Sleep Deprivation-Induced Blood-Brain Barrier Breakdown and Brain Dysfunction are Exacerbated by Size-Related Exposure to Ag and Cu Nanoparticles. Neuroprotective Effects of a 5-HT3 Receptor Antagonist Ondansetron

Abstract

Military personnel are often subjected to sleep deprivation (SD) during combat operations. Since SD is a severe stress and alters neurochemical metabolism in the brain, a possibility exists that acute or long-term SD will influence blood-brain barrier (BBB) function and brain pathology. This hypothesis was examined in young adult rats (age 12 to 14 weeks) using an inverted flowerpot model. Rats were placed over an inverted flowerpot platform (6.5 cm diameter) in a water pool where the water levels are just 3 cm below the surface. In this model, animals can go to sleep for brief periods but cannot achieve deep sleep as they would fall into water and thus experience sleep interruption. These animals showed leakage of Evans blue in the cerebellum, hippocampus, caudate nucleus, parietal, temporal, occipital, cingulate cerebral cortices, and brain stem. The ventricular walls of the lateral and fourth ventricles were also stained blue, indicating disruption of the BBB and the blood-cerebrospinal fluid barrier (BCSFB). Breakdown of the BBB or the BCSFB fluid barrier was progressive in nature from 12 to 48 h but no apparent differences in BBB leakage were seen between 48 and 72 h of SD. Interestingly, rats treated with metal nanoparticles, e.g., Cu or Ag, showed profound exacerbation of BBB disruption by 1.5- to 4-fold, depending on the duration of SD. Measurement of plasma and brain serotonin showed a close correlation between BBB disruption and the amine level. Repeated treatment with the serotonin 5-HT3 receptor antagonist ondansetron (1 mg/kg, s.c.) 4 and 8 h after SD markedly reduced BBB disruption and brain pathology after 12 to 24 h SD but not following 48 or 72 h after SD. However, TiO2-nanowired ondansetron (1 mg/kg, s.c) in an identical manner induced neuroprotection in rats following 48 or 72 h SD. However, plasma and serotonin levels were not affected by ondansetron treatment. Taken together, our observations are the first to show that (i) SD could induce BBB disruption and brain pathology, (ii) nanoparticles exacerbate SD-induced brain damage, and (iii) serotonin 5-HT3 receptor antagonist ondansetron is neuroprotective in SD that is further potentiated byTiO2-nanowired delivery, not reported earlier.

Sleep Deprivation Induces Cognitive Impairment by Increasing Blood-Brain Barrier Permeability via CD44

“…Sleep participates in the neural biological regulation by facilitating the elimination of metabolites along the BBB (55). As in severe stress, sleep deprivation impairs BBB function and induces brain pathology (21). Similarly, our study also showed that BBB permeability was significantly increased in mice with sleep deprivation induction, suggesting the vital effect of sleep deprivation on the BBB.…”

“…The sleep deprivation model was induced using an inverted flowerpot in a water tank (21). Briefly, sleep deprived (SD, n = 9) mice were placed on an inverted flowerpot (platform of 1.1 cm diameter) surrounded by a water-filled chamber of Plexiglas.…”

GABA-BZD Receptor Modulating Mechanism of Panax quinquefolius against 72-h Sleep Deprivation Induced Anxiety like Behavior: Possible Roles of Oxidative Stress, Mitochondrial Dysfunction and Neuroinflammation

“…In concordance with the above mentioned research inferences, the present study too reported that Panax quinquefolius (GIN) treatment for 8 days in sleep deprived animals significantly attenuated the anxiogenic like behavior, oxidative stress, mitochondrial dysfunction, serum corticosterone and pro-inflammatory marker (TNF-α) levels as well as minimized histological neuronal changes as compared to the sleep deprived vehicle treated animals. Although GABA is known to be a primarily involved in consequences of SD, but sleep research in recent times has also pointed toward significant alterations in 5-HT neurotransmission as well as neurochemical metabolism (under the control of molecules like 5-hydroxytryptamine transporter, 5-HTT and Glycogen synthase kinase 3-β) as a direct consequence of SD (Benedetti et al, 1999 , 2012 ; Monti et al, 2011 ; Zant et al, 2011 ; Elmenhorst et al, 2012 ; Sharma et al, 2015 ). Also, 5-HT receptor antagonists have recently be classified for their promising role against SD-induced brain dysfunctions (Youngblood et al, 1999 ; Morairty et al, 2008 ) affirming that the secondary neurological debilities manifested as a direct concern of SD can also be accredited to altered 5-HT neurotransmission.…”

Neurovascular dysfunction and neurodegeneration in dementia and Alzheimer's disease

“…Furthermore, mice undergoing chronic sleep restriction have decreased expression and function of GLUT1, impaired tight junction expression and BBB transport, and suppressed vascular reactivity with reduced inducible nitric oxide synthase (iNOS), endothelial NOS (eNOS) and ET-1 [147]. Also, rats subjected to sleep deprivation exhibited BBB breakdown and leakage [148]. …”

“…Experimental studies in rodents have shown that silver, copper or aluminum/aluminum oxide nanoparticles disrupt the BBB, reduce the expression of endothelial tight junctions, decrease CBF, and induce edema, synaptic dysfunction and neurodegeneration [157–160]. Interestingly, silver and copper nanoparticle exposure exacerbated BBB dysfunction when accompanying sleep deprivation [148] or diabetes [158]. …”