Role of melatonin and memantine for the treatment after traumatic brain injury



Targeting different pathophysiological events after traumatic brain injury in mice: Role of melatonin and memantine.
Taha Kelestemura, Burak Yulugb, Ahmet Burak Caglayana, Mustafa Caglar Bekera, Ulkan Kilicc, Berrak Caglayana, Esra Yalcina, Reyhan Zeynep Gundogdua, Ertugrul Kilica

Highlights
- Synergistic and anti-synergistic effect of melatonin and memantine on apoptosis and cell signalling.
- Targeting different events for the treatment of brain injury.
- Effects of memantine on signaling pathways were compared with a well-known neuroprotective melatonin.
- Effects of melatonin and memantine on cell signalling after traumatic brain injury.

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.

http://www.sciencedirect.com/science/article/pii/S0304394015302810






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