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Time-of-Day Dependent Neuronal Injury After Ischemic Stroke: Implication of Circadian Clock Transcriptional Factor Bmal1 and Survival Kinase AKT

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Abstract

Occurrence of stroke cases displays a time-of-day variation in human. However, the mechanism linking circadian rhythm to the internal response mechanisms against pathophysiological events after ischemic stroke remained largely unknown. To this end, temporal changes in the susceptibility to ischemia/reperfusion (I/R) injury were investigated in mice in which the ischemic stroke induced at four different Zeitgeber time points with 6-h intervals (ZT0, ZT6, ZT12, and ZT18). Besides infarct volume and brain swelling, neuronal survival, apoptosis, ischemia, and circadian rhythm related proteins were examined using immunohistochemistry, Western blot, planar surface immune assay, and liquid chromatography–mass spectrometry tools. Here, we present evidence that midnight (ZT18; 24:00) I/R injury in mice resulted in significantly improved infarct volume, brain swelling, neurological deficit score, neuronal survival, and decreased apoptotic cell death compared with ischemia induced at other time points, which were associated with increased expressions of circadian proteins Bmal1, PerI, and Clock proteins and survival kinases AKT and Erk-1/2. Moreover, ribosomal protein S6, mTOR, and Bad were also significantly increased, while the levels of PRAS40, negative regulator of AKT and mTOR, and phosphorylated p53 were decreased at this time point compared to ZT0 (06:00). Furthermore, detailed proteomic analysis revealed significantly decreased CSKP, HBB-1/2, and HBA levels, while increased GNAZ, NEGR1, IMPCT, and PDE1B at midnight as compared with early morning. Our results indicate that nighttime I/R injury results in less severe neuronal damage, with increased neuronal survival, increased levels of survival kinases and circadian clock proteins, and also alters the circadian-related proteins.

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Acknowledgements

This study was supported by The Turkish Academy of Sciences (TUBA) and Necmettin Erbakan University (Scientific Research Project: 161330001).

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Authors and Affiliations

  1. Regenerative and Restorative Medical Research Center, Istanbul Medipol University, Ekinciler Cad. 19, TR-34810, Istanbul, Turkey

    Mustafa Caglar Beker, Berrak Caglayan, Esra Yalcin, Ahmet Burak Caglayan, Seyma Turkseven, Busra Gurel, Taha Kelestemur, Elif Sertel, Ulkan Kilic & Ertugrul Kilic

  2. Department of Physiology, Istanbul Medipol University, 34810, Istanbul, Turkey

    Mustafa Caglar Beker, Berrak Caglayan, Esra Yalcin, Ahmet Burak Caglayan, Taha Kelestemur, Elif Sertel & Ertugrul Kilic

  3. Department of Physiology, Necmettin Erbakan University, 42060, Konya, Turkey

    Mustafa Caglar Beker, Ahmet Burak Caglayan, Taha Kelestemur & Selim Kutlu

  4. School of Medicine, Department of Medical Biochemistry, Acibadem University, 34752, Istanbul, Turkey

    Busra Gurel & Ahmet Tarik Baykal

  5. Department of Physiotherapy and Rehabilitation, Necmettin Erbakan University, 42060, Konya, Turkey

    Zafer Sahin

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  1. Mustafa Caglar Beker
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Correspondence to Ertugrul Kilic.

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Beker, M.C., Caglayan, B., Yalcin, E. et al. Time-of-Day Dependent Neuronal Injury After Ischemic Stroke: Implication of Circadian Clock Transcriptional Factor Bmal1 and Survival Kinase AKT. Mol Neurobiol 55, 2565–2576 (2018). https://doi.org/10.1007/s12035-017-0524-4

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