Repurposing Aprepitant: Can it protect against doxorubicin-induced Chemobrain beyond its antiemetic role?
The substance P (SP) and neurokinin-1 receptor (NK-1R) axis is crucial in numerous pathological processes, including inflammation, stress responses, pain perception, and vomiting. Consequently, aprepitant, an NK-1R blocker, is used as an antiemetic in chemotherapy, including the use of doxorubicin (...
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description | The substance P (SP) and neurokinin-1 receptor (NK-1R) axis is crucial in numerous pathological processes, including inflammation, stress responses, pain perception, and vomiting. Consequently, aprepitant, an NK-1R blocker, is used as an antiemetic in chemotherapy, including the use of doxorubicin (DOX), but whether aprepitant can also assuage DOX-mediated chemobrain remains to be unveiled. Here, we scrutinized the potential neuroprotective effect and underlying mechanisms of aprepitant using DOX-induced chemobrain model, where rats were allocated into 4 groups (control, aprepitant, DOX, and DOX+ aprepitant). Cognitive deficits were assessed through behavioral tests and hippocampal structural alterations were determined by H&E and toluidine blue staining. Biochemical measurements were performed using ELISA, real-time quantitative PCR, western blotting, and immunohistochemical methods. Aprepitant improved cognitive responses, and hippocampal morphology, enhancing the presence of intact neurons. At the molecular tier, aprepitant significantly reduced hippocampal contents of SP and the inflammatory markers NF-κB and IL-1β. Additionally, it signified its antioxidant and antiapoptotic capacities by downregulating cleaved caspase-3 protein expression and curbing the content of malondialdehyde but boosted those of glutathione and Bcl-2. Aprepitant also downregulated the expression of miR-146a and turned off the endoplasmic reticulum (ER) stress cascade PERK/eIF-2α/ATF-4/CHOP. To recapitulate, aprepitant demonstrates a neuroprotective effect against DOX-mediated chemobrain by alleviating inflammatory, oxidative, and apoptotic responses, partly by reducing SP, ER stress, and miR-146a. These findings not only underscore the potential of aprepitant as a neuroprotective agent but also offer new understanding of the mechanisms behind chemobrain, leading to better therapeutic strategies for cancer patients.
[Display omitted]
•Aprepitant has dual effects against DOX chemotherapy.•Aprepitant protected against DOX-induced chemobrain and rescued hippocampal neurons.•Aprepitant by inhibiting substance P alleviated cognitive deficiency.•Aprepitant curbed the endoplasmic reticulum stress cascade PERK/eIF-2α/ATF-4/CHOP.•It downregulated miR-146a, reduced inflammation, and restored redox balance. |
doi_str_mv | 10.1016/j.lfs.2024.123210 |
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[Display omitted]
•Aprepitant has dual effects against DOX chemotherapy.•Aprepitant protected against DOX-induced chemobrain and rescued hippocampal neurons.•Aprepitant by inhibiting substance P alleviated cognitive deficiency.•Aprepitant curbed the endoplasmic reticulum stress cascade PERK/eIF-2α/ATF-4/CHOP.•It downregulated miR-146a, reduced inflammation, and restored redox balance.</description><identifier>ISSN: 0024-3205</identifier><identifier>ISSN: 1879-0631</identifier><identifier>EISSN: 1879-0631</identifier><identifier>DOI: 10.1016/j.lfs.2024.123210</identifier><identifier>PMID: 39488263</identifier><language>eng</language><publisher>Netherlands: Elsevier Inc</publisher><subject>Animals ; antiemetics ; Antiemetics - pharmacology ; antioxidants ; apoptosis ; Apoptosis - drug effects ; Aprepitant ; Aprepitant - pharmacology ; caspase-3 ; Chemotherapy-Related Cognitive Impairment - drug therapy ; Chemotherapy-Related Cognitive Impairment - metabolism ; cognition ; Cognitive dysfunction ; doxorubicin ; Doxorubicin - adverse effects ; Doxorubicin - toxicity ; Drug Repositioning ; drug therapy ; endoplasmic reticulum ; ER stress ; glutathione ; Hippocampus - drug effects ; Hippocampus - metabolism ; immunohistochemistry ; inflammation ; Male ; malondialdehyde ; miR-146a ; Neuroprotective Agents - pharmacology ; neuroprotective effect ; pain ; PERK/eIF-2α/ATF-4/CHOP ; protein synthesis ; quantitative polymerase chain reaction ; Rats ; Rats, Wistar ; Substance P ; Substance P - metabolism ; toluidine blue</subject><ispartof>Life sciences (1973), 2024-12, Vol.359, p.123210, Article 123210</ispartof><rights>2024 Elsevier Inc.</rights><rights>Copyright © 2024 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c268t-59311595f2587328069377a18864b1a1495e36baf657edc65a80364a855a86803</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0024320524008002$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65534</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39488263$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Gomaa, Asmaa A.</creatorcontrib><creatorcontrib>Abdallah, Dalaal M.</creatorcontrib><creatorcontrib>El-Abhar, Hanan S.</creatorcontrib><creatorcontrib>El-Mokadem, Bassant M.</creatorcontrib><title>Repurposing Aprepitant: Can it protect against doxorubicin-induced Chemobrain beyond its antiemetic role?</title><title>Life sciences (1973)</title><addtitle>Life Sci</addtitle><description>The substance P (SP) and neurokinin-1 receptor (NK-1R) axis is crucial in numerous pathological processes, including inflammation, stress responses, pain perception, and vomiting. Consequently, aprepitant, an NK-1R blocker, is used as an antiemetic in chemotherapy, including the use of doxorubicin (DOX), but whether aprepitant can also assuage DOX-mediated chemobrain remains to be unveiled. Here, we scrutinized the potential neuroprotective effect and underlying mechanisms of aprepitant using DOX-induced chemobrain model, where rats were allocated into 4 groups (control, aprepitant, DOX, and DOX+ aprepitant). Cognitive deficits were assessed through behavioral tests and hippocampal structural alterations were determined by H&E and toluidine blue staining. Biochemical measurements were performed using ELISA, real-time quantitative PCR, western blotting, and immunohistochemical methods. Aprepitant improved cognitive responses, and hippocampal morphology, enhancing the presence of intact neurons. At the molecular tier, aprepitant significantly reduced hippocampal contents of SP and the inflammatory markers NF-κB and IL-1β. Additionally, it signified its antioxidant and antiapoptotic capacities by downregulating cleaved caspase-3 protein expression and curbing the content of malondialdehyde but boosted those of glutathione and Bcl-2. Aprepitant also downregulated the expression of miR-146a and turned off the endoplasmic reticulum (ER) stress cascade PERK/eIF-2α/ATF-4/CHOP. To recapitulate, aprepitant demonstrates a neuroprotective effect against DOX-mediated chemobrain by alleviating inflammatory, oxidative, and apoptotic responses, partly by reducing SP, ER stress, and miR-146a. These findings not only underscore the potential of aprepitant as a neuroprotective agent but also offer new understanding of the mechanisms behind chemobrain, leading to better therapeutic strategies for cancer patients.
[Display omitted]
•Aprepitant has dual effects against DOX chemotherapy.•Aprepitant protected against DOX-induced chemobrain and rescued hippocampal neurons.•Aprepitant by inhibiting substance P alleviated cognitive deficiency.•Aprepitant curbed the endoplasmic reticulum stress cascade PERK/eIF-2α/ATF-4/CHOP.•It downregulated miR-146a, reduced inflammation, and restored redox balance.</description><subject>Animals</subject><subject>antiemetics</subject><subject>Antiemetics - pharmacology</subject><subject>antioxidants</subject><subject>apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Aprepitant</subject><subject>Aprepitant - pharmacology</subject><subject>caspase-3</subject><subject>Chemotherapy-Related Cognitive Impairment - drug therapy</subject><subject>Chemotherapy-Related Cognitive Impairment - metabolism</subject><subject>cognition</subject><subject>Cognitive dysfunction</subject><subject>doxorubicin</subject><subject>Doxorubicin - adverse effects</subject><subject>Doxorubicin - toxicity</subject><subject>Drug Repositioning</subject><subject>drug therapy</subject><subject>endoplasmic reticulum</subject><subject>ER stress</subject><subject>glutathione</subject><subject>Hippocampus - drug effects</subject><subject>Hippocampus - metabolism</subject><subject>immunohistochemistry</subject><subject>inflammation</subject><subject>Male</subject><subject>malondialdehyde</subject><subject>miR-146a</subject><subject>Neuroprotective Agents - pharmacology</subject><subject>neuroprotective effect</subject><subject>pain</subject><subject>PERK/eIF-2α/ATF-4/CHOP</subject><subject>protein synthesis</subject><subject>quantitative polymerase chain reaction</subject><subject>Rats</subject><subject>Rats, Wistar</subject><subject>Substance P</subject><subject>Substance P - metabolism</subject><subject>toluidine blue</subject><issn>0024-3205</issn><issn>1879-0631</issn><issn>1879-0631</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkUtr3DAUhUVpaSaPH9BN0LIbT_WwZDlZlDAkaSBQCOlayPJ1qsGWHEkunX9fDZNkWbLSBX3ncO85CH2hZE0Jld-263FIa0ZYvaaMM0o-oBVVTVsRyelHtCLlp-KMiCN0nNKWECJEwz-jI97WSjHJV8g9wLzEOSTnn_DVHGF22fh8gTfGY5fxHEMGm7F5Ms6njPvwN8Slc9b5yvl-sdDjzW-YQhcLgDvYBd8XYcLFxcEE2VkcwwjfT9GnwYwJzl7eE_Tr5vpx86O6_3l7t7m6ryyTKlei5ZSKVgxMqIYzRWTLm8ZQpWTdUUPrVgCXnRmkaKC3UhhFuKyNEmWSZT5BXw--ZfXnBVLWk0sWxtF4CEvSnIq6nN4w8Q6UcSFK1HuUHlAbQ0oRBj1HN5m405TofRl6q0sZel-GPpRRNOcv9ks3Qf-meE2_AJcHAEoefxxEnawDXzJ1sYSu--D-Y_8PE5mY2g</recordid><startdate>20241215</startdate><enddate>20241215</enddate><creator>Gomaa, Asmaa A.</creator><creator>Abdallah, Dalaal M.</creator><creator>El-Abhar, Hanan S.</creator><creator>El-Mokadem, Bassant M.</creator><general>Elsevier Inc</general><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>7X8</scope><scope>7S9</scope><scope>L.6</scope></search><sort><creationdate>20241215</creationdate><title>Repurposing Aprepitant: Can it protect against doxorubicin-induced Chemobrain beyond its antiemetic role?</title><author>Gomaa, Asmaa A. ; Abdallah, Dalaal M. ; El-Abhar, Hanan S. ; El-Mokadem, Bassant M.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c268t-59311595f2587328069377a18864b1a1495e36baf657edc65a80364a855a86803</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Animals</topic><topic>antiemetics</topic><topic>Antiemetics - pharmacology</topic><topic>antioxidants</topic><topic>apoptosis</topic><topic>Apoptosis - drug effects</topic><topic>Aprepitant</topic><topic>Aprepitant - pharmacology</topic><topic>caspase-3</topic><topic>Chemotherapy-Related Cognitive Impairment - drug therapy</topic><topic>Chemotherapy-Related Cognitive Impairment - metabolism</topic><topic>cognition</topic><topic>Cognitive dysfunction</topic><topic>doxorubicin</topic><topic>Doxorubicin - adverse effects</topic><topic>Doxorubicin - toxicity</topic><topic>Drug Repositioning</topic><topic>drug therapy</topic><topic>endoplasmic reticulum</topic><topic>ER stress</topic><topic>glutathione</topic><topic>Hippocampus - drug effects</topic><topic>Hippocampus - metabolism</topic><topic>immunohistochemistry</topic><topic>inflammation</topic><topic>Male</topic><topic>malondialdehyde</topic><topic>miR-146a</topic><topic>Neuroprotective Agents - pharmacology</topic><topic>neuroprotective effect</topic><topic>pain</topic><topic>PERK/eIF-2α/ATF-4/CHOP</topic><topic>protein synthesis</topic><topic>quantitative polymerase chain reaction</topic><topic>Rats</topic><topic>Rats, Wistar</topic><topic>Substance P</topic><topic>Substance P - metabolism</topic><topic>toluidine blue</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Gomaa, Asmaa A.</creatorcontrib><creatorcontrib>Abdallah, Dalaal M.</creatorcontrib><creatorcontrib>El-Abhar, Hanan S.</creatorcontrib><creatorcontrib>El-Mokadem, Bassant M.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>AGRICOLA</collection><collection>AGRICOLA - Academic</collection><jtitle>Life sciences (1973)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Gomaa, Asmaa A.</au><au>Abdallah, Dalaal M.</au><au>El-Abhar, Hanan S.</au><au>El-Mokadem, Bassant M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Repurposing Aprepitant: Can it protect against doxorubicin-induced Chemobrain beyond its antiemetic role?</atitle><jtitle>Life sciences (1973)</jtitle><addtitle>Life Sci</addtitle><date>2024-12-15</date><risdate>2024</risdate><volume>359</volume><spage>123210</spage><pages>123210-</pages><artnum>123210</artnum><issn>0024-3205</issn><issn>1879-0631</issn><eissn>1879-0631</eissn><abstract>The substance P (SP) and neurokinin-1 receptor (NK-1R) axis is crucial in numerous pathological processes, including inflammation, stress responses, pain perception, and vomiting. Consequently, aprepitant, an NK-1R blocker, is used as an antiemetic in chemotherapy, including the use of doxorubicin (DOX), but whether aprepitant can also assuage DOX-mediated chemobrain remains to be unveiled. Here, we scrutinized the potential neuroprotective effect and underlying mechanisms of aprepitant using DOX-induced chemobrain model, where rats were allocated into 4 groups (control, aprepitant, DOX, and DOX+ aprepitant). Cognitive deficits were assessed through behavioral tests and hippocampal structural alterations were determined by H&E and toluidine blue staining. Biochemical measurements were performed using ELISA, real-time quantitative PCR, western blotting, and immunohistochemical methods. Aprepitant improved cognitive responses, and hippocampal morphology, enhancing the presence of intact neurons. At the molecular tier, aprepitant significantly reduced hippocampal contents of SP and the inflammatory markers NF-κB and IL-1β. Additionally, it signified its antioxidant and antiapoptotic capacities by downregulating cleaved caspase-3 protein expression and curbing the content of malondialdehyde but boosted those of glutathione and Bcl-2. Aprepitant also downregulated the expression of miR-146a and turned off the endoplasmic reticulum (ER) stress cascade PERK/eIF-2α/ATF-4/CHOP. To recapitulate, aprepitant demonstrates a neuroprotective effect against DOX-mediated chemobrain by alleviating inflammatory, oxidative, and apoptotic responses, partly by reducing SP, ER stress, and miR-146a. These findings not only underscore the potential of aprepitant as a neuroprotective agent but also offer new understanding of the mechanisms behind chemobrain, leading to better therapeutic strategies for cancer patients.
[Display omitted]
•Aprepitant has dual effects against DOX chemotherapy.•Aprepitant protected against DOX-induced chemobrain and rescued hippocampal neurons.•Aprepitant by inhibiting substance P alleviated cognitive deficiency.•Aprepitant curbed the endoplasmic reticulum stress cascade PERK/eIF-2α/ATF-4/CHOP.•It downregulated miR-146a, reduced inflammation, and restored redox balance.</abstract><cop>Netherlands</cop><pub>Elsevier Inc</pub><pmid>39488263</pmid><doi>10.1016/j.lfs.2024.123210</doi></addata></record> |
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subjects | Animals antiemetics Antiemetics - pharmacology antioxidants apoptosis Apoptosis - drug effects Aprepitant Aprepitant - pharmacology caspase-3 Chemotherapy-Related Cognitive Impairment - drug therapy Chemotherapy-Related Cognitive Impairment - metabolism cognition Cognitive dysfunction doxorubicin Doxorubicin - adverse effects Doxorubicin - toxicity Drug Repositioning drug therapy endoplasmic reticulum ER stress glutathione Hippocampus - drug effects Hippocampus - metabolism immunohistochemistry inflammation Male malondialdehyde miR-146a Neuroprotective Agents - pharmacology neuroprotective effect pain PERK/eIF-2α/ATF-4/CHOP protein synthesis quantitative polymerase chain reaction Rats Rats, Wistar Substance P Substance P - metabolism toluidine blue |
title | Repurposing Aprepitant: Can it protect against doxorubicin-induced Chemobrain beyond its antiemetic role? |
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