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Front. Cell. Neurosci. | doi: 10.3389/fncel.2018.00049

Caffeine and modafinil ameliorate the neuroinflammation and anxious behavior in rats during sleep deprivation by inhibiting the microglia activation

 Meetu Wadhwa1, Garima Chauhan1,  Koustav Roy1,  Surajit Sahu1, 2, Satyanarayan Deep3, 4, Vishal Jain1, Krishna Kishore1, Koushik Ray1, Lalan Thakur1 and  Usha Panjwani1*
  • 1Neurophysiology Division, Defence Institute of Physiology and Allied Sciences (DRDO), India
  • 2INSERM UMR1249 Institut de Neurobiologie de la Méditerranée, France
  • 3Neurobiology Division, Defence Research and Development Organisation (DRDO), India
  • 4Department of Neurology, University of New Mexico, United States

Background: Sleep deprivation (SD) plagues modern society due to the professional demands. It prevails in patients with mood and neuroinflammatory disorders. Although growing evidence suggests the improvement in the cognitive performance by psychostimulants during sleep-deprived conditions, the impending involved mechanism is rarely studied. Thus, we hypothesized that mood and inflammatory changes might be due to the glial cells activation induced modulation of the inflammatory cytokines during SD, which could be improved by administering psychostimulants. The present study evaluated the role of caffeine/modafinil on SD-induced behavioral and inflammatory consequences.
Methods: Adult male Sprague-Dawley rats were sleep deprived for 48 h using automated sleep deprivation apparatus. Caffeine (60 mg/kg/day) or modafinil (100 mg/kg/day) were administered orally to rats once every day during SD. Rats were subjected to anxious and depressive behavioral evaluation after SD. Subsequently, blood and brain were collected for biochemical, immunohistochemical, and molecular studies.
Results: Sleep deprived rats presented an increased number of entries and time spent in closed arms in elevated plus maze test and decreased total distance traveled in the open field test. Caffeine/modafinil treatment significantly improved these anxious consequences. However, we did not observe substantial changes in immobility and anhedonia in sleep-deprived rats. Caffeine/modafinil significantly down-regulated the pro- and up-regulated the anti-inflammatory cytokine mRNA and protein expression in the hippocampus during SD. Similar outcomes were observed in blood plasma cytokine levels. Caffeine/modafinil treatment significantly decreased the microglial immunoreactivity in DG, CA1, and CA3 regions of the hippocampus during SD, however, no significant increase in immunoreactivity of astrocytes was observed. Sholl analysis signified the improvement in the morphological alterations of astrocytes and microglia after caffeine/modafinil administration during SD. Stereological analysis demonstrated a significant improvement in the number of Iba-1 positive cells (different states) in different regions of the hippocampus after caffeine or modafinil treatment during SD without showing any significant change in total microglial cell number. Eventually, the correlation analysis displayed a positive relationship between anxiety, pro-inflammatory cytokines and activated microglial cell count during SD.
Conclusion: The present study suggests the role of caffeine/modafinil in the amelioration of SD-induced inflammatory response and anxious behavior in rats.

Keywords: Sleep Deprivation, Mood changes, Microglia, Cytokines, Neuroinflammation, Caffeine, Modafinil.

Received: 31 Dec 2017; Accepted: 15 Feb 2018.

Edited by:

Alexej Verkhratsky, University of Manchester, United Kingdom

Reviewed by:

Rodrigo A. Cunha, University of Coimbra, Portugal
Leanne Stokes, University of East Anglia, United Kingdom  

Copyright: © 2018 Wadhwa, Chauhan, Roy, Sahu, Deep, Jain, Kishore, Ray, Thakur and Panjwani. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Usha Panjwani, Defence Institute of Physiology and Allied Sciences (DRDO), Neurophysiology Division, Delhi, India,