Can Dexmedetomidine Attenuate Neuroapoptosis and Neuroinflammation Induced By Ketamine in Neonatal Rat Hippocampus via Modulation of TNF-Α, IL6, Β-Catenin, Caspase3 Expression and Adjustment of Mtor/Nrf2 Signaling Pathways?

Document Type : Original Article

Authors

1 Department of Anatomy and Embryology , Faculty of Medicine, Ain-Shams University, Cairo, Egypt.

2 Department of Anesthesia, intensive care and pain management, Faculty of Medicine, Ain shams university.

Abstract

Introduction: Ketamine is a commonly used anesthetic agent during surgical operations. Numerous clinical trials have indicated that neuronal apoptosis may be induced by repeated ketamine exposure during the period of brain development.
Aim of the Work: The current study aimed to evaluate the neuroprotective potential of dexmedetomidine against ketamine effect on neonatal rat hippocampus.
Materials and Methods: Twenty-eight neonatal rats were divided into 4 groups (7 rats each); group (I) didn't receive any treatment (control group), Group (II) (dexmedetomidine-treated): received 25 μg/kg dexmedetomidine by subcutaneous injection, group (III) received 75 mg/kg/day of ketamine intraperitoneally and group (IV) received 75 mg/kg/d ketamine intraperitoneally plus 25 μg/kg dexmedetomidine by subcutaneous injection. Drugs were given on postnatal day (7) to postnatal day (9). At the end of experiment, brains were dissected and prepared for histological, immunohistochemical and morphometric analysis.
Results: Group (III) revealed degenerative signs in all parts of hippocampus proper but were much more profound in the cornuamonis 3 and dentate gyrus. Most of neurons appeared distorted and exhibited pale scanty cytoplasm and dark shrunken pyknotic neuclei. Neurodegeneration was also confirmed by increased β-catenin expression. A significant rise in the quantity of apoptotic cells was determined by the expression of Caspase-3 and TUNEL assay. Western blot analysis revealed significantly decreased level of both mTOR/Nrf2 protein expressions and increased serum level of inflammatory cytokines TNF-α and IL6 in group III relative to groups I and II. All the observed changes were ameliorated in group (IV).
Conclusion: Novel dexmedetomidine attenuated most of histological signs of neurodegeneration, significantly decreased number of apoptotic cells and induced neuronal survival in the hippocampus of neonatal rats exposed to ketamine by restoring nearly normal levels of both mTOR/Nrf2 via modification of the PI3K/Akt signaling pathway.

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