Energy metabolism as a target for cyclobenzaprine: A drug candidate against Visceral Leishmaniasis
[Display omitted] •Cyclobenzaprine caused a decrease of ATP in L. infantum promastigotes.•The drug induced an irreversible depolarization of plasma membrane.•The drug collapsed the mitochondrial electrochemical potential.•It also induced Ca2+ imbalance and DNA fragmentation.•Cyclobenzaprine can be c...
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creator | Lima, Marta Lopes Abengózar, Maria A. Torres-Santos, Eduardo Caio Borborema, Samanta Etel Treiger Godzien, Joanna López-Gonzálvez, Ángeles Barbas, Coral Rivas, Luis Tempone, Andre Gustavo |
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•Cyclobenzaprine caused a decrease of ATP in L. infantum promastigotes.•The drug induced an irreversible depolarization of plasma membrane.•The drug collapsed the mitochondrial electrochemical potential.•It also induced Ca2+ imbalance and DNA fragmentation.•Cyclobenzaprine can be considered a promising drug candidate.
Leishmaniases have a broad spectrum of clinical manifestations, ranging from a cutaneous to a progressive and fatal visceral disease. Chemotherapy is nowadays the almost exclusive way to fight the disease but limited by its scarce therapeutic arsenal, on its own compromised by adverse side effects and clinical resistance. Cyclobenzaprine (CBP), an FDA-approved oral muscle relaxant drug has previously demonstrated in vitro and in vivo activity against Leishmania sp., but its targets were not fully unveiled. This study aimed to define the role of energy metabolism as a target for the leishmanicidal mechanisms of CBP. Methodology to assess CBP leishmanicidal mechanism variation of intracellular ATP levels using living Leishmania transfected with a cytoplasmic luciferase. Induction of plasma membrane permeability by assessing depolarization with DiSBAC(2)3 and entrance of the vital dye SYTOX® Green. Mitochondrial depolarization by rhodamine 123 accumulation. Mapping target site within the respiratory chain by oxygen consumption rate. Reactive oxygen species (ROS) production using MitoSOX. Morphological changes by transmission electron microscopy. CBP caused on L. infantum promastigotes a decrease of intracellular ATP levels, with irreversible depolarization of plasma membrane, the collapse of the mitochondrial electrochemical potential, mild uncoupling of the respiratory chain, and ROS production, with ensuing intracellular Ca2+ imbalance and DNA fragmentation. Electron microscopy supported autophagic features but not a massive plasma membrane disruption. The severe and irreversible mitochondrial damage induced by CBP endorsed the bioenergetics metabolism as a relevant target within the lethal programme induced by CBP in Leishmania. This, together with the mild-side effects of this oral drug, endorses CBP as an appealing novel candidate as a leishmanicidal drug under a drug repurposing strategy. |
doi_str_mv | 10.1016/j.bioorg.2022.106009 |
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•Cyclobenzaprine caused a decrease of ATP in L. infantum promastigotes.•The drug induced an irreversible depolarization of plasma membrane.•The drug collapsed the mitochondrial electrochemical potential.•It also induced Ca2+ imbalance and DNA fragmentation.•Cyclobenzaprine can be considered a promising drug candidate.
Leishmaniases have a broad spectrum of clinical manifestations, ranging from a cutaneous to a progressive and fatal visceral disease. Chemotherapy is nowadays the almost exclusive way to fight the disease but limited by its scarce therapeutic arsenal, on its own compromised by adverse side effects and clinical resistance. Cyclobenzaprine (CBP), an FDA-approved oral muscle relaxant drug has previously demonstrated in vitro and in vivo activity against Leishmania sp., but its targets were not fully unveiled. This study aimed to define the role of energy metabolism as a target for the leishmanicidal mechanisms of CBP. Methodology to assess CBP leishmanicidal mechanism variation of intracellular ATP levels using living Leishmania transfected with a cytoplasmic luciferase. Induction of plasma membrane permeability by assessing depolarization with DiSBAC(2)3 and entrance of the vital dye SYTOX® Green. Mitochondrial depolarization by rhodamine 123 accumulation. Mapping target site within the respiratory chain by oxygen consumption rate. Reactive oxygen species (ROS) production using MitoSOX. Morphological changes by transmission electron microscopy. CBP caused on L. infantum promastigotes a decrease of intracellular ATP levels, with irreversible depolarization of plasma membrane, the collapse of the mitochondrial electrochemical potential, mild uncoupling of the respiratory chain, and ROS production, with ensuing intracellular Ca2+ imbalance and DNA fragmentation. Electron microscopy supported autophagic features but not a massive plasma membrane disruption. The severe and irreversible mitochondrial damage induced by CBP endorsed the bioenergetics metabolism as a relevant target within the lethal programme induced by CBP in Leishmania. This, together with the mild-side effects of this oral drug, endorses CBP as an appealing novel candidate as a leishmanicidal drug under a drug repurposing strategy.</description><identifier>ISSN: 0045-2068</identifier><identifier>EISSN: 1090-2120</identifier><identifier>DOI: 10.1016/j.bioorg.2022.106009</identifier><language>eng</language><publisher>Elsevier Inc</publisher><subject>Cyclobenzaprine ; Drug repurposing ; Leishmania ; Leishmaniasis ; Mechanism of action ; Neglected diseases</subject><ispartof>Bioorganic chemistry, 2022-10, Vol.127, p.106009-106009, Article 106009</ispartof><rights>2022 Elsevier Inc.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c269t-2e576de174741f94ca000655afbc0daace0b311515676fb9ebd9e668ca36b5053</citedby><cites>FETCH-LOGICAL-c269t-2e576de174741f94ca000655afbc0daace0b311515676fb9ebd9e668ca36b5053</cites><orcidid>0000-0003-4722-491X ; 0000-0002-6363-7135</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bioorg.2022.106009$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids></links><search><creatorcontrib>Lima, Marta Lopes</creatorcontrib><creatorcontrib>Abengózar, Maria A.</creatorcontrib><creatorcontrib>Torres-Santos, Eduardo Caio</creatorcontrib><creatorcontrib>Borborema, Samanta Etel Treiger</creatorcontrib><creatorcontrib>Godzien, Joanna</creatorcontrib><creatorcontrib>López-Gonzálvez, Ángeles</creatorcontrib><creatorcontrib>Barbas, Coral</creatorcontrib><creatorcontrib>Rivas, Luis</creatorcontrib><creatorcontrib>Tempone, Andre Gustavo</creatorcontrib><title>Energy metabolism as a target for cyclobenzaprine: A drug candidate against Visceral Leishmaniasis</title><title>Bioorganic chemistry</title><description>[Display omitted]
•Cyclobenzaprine caused a decrease of ATP in L. infantum promastigotes.•The drug induced an irreversible depolarization of plasma membrane.•The drug collapsed the mitochondrial electrochemical potential.•It also induced Ca2+ imbalance and DNA fragmentation.•Cyclobenzaprine can be considered a promising drug candidate.
Leishmaniases have a broad spectrum of clinical manifestations, ranging from a cutaneous to a progressive and fatal visceral disease. Chemotherapy is nowadays the almost exclusive way to fight the disease but limited by its scarce therapeutic arsenal, on its own compromised by adverse side effects and clinical resistance. Cyclobenzaprine (CBP), an FDA-approved oral muscle relaxant drug has previously demonstrated in vitro and in vivo activity against Leishmania sp., but its targets were not fully unveiled. This study aimed to define the role of energy metabolism as a target for the leishmanicidal mechanisms of CBP. Methodology to assess CBP leishmanicidal mechanism variation of intracellular ATP levels using living Leishmania transfected with a cytoplasmic luciferase. Induction of plasma membrane permeability by assessing depolarization with DiSBAC(2)3 and entrance of the vital dye SYTOX® Green. Mitochondrial depolarization by rhodamine 123 accumulation. Mapping target site within the respiratory chain by oxygen consumption rate. Reactive oxygen species (ROS) production using MitoSOX. Morphological changes by transmission electron microscopy. CBP caused on L. infantum promastigotes a decrease of intracellular ATP levels, with irreversible depolarization of plasma membrane, the collapse of the mitochondrial electrochemical potential, mild uncoupling of the respiratory chain, and ROS production, with ensuing intracellular Ca2+ imbalance and DNA fragmentation. Electron microscopy supported autophagic features but not a massive plasma membrane disruption. The severe and irreversible mitochondrial damage induced by CBP endorsed the bioenergetics metabolism as a relevant target within the lethal programme induced by CBP in Leishmania. This, together with the mild-side effects of this oral drug, endorses CBP as an appealing novel candidate as a leishmanicidal drug under a drug repurposing strategy.</description><subject>Cyclobenzaprine</subject><subject>Drug repurposing</subject><subject>Leishmania</subject><subject>Leishmaniasis</subject><subject>Mechanism of action</subject><subject>Neglected diseases</subject><issn>0045-2068</issn><issn>1090-2120</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><recordid>eNp9kE9LxDAQxYMouK5-Aw85euk66Tap9SAsi_9gwYt6DZN0WrO0jSZZYf30dqlnTwPDe2_m_Ri7FLAQINT1dmGc96Fd5JDn40oBVEdsJqCCLBc5HLMZQCGzHNTNKTuLcQsgRFGqGTP3A4V2z3tKaHznYs8xcuQJQ0uJNz5wu7edNzT84GdwA93yFa_DruUWh9rVmIhji26Iib-7aClgxzfk4kePg8Po4jk7abCLdPE35-zt4f51_ZRtXh6f16tNZnNVpSwnWaqaRFmUhWiqwiIAKCmxMRZqREtglkJIIVWpGlORqStS6sbiUhkJcjlnV1PuZ_BfO4pJ94d_ug4H8ruoxysCJKiyGqXFJLXBxxio0WO1HsNeC9AHpHqrJ6T6gFRPSEfb3WSjsca3o6CjdTRYql0gm3Tt3f8Bv_FbgiM</recordid><startdate>202210</startdate><enddate>202210</enddate><creator>Lima, Marta Lopes</creator><creator>Abengózar, Maria A.</creator><creator>Torres-Santos, Eduardo Caio</creator><creator>Borborema, Samanta Etel Treiger</creator><creator>Godzien, Joanna</creator><creator>López-Gonzálvez, Ángeles</creator><creator>Barbas, Coral</creator><creator>Rivas, Luis</creator><creator>Tempone, Andre Gustavo</creator><general>Elsevier Inc</general><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0003-4722-491X</orcidid><orcidid>https://orcid.org/0000-0002-6363-7135</orcidid></search><sort><creationdate>202210</creationdate><title>Energy metabolism as a target for cyclobenzaprine: A drug candidate against Visceral Leishmaniasis</title><author>Lima, Marta Lopes ; Abengózar, Maria A. ; Torres-Santos, Eduardo Caio ; Borborema, Samanta Etel Treiger ; Godzien, Joanna ; López-Gonzálvez, Ángeles ; Barbas, Coral ; Rivas, Luis ; Tempone, Andre Gustavo</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c269t-2e576de174741f94ca000655afbc0daace0b311515676fb9ebd9e668ca36b5053</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Cyclobenzaprine</topic><topic>Drug repurposing</topic><topic>Leishmania</topic><topic>Leishmaniasis</topic><topic>Mechanism of action</topic><topic>Neglected diseases</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lima, Marta Lopes</creatorcontrib><creatorcontrib>Abengózar, Maria A.</creatorcontrib><creatorcontrib>Torres-Santos, Eduardo Caio</creatorcontrib><creatorcontrib>Borborema, Samanta Etel Treiger</creatorcontrib><creatorcontrib>Godzien, Joanna</creatorcontrib><creatorcontrib>López-Gonzálvez, Ángeles</creatorcontrib><creatorcontrib>Barbas, Coral</creatorcontrib><creatorcontrib>Rivas, Luis</creatorcontrib><creatorcontrib>Tempone, Andre Gustavo</creatorcontrib><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Bioorganic chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lima, Marta Lopes</au><au>Abengózar, Maria A.</au><au>Torres-Santos, Eduardo Caio</au><au>Borborema, Samanta Etel Treiger</au><au>Godzien, Joanna</au><au>López-Gonzálvez, Ángeles</au><au>Barbas, Coral</au><au>Rivas, Luis</au><au>Tempone, Andre Gustavo</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Energy metabolism as a target for cyclobenzaprine: A drug candidate against Visceral Leishmaniasis</atitle><jtitle>Bioorganic chemistry</jtitle><date>2022-10</date><risdate>2022</risdate><volume>127</volume><spage>106009</spage><epage>106009</epage><pages>106009-106009</pages><artnum>106009</artnum><issn>0045-2068</issn><eissn>1090-2120</eissn><abstract>[Display omitted]
•Cyclobenzaprine caused a decrease of ATP in L. infantum promastigotes.•The drug induced an irreversible depolarization of plasma membrane.•The drug collapsed the mitochondrial electrochemical potential.•It also induced Ca2+ imbalance and DNA fragmentation.•Cyclobenzaprine can be considered a promising drug candidate.
Leishmaniases have a broad spectrum of clinical manifestations, ranging from a cutaneous to a progressive and fatal visceral disease. Chemotherapy is nowadays the almost exclusive way to fight the disease but limited by its scarce therapeutic arsenal, on its own compromised by adverse side effects and clinical resistance. Cyclobenzaprine (CBP), an FDA-approved oral muscle relaxant drug has previously demonstrated in vitro and in vivo activity against Leishmania sp., but its targets were not fully unveiled. This study aimed to define the role of energy metabolism as a target for the leishmanicidal mechanisms of CBP. Methodology to assess CBP leishmanicidal mechanism variation of intracellular ATP levels using living Leishmania transfected with a cytoplasmic luciferase. Induction of plasma membrane permeability by assessing depolarization with DiSBAC(2)3 and entrance of the vital dye SYTOX® Green. Mitochondrial depolarization by rhodamine 123 accumulation. Mapping target site within the respiratory chain by oxygen consumption rate. Reactive oxygen species (ROS) production using MitoSOX. Morphological changes by transmission electron microscopy. CBP caused on L. infantum promastigotes a decrease of intracellular ATP levels, with irreversible depolarization of plasma membrane, the collapse of the mitochondrial electrochemical potential, mild uncoupling of the respiratory chain, and ROS production, with ensuing intracellular Ca2+ imbalance and DNA fragmentation. Electron microscopy supported autophagic features but not a massive plasma membrane disruption. The severe and irreversible mitochondrial damage induced by CBP endorsed the bioenergetics metabolism as a relevant target within the lethal programme induced by CBP in Leishmania. This, together with the mild-side effects of this oral drug, endorses CBP as an appealing novel candidate as a leishmanicidal drug under a drug repurposing strategy.</abstract><pub>Elsevier Inc</pub><doi>10.1016/j.bioorg.2022.106009</doi><tpages>1</tpages><orcidid>https://orcid.org/0000-0003-4722-491X</orcidid><orcidid>https://orcid.org/0000-0002-6363-7135</orcidid></addata></record> |
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subjects | Cyclobenzaprine Drug repurposing Leishmania Leishmaniasis Mechanism of action Neglected diseases |
title | Energy metabolism as a target for cyclobenzaprine: A drug candidate against Visceral Leishmaniasis |
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