title: Targeting different pathophysiological events after traumatic brain injury in mice: Role of melatonin and memantine.
abstract: The tissue damage that emerges during traumatic brain injury (TBI) is a consequence of a variety of pathophysiological events, including free radical generation and over-activation of N-methyl-d-aspartate-type glutamate receptors (NMDAR). Considering the complex pathophysiology of TBI, we hypothesized that combination of neuroprotective compounds, targeting different events which appear during injury, may be a more promising approach for patients. In this context, both NMDAR antagonist memantine and free radical scavenger melatonin are safe in humans and promising agents for the treatment of TBI. Herein, we examined the effects of melatonin administered alone or in combination with memantine on the activation of signaling pathways, injury development and DNA fragmentation. Both compounds reduced brain injury moderately and the density of DNA fragmentation significantly. Notably, melatonin/memantine combination decreased brain injury and DNA fragmentation significantly, which was associated with reduced p38 and ERK-1/2 phosphorylation. As compared with melatonin and memantine groups, SAPK/JNK-1/2 phosphorylation was also reduced in melatonin/memantine combined animals. In addition, melatonin, memantine and their combination decreased iNOS activity significantly. Here, we provide evidence that melatonin/memantine combination protects brain from traumatic injury, which was associated with decreased DNA fragmentation, p38 phosphorylation and iNOS activity.
authors.affiliation: Department of Physiology, Regenerative and Restorative Medical Research Center, University of Istanbul Medipol, Turkey.
authors.forename: Taha
authors.initials: T
authors.lastname: Kelestemur
authors.affiliation: Department of Neurology, University of Istanbul Medipol, Turkey.
authors.forename: Burak
authors.initials: B
authors.lastname: Yulug
authors.affiliation: Department of Physiology, Regenerative and Restorative Medical Research Center, University of Istanbul Medipol, Turkey.
authors.forename: Ahmet Burak
authors.initials: AB
authors.lastname: Caglayan
authors.affiliation: Department of Physiology, Regenerative and Restorative Medical Research Center, University of Istanbul Medipol, Turkey.
authors.forename: Mustafa Caglar
authors.initials: MC
authors.lastname: Beker
authors.affiliation: Department of Medical Biology, University of Istanbul Medipol, Turkey.
authors.forename: Ulkan
authors.initials: U
authors.lastname: Kilic
authors.affiliation: Department of Physiology, Regenerative and Restorative Medical Research Center, University of Istanbul Medipol, Turkey.
authors.forename: Berrak
authors.initials: B
authors.lastname: Caglayan
authors.affiliation: Department of Physiology, Regenerative and Restorative Medical Research Center, University of Istanbul Medipol, Turkey.
authors.forename: Esra
authors.initials: E
authors.lastname: Yalcin
authors.affiliation: Department of Physiology, Regenerative and Restorative Medical Research Center, University of Istanbul Medipol, Turkey.
authors.forename: Reyhan Zeynep
authors.initials: RZ
authors.lastname: Gundogdu
authors.affiliation: Department of Physiology, Regenerative and Restorative Medical Research Center, University of Istanbul Medipol, Turkey. Electronic address: ekilic@medipol.edu.tr.
authors.forename: Ertugrul
authors.initials: E
authors.lastname: Kilic
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000473:pathology; D020520:Brain Infarction / Q000473:pathology; D001930:Brain Injuries / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D053938:DNA Fragmentation / Q000187:drug effects; D016166:Free Radical Scavengers / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D008550:Melatonin / Q000494:pharmacology* / Q000627:therapeutic use; D008559:Memantine / Q000494:pharmacology* / Q000627:therapeutic use; D008807:Mice, Inbred BALB C; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D016166:Free Radical Scavengers; D018696:Neuroprotective Agents; D008550:Melatonin; D008559:Memantine
keywords: DNA fragmentation; Melatonin; Memantine; Traumatic Brain Injury