Caffeine and Modafinil Ameliorate the Neuroinflammation and Anxious Behavior in Rats during Sleep Deprivation by Inhibiting the Microglia Activation

Abstract

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 SD 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 (OF) 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 ionized calcium binding adapter molecule I (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 or modafinil in the amelioration of SD-induced inflammatory response and anxious behavior in rats.Highlights- SD induced mood alterations in rats.- Glial cells activated in association with the changes in the inflammatory cytokines.- Caffeine or modafinil improved the mood and restored inflammatory changes during SD.- SD-induced anxious behavior correlated with the inflammatory consequences.

Protective effects of Genistein on the cognitive deficits induced by chronic sleep deprivation

“…Recently, growing lines of evidence had demonstrated that SD could trigger neuroinflammation and then resulted in neurobehavioral alterations including memory impairments (Xia et al, 2017;Zielinski et al, 2017). It was reported that pro-inflammatory cytokines such as IL-1β, TNF-α, IL-6 are found to be increased upon SD in humans as well as experimental animals, and activation of NF-κB was shown in cortex and hippocampus regions of CSD rat (Manchanda, Singh, Kaur, & Kaur, 2018;Wadhwa et al, 2018). NF-κB is sequestered in the cytoplasm and occupies a vital position in the inflammatory cascade; once under oxidative stress, it translocates into the nucleus and induces various inflammatory proteins such as iNOS and COX-2 (Qiao, Jiang, & Gao, 2018).…”

Extracellular adenosine and slow-wave sleep are increased after ablation of nucleus accumbens core astrocytes and neurons in mice

“…The role of microglia in sleep regulation remains elusive. Some studies reported that microglia are activated after sleep deprivation (Huang et al, 2014;Wadhwa et al, 2018;Wisor et al, 2011). Microglia activation is likely a consequence of sleep loss, however, rather than the cause of sleep rebound.…”

Dual modulation on glial cells by tetrahydroxystilbene glucoside protects against dopamine neuronal loss

“…Astroglia become activated by inflammatory cytokines, such as IL-1β, and secrete several neurotoxic substances along with an enhanced GFAP protein expression. This enhanced GFAP expression relates to the astroglia activation severity [ 34 ]. However, strong activation of astroglia results in the secretion of a large number of chemokines, cytokines, ROS, and pro-inflammatory factors, further affecting the cellular state of surrounding cells, such as neurons, microglia, and astroglia themselves, thereby leading to excitotoxicity and neurodegeneration [ 35 ].…”