‐tryptophan (100 mg kg−1), ladostigil completely inhibited these behavioral hyperactivity syndromes. Accordingly, acute rivastigmine (2 mg kg−1) and chronic TV3279 abolished the ability of TCP to initiate L‐dopa‐induced hyperactivity, while scopolamine (0.5 mg kg−1) reversed the inhibitory effect of chronic ladostigil on L‐dopa‐induced hyperactivity, suggesting that ladostigil may attenuate successive locomotion by activating central cholinergic muscarinic receptors. Finally, while chronic ladostigil administration to naïve rats resulted in preserved spontaneous motor behavior, acute treatment with ladostigil decreased motor performance, compared to control animals. In contrast, chronic as well as acute treatments with TV3279 reduced spontaneous motor activity. Thus, the aminergic potentiation by ladostigil may counteract its cholinergic inhibitory effect on spontaneous motor behavior. Our results suggest that potentiation of both aminergic and cholinergic transmission systems by ladostigil contributes equally to motor behavior performance, which is substantially impaired in comorbidity of dementia with Parkinsonism including dementia with Lewy bodies (DLB). British Journal of Pharmacology (2005) 146, 553–560. doi:10.1038/sj.bjp.0706355
doi_str_mv 10.1038/sj.bjp.0706355
format Article
fullrecord <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_1751181</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>68692565</sourcerecordid><originalsourceid>FETCH-LOGICAL-c4894-1b8fbefa2153d725a8823c498cec855a086e07bffe047f9d2e1e3b4e7fb673e33</originalsourceid><addsrcrecordid>eNqFkcFu1DAQhiMEokvhyhFZSHBqFjuOY-8FCSqgSCvBoZwtx5k0jhI72NmFvfURkHgE3qxPwiy7osCFkzUzn-efmT_LHjO6ZJSrF6lf1v20pJJWXIg72YKVssoFV-xutqCUypwxpU6yByn1lGJRivvZCauoqijni-zHZQfEwyYG28HorBmI8Q2poTNbFyKG0LZg50RCS-Y9G7YwENuFwXlIM0ST4Ob6-xh8MCOmSPjqGswR5ztXuznEMzKYJqTZXbnhDNMkQpqCR2QOZH1z_a0Jk_mlug_muJvmMHXGH1gzp4fZvdYMCR4d39Ps09s3l-cX-frDu_fnr9a5LdWqzFmt2hpaUzDBG1kIo1TBbblSFqwSwuDKQGWN69BStqumAAa8LkG2dSU5cH6avTz0nTb1CI0FP-MB9BTdaOJOB-P03xXvOn0VtppJgVdm2OD5sUEMnzd4HT26ZGEYjIewSbpS1aoQlUDw6T9gHzbR43K6YJKtZKEUQssDZGNIKUL7exJG9d58nXqN5uuj-fjhyZ_z3-JHtxF4dgRMQqfbaLx16ZZD5UrxCjl-4L64AXb_kdWvP14UpSz5T98L0EY</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>217197288</pqid></control><display><type>article</type><title>The neurochemical and behavioral effects of the novel cholinesterase–monoamine oxidase inhibitor, ladostigil, in response to L‐dopa and L‐tryptophan, in rats</title><source>MEDLINE</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>Wiley Free Content</source><source>Wiley Online Library All Journals</source><source>PubMed Central</source><source>Alma/SFX Local Collection</source><creator>Sagi, Yotam ; Driguès, Noam ; Youdim, Moussa B H</creator><creatorcontrib>Sagi, Yotam ; Driguès, Noam ; Youdim, Moussa B H</creatorcontrib><description>The novel drugs, ladostigil (TV3326) and TV3279, are R and S isomers, respectively, derived from a combination of the carbamate cholinesterase (ChE) inhibitor, rivastigmine, and the pharmacophore of the monoamine oxidase (MAO) B inhibitor, rasagiline. They were developed for the treatment of comorbidity of dementia with Parkinsonism. In the present study, we determined the effects of these drugs on both aminergic neurotransmitter levels and motor behavioral activity in naïve and in L‐dopa‐ or L‐tryptophan‐induced rats. Chronic treatment of rats with ladostigil (52 mg kg−1 for 21 days) inhibited hippocampal and striatal MAO A and B activities by &gt;90%, increased striatal levels of dopamine and serotonin, and inhibited striatal ChE activity by ∼50%. Chronic TV3279 (26 mg kg−1 for 21 days) similarly inhibited ∼50% of striatal ChE activity, but did not affect MAO activity or amine levels. In sharp contrast to the inductive effect of the MAO A/B inhibitor, tranylcypromine (TCP), on stereotyped hyperactivity in response to L‐dopa (50 mg kg−1) or L‐tryptophan (100 mg kg−1), ladostigil completely inhibited these behavioral hyperactivity syndromes. Accordingly, acute rivastigmine (2 mg kg−1) and chronic TV3279 abolished the ability of TCP to initiate L‐dopa‐induced hyperactivity, while scopolamine (0.5 mg kg−1) reversed the inhibitory effect of chronic ladostigil on L‐dopa‐induced hyperactivity, suggesting that ladostigil may attenuate successive locomotion by activating central cholinergic muscarinic receptors. Finally, while chronic ladostigil administration to naïve rats resulted in preserved spontaneous motor behavior, acute treatment with ladostigil decreased motor performance, compared to control animals. In contrast, chronic as well as acute treatments with TV3279 reduced spontaneous motor activity. Thus, the aminergic potentiation by ladostigil may counteract its cholinergic inhibitory effect on spontaneous motor behavior. Our results suggest that potentiation of both aminergic and cholinergic transmission systems by ladostigil contributes equally to motor behavior performance, which is substantially impaired in comorbidity of dementia with Parkinsonism including dementia with Lewy bodies (DLB). British Journal of Pharmacology (2005) 146, 553–560. doi:10.1038/sj.bjp.0706355</description><identifier>ISSN: 0007-1188</identifier><identifier>EISSN: 1476-5381</identifier><identifier>DOI: 10.1038/sj.bjp.0706355</identifier><identifier>PMID: 16086033</identifier><identifier>CODEN: BJPCBM</identifier><language>eng</language><publisher>Oxford, UK: Blackwell Publishing Ltd</publisher><subject><![CDATA[Animals ; Basal Ganglia - drug effects ; Basal Ganglia - enzymology ; Behavior, Animal - drug effects ; Biological and medical sciences ; Carbamates - administration & dosage ; Carbamates - pharmacology ; catecholamine ; cholinesterase inhibitor ; Cholinesterase Inhibitors - administration & dosage ; Cholinesterase Inhibitors - pharmacology ; dementia with Lewy bodies ; Dopamine - metabolism ; Hippocampus - drug effects ; Hippocampus - enzymology ; Hyperkinesis - chemically induced ; Hyperkinesis - prevention & control ; Indans - administration & dosage ; Indans - pharmacology ; Ladostigil ; Levodopa - administration & dosage ; Levodopa - adverse effects ; Lewy Body Disease - drug therapy ; Male ; Medical sciences ; monoamine oxidase inhibitor ; Monoamine Oxidase Inhibitors - administration & dosage ; Monoamine Oxidase Inhibitors - pharmacology ; motor activity ; Motor Activity - drug effects ; multifunctional drug therapy ; Muscarinic Antagonists - administration & dosage ; Muscarinic Antagonists - pharmacology ; Norepinephrine - metabolism ; Pharmacology. Drug treatments ; Phenylcarbamates - administration & dosage ; Phenylcarbamates - pharmacology ; Rats ; Rats, Sprague-Dawley ; Rivastigmine ; Scopolamine - administration & dosage ; Scopolamine - pharmacology ; serotonin ; Serotonin - metabolism ; stereotypy ; Time Factors ; Tranylcypromine - administration & dosage ; Tranylcypromine - adverse effects ; Tranylcypromine - pharmacology ; Tryptophan - administration & dosage ; Tryptophan - adverse effects]]></subject><ispartof>British journal of pharmacology, 2005-10, Vol.146 (4), p.553-560</ispartof><rights>2005 British Pharmacological Society</rights><rights>2005 INIST-CNRS</rights><rights>Copyright Nature Publishing Group Oct 2005</rights><rights>Copyright 2005, Nature Publishing Group 2005 Nature Publishing Group</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4894-1b8fbefa2153d725a8823c498cec855a086e07bffe047f9d2e1e3b4e7fb673e33</citedby><cites>FETCH-LOGICAL-c4894-1b8fbefa2153d725a8823c498cec855a086e07bffe047f9d2e1e3b4e7fb673e33</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC1751181/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC1751181/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,1416,1432,27922,27923,45572,45573,46407,46831,53789,53791</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&amp;idt=17196836$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16086033$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sagi, Yotam</creatorcontrib><creatorcontrib>Driguès, Noam</creatorcontrib><creatorcontrib>Youdim, Moussa B H</creatorcontrib><title>The neurochemical and behavioral effects of the novel cholinesterase–monoamine oxidase inhibitor, ladostigil, in response to L‐dopa and L‐tryptophan, in rats</title><title>British journal of pharmacology</title><addtitle>Br J Pharmacol</addtitle><description>The novel drugs, ladostigil (TV3326) and TV3279, are R and S isomers, respectively, derived from a combination of the carbamate cholinesterase (ChE) inhibitor, rivastigmine, and the pharmacophore of the monoamine oxidase (MAO) B inhibitor, rasagiline. They were developed for the treatment of comorbidity of dementia with Parkinsonism. In the present study, we determined the effects of these drugs on both aminergic neurotransmitter levels and motor behavioral activity in naïve and in L‐dopa‐ or L‐tryptophan‐induced rats. Chronic treatment of rats with ladostigil (52 mg kg−1 for 21 days) inhibited hippocampal and striatal MAO A and B activities by &gt;90%, increased striatal levels of dopamine and serotonin, and inhibited striatal ChE activity by ∼50%. Chronic TV3279 (26 mg kg−1 for 21 days) similarly inhibited ∼50% of striatal ChE activity, but did not affect MAO activity or amine levels. In sharp contrast to the inductive effect of the MAO A/B inhibitor, tranylcypromine (TCP), on stereotyped hyperactivity in response to L‐dopa (50 mg kg−1) or L‐tryptophan (100 mg kg−1), ladostigil completely inhibited these behavioral hyperactivity syndromes. Accordingly, acute rivastigmine (2 mg kg−1) and chronic TV3279 abolished the ability of TCP to initiate L‐dopa‐induced hyperactivity, while scopolamine (0.5 mg kg−1) reversed the inhibitory effect of chronic ladostigil on L‐dopa‐induced hyperactivity, suggesting that ladostigil may attenuate successive locomotion by activating central cholinergic muscarinic receptors. Finally, while chronic ladostigil administration to naïve rats resulted in preserved spontaneous motor behavior, acute treatment with ladostigil decreased motor performance, compared to control animals. In contrast, chronic as well as acute treatments with TV3279 reduced spontaneous motor activity. Thus, the aminergic potentiation by ladostigil may counteract its cholinergic inhibitory effect on spontaneous motor behavior. Our results suggest that potentiation of both aminergic and cholinergic transmission systems by ladostigil contributes equally to motor behavior performance, which is substantially impaired in comorbidity of dementia with Parkinsonism including dementia with Lewy bodies (DLB). British Journal of Pharmacology (2005) 146, 553–560. doi:10.1038/sj.bjp.0706355</description><subject>Animals</subject><subject>Basal Ganglia - drug effects</subject><subject>Basal Ganglia - enzymology</subject><subject>Behavior, Animal - drug effects</subject><subject>Biological and medical sciences</subject><subject>Carbamates - administration &amp; dosage</subject><subject>Carbamates - pharmacology</subject><subject>catecholamine</subject><subject>cholinesterase inhibitor</subject><subject>Cholinesterase Inhibitors - administration &amp; dosage</subject><subject>Cholinesterase Inhibitors - pharmacology</subject><subject>dementia with Lewy bodies</subject><subject>Dopamine - metabolism</subject><subject>Hippocampus - drug effects</subject><subject>Hippocampus - enzymology</subject><subject>Hyperkinesis - chemically induced</subject><subject>Hyperkinesis - prevention &amp; control</subject><subject>Indans - administration &amp; dosage</subject><subject>Indans - pharmacology</subject><subject>Ladostigil</subject><subject>Levodopa - administration &amp; dosage</subject><subject>Levodopa - adverse effects</subject><subject>Lewy Body Disease - drug therapy</subject><subject>Male</subject><subject>Medical sciences</subject><subject>monoamine oxidase inhibitor</subject><subject>Monoamine Oxidase Inhibitors - administration &amp; dosage</subject><subject>Monoamine Oxidase Inhibitors - pharmacology</subject><subject>motor activity</subject><subject>Motor Activity - drug effects</subject><subject>multifunctional drug therapy</subject><subject>Muscarinic Antagonists - administration &amp; dosage</subject><subject>Muscarinic Antagonists - pharmacology</subject><subject>Norepinephrine - metabolism</subject><subject>Pharmacology. Drug treatments</subject><subject>Phenylcarbamates - administration &amp; dosage</subject><subject>Phenylcarbamates - pharmacology</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Rivastigmine</subject><subject>Scopolamine - administration &amp; dosage</subject><subject>Scopolamine - pharmacology</subject><subject>serotonin</subject><subject>Serotonin - metabolism</subject><subject>stereotypy</subject><subject>Time Factors</subject><subject>Tranylcypromine - administration &amp; dosage</subject><subject>Tranylcypromine - adverse effects</subject><subject>Tranylcypromine - pharmacology</subject><subject>Tryptophan - administration &amp; dosage</subject><subject>Tryptophan - adverse effects</subject><issn>0007-1188</issn><issn>1476-5381</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2005</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNqFkcFu1DAQhiMEokvhyhFZSHBqFjuOY-8FCSqgSCvBoZwtx5k0jhI72NmFvfURkHgE3qxPwiy7osCFkzUzn-efmT_LHjO6ZJSrF6lf1v20pJJWXIg72YKVssoFV-xutqCUypwxpU6yByn1lGJRivvZCauoqijni-zHZQfEwyYG28HorBmI8Q2poTNbFyKG0LZg50RCS-Y9G7YwENuFwXlIM0ST4Ob6-xh8MCOmSPjqGswR5ztXuznEMzKYJqTZXbnhDNMkQpqCR2QOZH1z_a0Jk_mlug_muJvmMHXGH1gzp4fZvdYMCR4d39Ps09s3l-cX-frDu_fnr9a5LdWqzFmt2hpaUzDBG1kIo1TBbblSFqwSwuDKQGWN69BStqumAAa8LkG2dSU5cH6avTz0nTb1CI0FP-MB9BTdaOJOB-P03xXvOn0VtppJgVdm2OD5sUEMnzd4HT26ZGEYjIewSbpS1aoQlUDw6T9gHzbR43K6YJKtZKEUQssDZGNIKUL7exJG9d58nXqN5uuj-fjhyZ_z3-JHtxF4dgRMQqfbaLx16ZZD5UrxCjl-4L64AXb_kdWvP14UpSz5T98L0EY</recordid><startdate>200510</startdate><enddate>200510</enddate><creator>Sagi, Yotam</creator><creator>Driguès, Noam</creator><creator>Youdim, Moussa B H</creator><general>Blackwell Publishing Ltd</general><general>Nature Publishing</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QP</scope><scope>7RV</scope><scope>7TK</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>200510</creationdate><title>The neurochemical and behavioral effects of the novel cholinesterase–monoamine oxidase inhibitor, ladostigil, in response to L‐dopa and L‐tryptophan, in rats</title><author>Sagi, Yotam ; Driguès, Noam ; Youdim, Moussa B H</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4894-1b8fbefa2153d725a8823c498cec855a086e07bffe047f9d2e1e3b4e7fb673e33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2005</creationdate><topic>Animals</topic><topic>Basal Ganglia - drug effects</topic><topic>Basal Ganglia - enzymology</topic><topic>Behavior, Animal - drug effects</topic><topic>Biological and medical sciences</topic><topic>Carbamates - administration &amp; dosage</topic><topic>Carbamates - pharmacology</topic><topic>catecholamine</topic><topic>cholinesterase inhibitor</topic><topic>Cholinesterase Inhibitors - administration &amp; dosage</topic><topic>Cholinesterase Inhibitors - pharmacology</topic><topic>dementia with Lewy bodies</topic><topic>Dopamine - metabolism</topic><topic>Hippocampus - drug effects</topic><topic>Hippocampus - enzymology</topic><topic>Hyperkinesis - chemically induced</topic><topic>Hyperkinesis - prevention &amp; control</topic><topic>Indans - administration &amp; dosage</topic><topic>Indans - pharmacology</topic><topic>Ladostigil</topic><topic>Levodopa - administration &amp; dosage</topic><topic>Levodopa - adverse effects</topic><topic>Lewy Body Disease - drug therapy</topic><topic>Male</topic><topic>Medical sciences</topic><topic>monoamine oxidase inhibitor</topic><topic>Monoamine Oxidase Inhibitors - administration &amp; dosage</topic><topic>Monoamine Oxidase Inhibitors - pharmacology</topic><topic>motor activity</topic><topic>Motor Activity - drug effects</topic><topic>multifunctional drug therapy</topic><topic>Muscarinic Antagonists - administration &amp; dosage</topic><topic>Muscarinic Antagonists - pharmacology</topic><topic>Norepinephrine - metabolism</topic><topic>Pharmacology. Drug treatments</topic><topic>Phenylcarbamates - administration &amp; dosage</topic><topic>Phenylcarbamates - pharmacology</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Rivastigmine</topic><topic>Scopolamine - administration &amp; dosage</topic><topic>Scopolamine - pharmacology</topic><topic>serotonin</topic><topic>Serotonin - metabolism</topic><topic>stereotypy</topic><topic>Time Factors</topic><topic>Tranylcypromine - administration &amp; dosage</topic><topic>Tranylcypromine - adverse effects</topic><topic>Tranylcypromine - pharmacology</topic><topic>Tryptophan - administration &amp; dosage</topic><topic>Tryptophan - adverse effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sagi, Yotam</creatorcontrib><creatorcontrib>Driguès, Noam</creatorcontrib><creatorcontrib>Youdim, Moussa B H</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Calcium &amp; Calcified Tissue Abstracts</collection><collection>Nursing &amp; Allied Health Database</collection><collection>Neurosciences Abstracts</collection><collection>Health &amp; Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health &amp; Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health &amp; Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>Nursing &amp; Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>British journal of pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sagi, Yotam</au><au>Driguès, Noam</au><au>Youdim, Moussa B H</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The neurochemical and behavioral effects of the novel cholinesterase–monoamine oxidase inhibitor, ladostigil, in response to L‐dopa and L‐tryptophan, in rats</atitle><jtitle>British journal of pharmacology</jtitle><addtitle>Br J Pharmacol</addtitle><date>2005-10</date><risdate>2005</risdate><volume>146</volume><issue>4</issue><spage>553</spage><epage>560</epage><pages>553-560</pages><issn>0007-1188</issn><eissn>1476-5381</eissn><coden>BJPCBM</coden><abstract>The novel drugs, ladostigil (TV3326) and TV3279, are R and S isomers, respectively, derived from a combination of the carbamate cholinesterase (ChE) inhibitor, rivastigmine, and the pharmacophore of the monoamine oxidase (MAO) B inhibitor, rasagiline. They were developed for the treatment of comorbidity of dementia with Parkinsonism. In the present study, we determined the effects of these drugs on both aminergic neurotransmitter levels and motor behavioral activity in naïve and in L‐dopa‐ or L‐tryptophan‐induced rats. Chronic treatment of rats with ladostigil (52 mg kg−1 for 21 days) inhibited hippocampal and striatal MAO A and B activities by &gt;90%, increased striatal levels of dopamine and serotonin, and inhibited striatal ChE activity by ∼50%. Chronic TV3279 (26 mg kg−1 for 21 days) similarly inhibited ∼50% of striatal ChE activity, but did not affect MAO activity or amine levels. In sharp contrast to the inductive effect of the MAO A/B inhibitor, tranylcypromine (TCP), on stereotyped hyperactivity in response to L‐dopa (50 mg kg−1) or L‐tryptophan (100 mg kg−1), ladostigil completely inhibited these behavioral hyperactivity syndromes. Accordingly, acute rivastigmine (2 mg kg−1) and chronic TV3279 abolished the ability of TCP to initiate L‐dopa‐induced hyperactivity, while scopolamine (0.5 mg kg−1) reversed the inhibitory effect of chronic ladostigil on L‐dopa‐induced hyperactivity, suggesting that ladostigil may attenuate successive locomotion by activating central cholinergic muscarinic receptors. Finally, while chronic ladostigil administration to naïve rats resulted in preserved spontaneous motor behavior, acute treatment with ladostigil decreased motor performance, compared to control animals. In contrast, chronic as well as acute treatments with TV3279 reduced spontaneous motor activity. Thus, the aminergic potentiation by ladostigil may counteract its cholinergic inhibitory effect on spontaneous motor behavior. Our results suggest that potentiation of both aminergic and cholinergic transmission systems by ladostigil contributes equally to motor behavior performance, which is substantially impaired in comorbidity of dementia with Parkinsonism including dementia with Lewy bodies (DLB). British Journal of Pharmacology (2005) 146, 553–560. doi:10.1038/sj.bjp.0706355</abstract><cop>Oxford, UK</cop><pub>Blackwell Publishing Ltd</pub><pmid>16086033</pmid><doi>10.1038/sj.bjp.0706355</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record>
fulltext fulltext
identifier ISSN: 0007-1188
ispartof British journal of pharmacology, 2005-10, Vol.146 (4), p.553-560
issn 0007-1188
1476-5381
language eng
recordid cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_1751181
source MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Wiley Free Content; Wiley Online Library All Journals; PubMed Central; Alma/SFX Local Collection
subjects Animals
Basal Ganglia - drug effects
Basal Ganglia - enzymology
Behavior, Animal - drug effects
Biological and medical sciences
Carbamates - administration & dosage
Carbamates - pharmacology
catecholamine
cholinesterase inhibitor
Cholinesterase Inhibitors - administration & dosage
Cholinesterase Inhibitors - pharmacology
dementia with Lewy bodies
Dopamine - metabolism
Hippocampus - drug effects
Hippocampus - enzymology
Hyperkinesis - chemically induced
Hyperkinesis - prevention & control
Indans - administration & dosage
Indans - pharmacology
Ladostigil
Levodopa - administration & dosage
Levodopa - adverse effects
Lewy Body Disease - drug therapy
Male
Medical sciences
monoamine oxidase inhibitor
Monoamine Oxidase Inhibitors - administration & dosage
Monoamine Oxidase Inhibitors - pharmacology
motor activity
Motor Activity - drug effects
multifunctional drug therapy
Muscarinic Antagonists - administration & dosage
Muscarinic Antagonists - pharmacology
Norepinephrine - metabolism
Pharmacology. Drug treatments
Phenylcarbamates - administration & dosage
Phenylcarbamates - pharmacology
Rats
Rats, Sprague-Dawley
Rivastigmine
Scopolamine - administration & dosage
Scopolamine - pharmacology
serotonin
Serotonin - metabolism
stereotypy
Time Factors
Tranylcypromine - administration & dosage
Tranylcypromine - adverse effects
Tranylcypromine - pharmacology
Tryptophan - administration & dosage
Tryptophan - adverse effects
title The neurochemical and behavioral effects of the novel cholinesterase–monoamine oxidase inhibitor, ladostigil, in response to L‐dopa and L‐tryptophan, in rats
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-09T23%3A07%3A38IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=The%20neurochemical%20and%20behavioral%20effects%20of%20the%20novel%20cholinesterase%E2%80%93monoamine%20oxidase%20inhibitor,%20ladostigil,%20in%20response%20to%20L%E2%80%90dopa%20and%20L%E2%80%90tryptophan,%20in%20rats&rft.jtitle=British%20journal%20of%20pharmacology&rft.au=Sagi,%20Yotam&rft.date=2005-10&rft.volume=146&rft.issue=4&rft.spage=553&rft.epage=560&rft.pages=553-560&rft.issn=0007-1188&rft.eissn=1476-5381&rft.coden=BJPCBM&rft_id=info:doi/10.1038/sj.bjp.0706355&rft_dat=%3Cproquest_pubme%3E68692565%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=217197288&rft_id=info:pmid/16086033&rfr_iscdi=true