Systemic and transdermal melatonin administration prevents neuropathology in response to perinatal asphyxia in newborn lambs
Perinatal asphyxia remains a principal cause of infant mortality and long‐term neurological morbidity, particularly in low‐resource countries. No neuroprotective interventions are currently available. Melatonin (MLT), a potent antioxidant, anti‐inflammatory and antiapoptotic agent, offers promise as...
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| Veröffentlicht in: | Journal of pineal research 2018-05, Vol.64 (4), p.e12479-n/a |
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| creator | Aridas, James D. S. Yawno, Tamara Sutherland, Amy E. Nitsos, Ilias Ditchfield, Michael Wong, Flora Y. Hunt, Rod W. Fahey, Michael C. Malhotra, Atul Wallace, Euan M. Jenkin, Graham Miller, Suzanne L. |
| description | Perinatal asphyxia remains a principal cause of infant mortality and long‐term neurological morbidity, particularly in low‐resource countries. No neuroprotective interventions are currently available. Melatonin (MLT), a potent antioxidant, anti‐inflammatory and antiapoptotic agent, offers promise as an intravenous (IV) or transdermal therapy to protect the brain. We aimed to determine the effect of melatonin (IV or transdermal patch) on neuropathology in a lamb model of perinatal asphyxia. Asphyxia was induced in newborn lambs via umbilical cord occlusion at birth. Animals were randomly allocated to melatonin commencing 30 minutes after birth (60 mg in 24 hours; IV or transdermal patch). Brain magnetic resonance spectroscopy (MRS) was undertaken at 12 and 72 hours. Animals (control n = 9; control+MLT n = 6; asphyxia n = 16; asphyxia+MLT [IV n = 14; patch n = 4]) were euthanised at 72 hours, and cerebrospinal fluid (CSF) and brains were collected for analysis. Asphyxia resulted in severe acidosis (pH 6.9 ± 0.0; lactate 9 ± 2 mmol/L) and altered determinants of encephalopathy. MRS lactate:N‐acetyl aspartate ratio was 2.5‐fold higher in asphyxia lambs compared with controls at 12 hours and 3‐fold higher at 72 hours (P |
| doi_str_mv | 10.1111/jpi.12479 |
| format | Article |
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S. ; Yawno, Tamara ; Sutherland, Amy E. ; Nitsos, Ilias ; Ditchfield, Michael ; Wong, Flora Y. ; Hunt, Rod W. ; Fahey, Michael C. ; Malhotra, Atul ; Wallace, Euan M. ; Jenkin, Graham ; Miller, Suzanne L.</creator><creatorcontrib>Aridas, James D. S. ; Yawno, Tamara ; Sutherland, Amy E. ; Nitsos, Ilias ; Ditchfield, Michael ; Wong, Flora Y. ; Hunt, Rod W. ; Fahey, Michael C. ; Malhotra, Atul ; Wallace, Euan M. ; Jenkin, Graham ; Miller, Suzanne L.</creatorcontrib><description>Perinatal asphyxia remains a principal cause of infant mortality and long‐term neurological morbidity, particularly in low‐resource countries. No neuroprotective interventions are currently available. Melatonin (MLT), a potent antioxidant, anti‐inflammatory and antiapoptotic agent, offers promise as an intravenous (IV) or transdermal therapy to protect the brain. We aimed to determine the effect of melatonin (IV or transdermal patch) on neuropathology in a lamb model of perinatal asphyxia. Asphyxia was induced in newborn lambs via umbilical cord occlusion at birth. Animals were randomly allocated to melatonin commencing 30 minutes after birth (60 mg in 24 hours; IV or transdermal patch). Brain magnetic resonance spectroscopy (MRS) was undertaken at 12 and 72 hours. Animals (control n = 9; control+MLT n = 6; asphyxia n = 16; asphyxia+MLT [IV n = 14; patch n = 4]) were euthanised at 72 hours, and cerebrospinal fluid (CSF) and brains were collected for analysis. Asphyxia resulted in severe acidosis (pH 6.9 ± 0.0; lactate 9 ± 2 mmol/L) and altered determinants of encephalopathy. MRS lactate:N‐acetyl aspartate ratio was 2.5‐fold higher in asphyxia lambs compared with controls at 12 hours and 3‐fold higher at 72 hours (P < .05). Melatonin prevented this rise (3.5‐fold reduced vs asphyxia; P = .02). Asphyxia significantly increased brain white and grey matter apoptotic cell death (activated caspase‐3), lipid peroxidation (4HNE) and neuroinflammation (IBA‐1). These changes were significantly mitigated by both IV and patch melatonin. Systemic or transdermal neonatal melatonin administration significantly reduces the neuropathology and encephalopathy signs associated with perinatal asphyxia. A simple melatonin patch, administered soon after birth, may improve outcome in infants affected by asphyxia, especially in low‐resource settings.</description><identifier>ISSN: 0742-3098</identifier><identifier>EISSN: 1600-079X</identifier><identifier>DOI: 10.1111/jpi.12479</identifier><identifier>PMID: 29464766</identifier><language>eng</language><publisher>England: John Wiley and Sons Inc</publisher><subject>Animals ; Animals, Newborn ; Asphyxia Neonatorum - pathology ; Brain - drug effects ; Brain - pathology ; brain injury ; cell death ; melatonin ; Melatonin - pharmacology ; neuroprotection ; Neuroprotective Agents - pharmacology ; Original ; oxidative stress ; perinatal asphyxia ; radiology ; Random Allocation ; Sheep ; transdermal</subject><ispartof>Journal of pineal research, 2018-05, Vol.64 (4), p.e12479-n/a</ispartof><rights>2018 The Authors. Published by John Wiley & Sons Ltd</rights><rights>2018 The Authors. Journal of Pineal Research Published by John Wiley & Sons Ltd.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4159-ffb32ca9d160aa50ab72eaf4462b9ea433b49638f33117ea92baac1a295e45103</citedby><cites>FETCH-LOGICAL-c4159-ffb32ca9d160aa50ab72eaf4462b9ea433b49638f33117ea92baac1a295e45103</cites><orcidid>0000-0002-4000-2110 ; 0000-0002-4506-5233</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fjpi.12479$$EPDF$$P50$$Gwiley$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fjpi.12479$$EHTML$$P50$$Gwiley$$Hfree_for_read</linktohtml><link.rule.ids>230,314,780,784,885,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29464766$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Aridas, James D. S.</creatorcontrib><creatorcontrib>Yawno, Tamara</creatorcontrib><creatorcontrib>Sutherland, Amy E.</creatorcontrib><creatorcontrib>Nitsos, Ilias</creatorcontrib><creatorcontrib>Ditchfield, Michael</creatorcontrib><creatorcontrib>Wong, Flora Y.</creatorcontrib><creatorcontrib>Hunt, Rod W.</creatorcontrib><creatorcontrib>Fahey, Michael C.</creatorcontrib><creatorcontrib>Malhotra, Atul</creatorcontrib><creatorcontrib>Wallace, Euan M.</creatorcontrib><creatorcontrib>Jenkin, Graham</creatorcontrib><creatorcontrib>Miller, Suzanne L.</creatorcontrib><title>Systemic and transdermal melatonin administration prevents neuropathology in response to perinatal asphyxia in newborn lambs</title><title>Journal of pineal research</title><addtitle>J Pineal Res</addtitle><description>Perinatal asphyxia remains a principal cause of infant mortality and long‐term neurological morbidity, particularly in low‐resource countries. No neuroprotective interventions are currently available. Melatonin (MLT), a potent antioxidant, anti‐inflammatory and antiapoptotic agent, offers promise as an intravenous (IV) or transdermal therapy to protect the brain. We aimed to determine the effect of melatonin (IV or transdermal patch) on neuropathology in a lamb model of perinatal asphyxia. Asphyxia was induced in newborn lambs via umbilical cord occlusion at birth. Animals were randomly allocated to melatonin commencing 30 minutes after birth (60 mg in 24 hours; IV or transdermal patch). Brain magnetic resonance spectroscopy (MRS) was undertaken at 12 and 72 hours. Animals (control n = 9; control+MLT n = 6; asphyxia n = 16; asphyxia+MLT [IV n = 14; patch n = 4]) were euthanised at 72 hours, and cerebrospinal fluid (CSF) and brains were collected for analysis. Asphyxia resulted in severe acidosis (pH 6.9 ± 0.0; lactate 9 ± 2 mmol/L) and altered determinants of encephalopathy. MRS lactate:N‐acetyl aspartate ratio was 2.5‐fold higher in asphyxia lambs compared with controls at 12 hours and 3‐fold higher at 72 hours (P < .05). Melatonin prevented this rise (3.5‐fold reduced vs asphyxia; P = .02). Asphyxia significantly increased brain white and grey matter apoptotic cell death (activated caspase‐3), lipid peroxidation (4HNE) and neuroinflammation (IBA‐1). These changes were significantly mitigated by both IV and patch melatonin. Systemic or transdermal neonatal melatonin administration significantly reduces the neuropathology and encephalopathy signs associated with perinatal asphyxia. A simple melatonin patch, administered soon after birth, may improve outcome in infants affected by asphyxia, especially in low‐resource settings.</description><subject>Animals</subject><subject>Animals, Newborn</subject><subject>Asphyxia Neonatorum - pathology</subject><subject>Brain - drug effects</subject><subject>Brain - pathology</subject><subject>brain injury</subject><subject>cell death</subject><subject>melatonin</subject><subject>Melatonin - pharmacology</subject><subject>neuroprotection</subject><subject>Neuroprotective Agents - pharmacology</subject><subject>Original</subject><subject>oxidative stress</subject><subject>perinatal asphyxia</subject><subject>radiology</subject><subject>Random Allocation</subject><subject>Sheep</subject><subject>transdermal</subject><issn>0742-3098</issn><issn>1600-079X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>WIN</sourceid><sourceid>EIF</sourceid><recordid>eNp1kc1u1TAQRi0EoreFBS-AvIRFWv8ljjdIqCqlqBJIgMTOmiSTXleJHWzflkg8PC63VLBgNrOYozMz-gh5wdkxL3VyvbhjLpQ2j8iGN4xVTJtvj8mGaSUqyUx7QA5TumaMtW3bPCUHwqhG6abZkJ-f15Rxdj0FP9AcwacB4wwTnXGCHLzzFIbZeZfKMLvg6RLxBn1O1OMuhgXyNkzhaqWFjJiW4BPSHOiC0XnIxQRp2a4_HNwRHm-7ED2dYO7SM_JkhCnh8_t-RL6-O_ty-r66_Hh-cfr2suoVr001jp0UPZih_AZQM-i0QBiVakRnEJSUnTKNbEcpOdcIRnQAPQdhalQ1Z_KIvNl7l10349CX6yNMdoluhrjaAM7-O_Fua6_Cja2N0lzxInh1L4jh-w5TtrNLPU4TeAy7ZAVjmnOpal3Q13u0jyGliOPDGs7sXVq2pGV_p1XYl3_f9UD-iacAJ3vg1k24_t9kP3y62Ct_ARzupCs</recordid><startdate>201805</startdate><enddate>201805</enddate><creator>Aridas, James D. S.</creator><creator>Yawno, Tamara</creator><creator>Sutherland, Amy E.</creator><creator>Nitsos, Ilias</creator><creator>Ditchfield, Michael</creator><creator>Wong, Flora Y.</creator><creator>Hunt, Rod W.</creator><creator>Fahey, Michael C.</creator><creator>Malhotra, Atul</creator><creator>Wallace, Euan M.</creator><creator>Jenkin, Graham</creator><creator>Miller, Suzanne L.</creator><general>John Wiley and Sons Inc</general><scope>24P</scope><scope>WIN</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>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-4000-2110</orcidid><orcidid>https://orcid.org/0000-0002-4506-5233</orcidid></search><sort><creationdate>201805</creationdate><title>Systemic and transdermal melatonin administration prevents neuropathology in response to perinatal asphyxia in newborn lambs</title><author>Aridas, James D. S. ; Yawno, Tamara ; Sutherland, Amy E. ; Nitsos, Ilias ; Ditchfield, Michael ; Wong, Flora Y. ; Hunt, Rod W. ; Fahey, Michael C. ; Malhotra, Atul ; Wallace, Euan M. ; Jenkin, Graham ; Miller, Suzanne L.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4159-ffb32ca9d160aa50ab72eaf4462b9ea433b49638f33117ea92baac1a295e45103</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Animals</topic><topic>Animals, Newborn</topic><topic>Asphyxia Neonatorum - pathology</topic><topic>Brain - drug effects</topic><topic>Brain - pathology</topic><topic>brain injury</topic><topic>cell death</topic><topic>melatonin</topic><topic>Melatonin - pharmacology</topic><topic>neuroprotection</topic><topic>Neuroprotective Agents - pharmacology</topic><topic>Original</topic><topic>oxidative stress</topic><topic>perinatal asphyxia</topic><topic>radiology</topic><topic>Random Allocation</topic><topic>Sheep</topic><topic>transdermal</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Aridas, James D. S.</creatorcontrib><creatorcontrib>Yawno, Tamara</creatorcontrib><creatorcontrib>Sutherland, Amy E.</creatorcontrib><creatorcontrib>Nitsos, Ilias</creatorcontrib><creatorcontrib>Ditchfield, Michael</creatorcontrib><creatorcontrib>Wong, Flora Y.</creatorcontrib><creatorcontrib>Hunt, Rod W.</creatorcontrib><creatorcontrib>Fahey, Michael C.</creatorcontrib><creatorcontrib>Malhotra, Atul</creatorcontrib><creatorcontrib>Wallace, Euan M.</creatorcontrib><creatorcontrib>Jenkin, Graham</creatorcontrib><creatorcontrib>Miller, Suzanne L.</creatorcontrib><collection>Wiley Online Library (Open Access Collection)</collection><collection>Wiley Online Library (Open Access Collection)</collection><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>PubMed Central (Full Participant titles)</collection><jtitle>Journal of pineal research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Aridas, James D. S.</au><au>Yawno, Tamara</au><au>Sutherland, Amy E.</au><au>Nitsos, Ilias</au><au>Ditchfield, Michael</au><au>Wong, Flora Y.</au><au>Hunt, Rod W.</au><au>Fahey, Michael C.</au><au>Malhotra, Atul</au><au>Wallace, Euan M.</au><au>Jenkin, Graham</au><au>Miller, Suzanne L.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Systemic and transdermal melatonin administration prevents neuropathology in response to perinatal asphyxia in newborn lambs</atitle><jtitle>Journal of pineal research</jtitle><addtitle>J Pineal Res</addtitle><date>2018-05</date><risdate>2018</risdate><volume>64</volume><issue>4</issue><spage>e12479</spage><epage>n/a</epage><pages>e12479-n/a</pages><issn>0742-3098</issn><eissn>1600-079X</eissn><abstract>Perinatal asphyxia remains a principal cause of infant mortality and long‐term neurological morbidity, particularly in low‐resource countries. No neuroprotective interventions are currently available. Melatonin (MLT), a potent antioxidant, anti‐inflammatory and antiapoptotic agent, offers promise as an intravenous (IV) or transdermal therapy to protect the brain. We aimed to determine the effect of melatonin (IV or transdermal patch) on neuropathology in a lamb model of perinatal asphyxia. Asphyxia was induced in newborn lambs via umbilical cord occlusion at birth. Animals were randomly allocated to melatonin commencing 30 minutes after birth (60 mg in 24 hours; IV or transdermal patch). Brain magnetic resonance spectroscopy (MRS) was undertaken at 12 and 72 hours. Animals (control n = 9; control+MLT n = 6; asphyxia n = 16; asphyxia+MLT [IV n = 14; patch n = 4]) were euthanised at 72 hours, and cerebrospinal fluid (CSF) and brains were collected for analysis. Asphyxia resulted in severe acidosis (pH 6.9 ± 0.0; lactate 9 ± 2 mmol/L) and altered determinants of encephalopathy. MRS lactate:N‐acetyl aspartate ratio was 2.5‐fold higher in asphyxia lambs compared with controls at 12 hours and 3‐fold higher at 72 hours (P < .05). Melatonin prevented this rise (3.5‐fold reduced vs asphyxia; P = .02). Asphyxia significantly increased brain white and grey matter apoptotic cell death (activated caspase‐3), lipid peroxidation (4HNE) and neuroinflammation (IBA‐1). These changes were significantly mitigated by both IV and patch melatonin. Systemic or transdermal neonatal melatonin administration significantly reduces the neuropathology and encephalopathy signs associated with perinatal asphyxia. A simple melatonin patch, administered soon after birth, may improve outcome in infants affected by asphyxia, especially in low‐resource settings.</abstract><cop>England</cop><pub>John Wiley and Sons Inc</pub><pmid>29464766</pmid><doi>10.1111/jpi.12479</doi><tpages>14</tpages><orcidid>https://orcid.org/0000-0002-4000-2110</orcidid><orcidid>https://orcid.org/0000-0002-4506-5233</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Animals, Newborn Asphyxia Neonatorum - pathology Brain - drug effects Brain - pathology brain injury cell death melatonin Melatonin - pharmacology neuroprotection Neuroprotective Agents - pharmacology Original oxidative stress perinatal asphyxia radiology Random Allocation Sheep transdermal |
| title | Systemic and transdermal melatonin administration prevents neuropathology in response to perinatal asphyxia in newborn lambs |
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