{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T20:30:59Z","timestamp":1791664259071,"version":"4.3.4"},"reference-count":73,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2019,7,21]],"date-time":"2019-07-21T00:00:00Z","timestamp":1563667200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Oxidative stress and energy imbalance strongly correlate in neurodegenerative diseases. Repeated concussion is becoming a serious public health issue with uncontrollable adverse effects in the human population, which involve cognitive dysfunction and even permanent disability. Here, we demonstrate that traumatic brain injury (TBI) evokes oxidative stress, disrupts brain energy homeostasis, and boosts neuroinflammation, which further contributes to neuronal degeneration and cognitive dysfunction in the mouse brain. We also demonstrate that melatonin (an anti-oxidant agent) treatment exerts neuroprotective effects, while overcoming oxidative stress and energy depletion and reducing neuroinflammation and neurodegeneration. Male C57BL\/6N mice were used as a model for repetitive mild traumatic brain injury (rmTBI) and were treated with melatonin. Protein expressions were examined via Western blot analysis, immunofluorescence, and ELISA; meanwhile, behavior analysis was performed through a Morris water maze test, and Y-maze and beam-walking tests. We found elevated oxidative stress, depressed phospho-5\u2032AMP-activated protein kinase (p-AMPK) and phospho- CAMP-response element-binding (p-CREB) levels, and elevated p-NF-\u03baB in rmTBI mouse brains, while melatonin treatment significantly regulated p-AMPK, p-CREB, and p-NF-\u03baB in the rmTBI mouse brain. Furthermore, rmTBI mouse brains showed a deregulated mitochondrial system, abnormal amyloidogenic pathway activation, and cognitive functions which were significantly regulated by melatonin treatment in the mice. These findings provide evidence, for the first time, that rmTBI induces brain energy imbalance and reduces neuronal cell survival, and that melatonin treatment overcomes energy depletion and protects against brain damage via the regulation of p-AMPK\/p-CREB signaling pathways in the mouse brain.<\/jats:p>","DOI":"10.3390\/cells8070760","type":"journal-article","created":{"date-parts":[[2019,7,22]],"date-time":"2019-07-22T02:55:37Z","timestamp":1563764137000},"page":"760","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":172,"title":["Neurological Enhancement Effects of Melatonin against Brain Injury-Induced Oxidative Stress, Neuroinflammation, and Neurodegeneration via AMPK\/CREB Signaling"],"prefix":"10.3390","volume":"8","author":[{"given":"Shafiq","family":"Rehman","sequence":"first","affiliation":[{"name":"Division of Life sciences and Applied Life Science (BK 21plus), College of Natural Science, Gyeongsang National University, Jinju 52828, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad","family":"Ikram","sequence":"additional","affiliation":[{"name":"Division of Life sciences and Applied Life Science (BK 21plus), College of Natural Science, Gyeongsang National University, Jinju 52828, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Najeeb","family":"Ullah","sequence":"additional","affiliation":[{"name":"Division of Life sciences and Applied Life Science (BK 21plus), College of Natural Science, Gyeongsang National University, Jinju 52828, Korea"},{"name":"Institute of Basic Medical Sciences, Khyber Medical University, Peshawar, Khyber Pakhtunkhwa 25100, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sayed","family":"Alam","sequence":"additional","affiliation":[{"name":"Division of Life sciences and Applied Life Science (BK 21plus), College of Natural Science, Gyeongsang National University, Jinju 52828, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyun","family":"Park","sequence":"additional","affiliation":[{"name":"Maastricht University Medical Center (MUMC+), School for Mental Health and Neuroscience|Alzheimer Center Limburg, Maastricht 6229ER, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2959-0414","authenticated-orcid":false,"given":"Haroon","family":"Badshah","sequence":"additional","affiliation":[{"name":"Division of Life sciences and Applied Life Science (BK 21plus), College of Natural Science, Gyeongsang National University, Jinju 52828, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyonghwan","family":"Choe","sequence":"additional","affiliation":[{"name":"Maastricht University Medical Center (MUMC+), School for Mental Health and Neuroscience|Alzheimer Center Limburg, Maastricht 6229ER, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myeong","family":"Ok Kim","sequence":"additional","affiliation":[{"name":"Division of Life sciences and Applied Life Science (BK 21plus), College of Natural Science, Gyeongsang National University, Jinju 52828, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,7,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"13182","DOI":"10.1074\/jbc.M111.302612","article-title":"Targeted gene inactivation of calpain-1 suppresses cortical degeneration due to traumatic brain injury and neuronal apoptosis induced by oxidative stress","volume":"287","author":"Yamada","year":"2012","journal-title":"J. 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