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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Veröffentlicht in:Life sciences (1973) 2024-12, Vol.359, p.123210, Article 123210
Hauptverfasser: Gomaa, Asmaa A., Abdallah, Dalaal M., El-Abhar, Hanan S., El-Mokadem, Bassant M.
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container_start_page 123210
container_title Life sciences (1973)
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creator Gomaa, Asmaa A.
Abdallah, Dalaal M.
El-Abhar, Hanan S.
El-Mokadem, Bassant M.
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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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&amp;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><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. 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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. ; 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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&amp;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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