Thioredoxin-Mimetic-Peptides Protect Cognitive Function after Mild Traumatic Brain Injury (mTBI)
Mild traumatic brain injury (mTBI) is recognized as a common injury among children, sportsmen, and elderly population. mTBI lacks visible objective structural brain damage but patients frequently suffer from long-lasting cognitive, behavioral and emotional difficulties associated with biochemical an...
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| creator | Baratz-Goldstein, Renana Deselms, Hanna Heim, Leore Raphael Khomski, Lena Hoffer, Barry J Atlas, Daphne Pick, Chaim G |
| description | Mild traumatic brain injury (mTBI) is recognized as a common injury among children, sportsmen, and elderly population. mTBI lacks visible objective structural brain damage but patients frequently suffer from long-lasting cognitive, behavioral and emotional difficulties associated with biochemical and cellular changes. Currently there is no effective treatment for patients with mTBI. The thioredoxin reductase/thioredoxin pathway (TrxR/Trx1) has both anti-inflammatory and anti-oxidative properties. If the system is compromised, Trx1 remains oxidized and triggers cell death via an ASK1-Trx1 signal transduction mechanism. We previously showed tri and tetra peptides which were derived from the canonical -CxxC- motif of the Trx1-active site, called thioredoxin mimetic (TXM) peptides, reversed inflammatory and oxidative stress damage mimicking Trx1 activity. Here, TXM-peptides were examined for protecting cognitive function following weight drop closed-head injury in a mouse model of mTBI. TXM-CB3 (AcCys-Pro-CysNH2), TXM-CB13 (DY-70; AcCys-Met-Lys-CysNH2) or AD4 (ACysNH2) were administered at 50 mg/kg, 60 min after injury and cognitive performance was monitored by the novel-object-recognition and Y-maze tests. Behavioral deficits subsequent to mTBI injury were reversed by a single dose of TXM-CB3, TXM-CB13 and, to a lesser extent, by AD4. TXM-CB13 similar to TXM-CB3 and AD4 reversed oxidative stress-induced phosphorylation of mitogen-activated kinases, p38MAPK and c-Jun N-terminal kinase, (JNK) in human neuronal SH-SY5Y cells. We conclude that significantly improved cognitive behavior post mTBI by the TXM-peptides could result from anti-apoptotic, and/or anti-inflammatory activities. Future preclinical studies are required to establish the TXM-peptides as potential therapeutic drugs for brain injuries. |
| doi_str_mv | 10.1371/journal.pone.0157064 |
| format | Article |
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Currently there is no effective treatment for patients with mTBI. The thioredoxin reductase/thioredoxin pathway (TrxR/Trx1) has both anti-inflammatory and anti-oxidative properties. If the system is compromised, Trx1 remains oxidized and triggers cell death via an ASK1-Trx1 signal transduction mechanism. We previously showed tri and tetra peptides which were derived from the canonical -CxxC- motif of the Trx1-active site, called thioredoxin mimetic (TXM) peptides, reversed inflammatory and oxidative stress damage mimicking Trx1 activity. Here, TXM-peptides were examined for protecting cognitive function following weight drop closed-head injury in a mouse model of mTBI. TXM-CB3 (AcCys-Pro-CysNH2), TXM-CB13 (DY-70; AcCys-Met-Lys-CysNH2) or AD4 (ACysNH2) were administered at 50 mg/kg, 60 min after injury and cognitive performance was monitored by the novel-object-recognition and Y-maze tests. Behavioral deficits subsequent to mTBI injury were reversed by a single dose of TXM-CB3, TXM-CB13 and, to a lesser extent, by AD4. TXM-CB13 similar to TXM-CB3 and AD4 reversed oxidative stress-induced phosphorylation of mitogen-activated kinases, p38MAPK and c-Jun N-terminal kinase, (JNK) in human neuronal SH-SY5Y cells. We conclude that significantly improved cognitive behavior post mTBI by the TXM-peptides could result from anti-apoptotic, and/or anti-inflammatory activities. Future preclinical studies are required to establish the TXM-peptides as potential therapeutic drugs for brain injuries.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0157064</identifier><identifier>PMID: 27285176</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Animals ; Apoptosis ; Athletes ; Behavior, Animal - drug effects ; Biology and Life Sciences ; Biomimetics ; Brain ; Brain Concussion - drug therapy ; Brain Concussion - pathology ; Brain Concussion - physiopathology ; Brain Concussion - psychology ; Brain damage ; Brain injuries ; c-Jun protein ; Care and treatment ; Cell death ; Children ; Cognition - drug effects ; Cognitive ability ; Cognitive disorders ; Complications and side effects ; Disease Models, Animal ; Drugs ; Emotional behavior ; Geriatrics ; Head injuries ; Human behavior ; Inflammation ; JNK protein ; Kinases ; Male ; MAP kinase ; Medicine and Health Sciences ; Mice ; Mice, Inbred ICR ; Mimicry ; Neuroprotective Agents - chemistry ; Neuroprotective Agents - pharmacology ; Object recognition ; Older people ; Oxidative stress ; Patients ; Peptides ; Peptides - chemistry ; Peptides - pharmacology ; Phosphorylation ; Physiological aspects ; Prevention ; Reductase ; Risk factors ; Social Sciences ; Thioredoxin ; Thioredoxins ; Thioredoxins - chemistry ; Thioredoxins - pharmacology ; Transcription factors ; Traumatic brain injury ; Tumor necrosis factor-TNF</subject><ispartof>PloS one, 2016-06, Vol.11 (6), p.e0157064-e0157064</ispartof><rights>COPYRIGHT 2016 Public Library of Science</rights><rights>2016 Baratz-Goldstein et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2016 Baratz-Goldstein et al 2016 Baratz-Goldstein et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c725t-c5e877cd6180cf4ff0afd1477d58a8a18b0a3d48a955d4abce07aef28783139a3</citedby><cites>FETCH-LOGICAL-c725t-c5e877cd6180cf4ff0afd1477d58a8a18b0a3d48a955d4abce07aef28783139a3</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/PMC4902227/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4902227/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,729,782,786,866,887,2106,2932,23875,27933,27934,53800,53802</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27285176$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Harvey, Brandon K</contributor><creatorcontrib>Baratz-Goldstein, Renana</creatorcontrib><creatorcontrib>Deselms, Hanna</creatorcontrib><creatorcontrib>Heim, Leore Raphael</creatorcontrib><creatorcontrib>Khomski, Lena</creatorcontrib><creatorcontrib>Hoffer, Barry J</creatorcontrib><creatorcontrib>Atlas, Daphne</creatorcontrib><creatorcontrib>Pick, Chaim G</creatorcontrib><title>Thioredoxin-Mimetic-Peptides Protect Cognitive Function after Mild Traumatic Brain Injury (mTBI)</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Mild traumatic brain injury (mTBI) is recognized as a common injury among children, sportsmen, and elderly population. mTBI lacks visible objective structural brain damage but patients frequently suffer from long-lasting cognitive, behavioral and emotional difficulties associated with biochemical and cellular changes. Currently there is no effective treatment for patients with mTBI. The thioredoxin reductase/thioredoxin pathway (TrxR/Trx1) has both anti-inflammatory and anti-oxidative properties. If the system is compromised, Trx1 remains oxidized and triggers cell death via an ASK1-Trx1 signal transduction mechanism. We previously showed tri and tetra peptides which were derived from the canonical -CxxC- motif of the Trx1-active site, called thioredoxin mimetic (TXM) peptides, reversed inflammatory and oxidative stress damage mimicking Trx1 activity. Here, TXM-peptides were examined for protecting cognitive function following weight drop closed-head injury in a mouse model of mTBI. TXM-CB3 (AcCys-Pro-CysNH2), TXM-CB13 (DY-70; AcCys-Met-Lys-CysNH2) or AD4 (ACysNH2) were administered at 50 mg/kg, 60 min after injury and cognitive performance was monitored by the novel-object-recognition and Y-maze tests. Behavioral deficits subsequent to mTBI injury were reversed by a single dose of TXM-CB3, TXM-CB13 and, to a lesser extent, by AD4. TXM-CB13 similar to TXM-CB3 and AD4 reversed oxidative stress-induced phosphorylation of mitogen-activated kinases, p38MAPK and c-Jun N-terminal kinase, (JNK) in human neuronal SH-SY5Y cells. We conclude that significantly improved cognitive behavior post mTBI by the TXM-peptides could result from anti-apoptotic, and/or anti-inflammatory activities. Future preclinical studies are required to establish the TXM-peptides as potential therapeutic drugs for brain injuries.</description><subject>Animals</subject><subject>Apoptosis</subject><subject>Athletes</subject><subject>Behavior, Animal - drug effects</subject><subject>Biology and Life Sciences</subject><subject>Biomimetics</subject><subject>Brain</subject><subject>Brain Concussion - drug therapy</subject><subject>Brain Concussion - pathology</subject><subject>Brain Concussion - physiopathology</subject><subject>Brain Concussion - psychology</subject><subject>Brain damage</subject><subject>Brain injuries</subject><subject>c-Jun protein</subject><subject>Care and treatment</subject><subject>Cell death</subject><subject>Children</subject><subject>Cognition - drug effects</subject><subject>Cognitive ability</subject><subject>Cognitive disorders</subject><subject>Complications and side effects</subject><subject>Disease Models, Animal</subject><subject>Drugs</subject><subject>Emotional behavior</subject><subject>Geriatrics</subject><subject>Head injuries</subject><subject>Human behavior</subject><subject>Inflammation</subject><subject>JNK protein</subject><subject>Kinases</subject><subject>Male</subject><subject>MAP kinase</subject><subject>Medicine and Health Sciences</subject><subject>Mice</subject><subject>Mice, Inbred ICR</subject><subject>Mimicry</subject><subject>Neuroprotective Agents - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Baratz-Goldstein, Renana</au><au>Deselms, Hanna</au><au>Heim, Leore Raphael</au><au>Khomski, Lena</au><au>Hoffer, Barry J</au><au>Atlas, Daphne</au><au>Pick, Chaim G</au><au>Harvey, Brandon K</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Thioredoxin-Mimetic-Peptides Protect Cognitive Function after Mild Traumatic Brain Injury (mTBI)</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2016-06-10</date><risdate>2016</risdate><volume>11</volume><issue>6</issue><spage>e0157064</spage><epage>e0157064</epage><pages>e0157064-e0157064</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Mild traumatic brain injury (mTBI) is recognized as a common injury among children, sportsmen, and elderly population. mTBI lacks visible objective structural brain damage but patients frequently suffer from long-lasting cognitive, behavioral and emotional difficulties associated with biochemical and cellular changes. Currently there is no effective treatment for patients with mTBI. The thioredoxin reductase/thioredoxin pathway (TrxR/Trx1) has both anti-inflammatory and anti-oxidative properties. If the system is compromised, Trx1 remains oxidized and triggers cell death via an ASK1-Trx1 signal transduction mechanism. We previously showed tri and tetra peptides which were derived from the canonical -CxxC- motif of the Trx1-active site, called thioredoxin mimetic (TXM) peptides, reversed inflammatory and oxidative stress damage mimicking Trx1 activity. Here, TXM-peptides were examined for protecting cognitive function following weight drop closed-head injury in a mouse model of mTBI. TXM-CB3 (AcCys-Pro-CysNH2), TXM-CB13 (DY-70; AcCys-Met-Lys-CysNH2) or AD4 (ACysNH2) were administered at 50 mg/kg, 60 min after injury and cognitive performance was monitored by the novel-object-recognition and Y-maze tests. Behavioral deficits subsequent to mTBI injury were reversed by a single dose of TXM-CB3, TXM-CB13 and, to a lesser extent, by AD4. TXM-CB13 similar to TXM-CB3 and AD4 reversed oxidative stress-induced phosphorylation of mitogen-activated kinases, p38MAPK and c-Jun N-terminal kinase, (JNK) in human neuronal SH-SY5Y cells. We conclude that significantly improved cognitive behavior post mTBI by the TXM-peptides could result from anti-apoptotic, and/or anti-inflammatory activities. Future preclinical studies are required to establish the TXM-peptides as potential therapeutic drugs for brain injuries.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>27285176</pmid><doi>10.1371/journal.pone.0157064</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2016-06, Vol.11 (6), p.e0157064-e0157064 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1795664521 |
| source | Public Library of Science (PLoS) Journals Open Access; MEDLINE; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Animals Apoptosis Athletes Behavior, Animal - drug effects Biology and Life Sciences Biomimetics Brain Brain Concussion - drug therapy Brain Concussion - pathology Brain Concussion - physiopathology Brain Concussion - psychology Brain damage Brain injuries c-Jun protein Care and treatment Cell death Children Cognition - drug effects Cognitive ability Cognitive disorders Complications and side effects Disease Models, Animal Drugs Emotional behavior Geriatrics Head injuries Human behavior Inflammation JNK protein Kinases Male MAP kinase Medicine and Health Sciences Mice Mice, Inbred ICR Mimicry Neuroprotective Agents - chemistry Neuroprotective Agents - pharmacology Object recognition Older people Oxidative stress Patients Peptides Peptides - chemistry Peptides - pharmacology Phosphorylation Physiological aspects Prevention Reductase Risk factors Social Sciences Thioredoxin Thioredoxins Thioredoxins - chemistry Thioredoxins - pharmacology Transcription factors Traumatic brain injury Tumor necrosis factor-TNF |
| title | Thioredoxin-Mimetic-Peptides Protect Cognitive Function after Mild Traumatic Brain Injury (mTBI) |
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