Abstract
Melatonin has a role in the cell survival signaling pathways as a candidate for secondary stroke prevention. Therefore, in the present study, the coordination of ipsilateral and contralateral hemispheres to evaluate delayed post-acute effect of melatonin was examined on recovery of the cell survival and apoptosis after stroke. Melatonin was administered (4 mg/kg/day) intraperitoneally for 45 days, starting 3 days after 30 min of middle cerebral artery occlusion. The genes and proteins related to the cell survival and apoptosis were investigated by immunofluorescence, western blotting, and RT-PCR techniques after behavioral experiments. Melatonin produced delayed neurological recovery by improving motor coordination on grip strength and rotarod tests. This neurological recovery was also reflected by high level of NeuN positive cells and low level of TUNEL-positive cells suggesting enhanced neuronal survival and reduced apoptosis at the fifty-fifth day of stroke. The increase of NGF, Nrp1, c-jun; activation of AKT; and dephosphorylation of ERK and JNK at the fifty-fifth day showed that cell survival and apoptosis signaling molecules compete to contribute to the remodeling of brain. Furthermore, an increase in the CREB and Atf-1 expressions suggested the melatonin’s strong reformative effect on neuronal regeneration. The contralateral hemisphere was more active at the latter stages of the molecular and functional regeneration which provides a further proof of principle about melatonin’s action on the promotion of brain plasticity and recovery after stroke.
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This work was financially supported by the grant from the Turkish Scientific and Technical Council (TUBITAK, Grant number:111S418).
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UK and EK designed all the experiments and ABC and MCB carried out experimental cerebral ischemia model. BE and MB performed western blot and histological analysis. BAT performed quantitative RT-PCR analysis. BE and OU executed data analysis and performed statistical analysis. BY contributed to the work by technical and analytical support. UK and BE participated in preparation of the manuscript. All authors read and approved the final manuscript.
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Kilic, U., Elibol, B., Caglayan, A.B. et al. Delayed Therapeutic Administration of Melatonin Enhances Neuronal Survival Through AKT and MAPK Signaling Pathways Following Focal Brain Ischemia in Mice. J Mol Neurosci 72, 994–1007 (2022). https://doi.org/10.1007/s12031-022-01995-y
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DOI: https://doi.org/10.1007/s12031-022-01995-y