Intermittent fasting attenuates lipopolysaccharide-induced neuroinflammation and memory impairment

Abstract

BackgroundSystemic bacterial infections often result in enduring cognitive impairment and are a risk factor for dementia. There are currently no effective treatments for infection-induced cognitive impairment. Previous studies have shown that intermittent fasting (IF) can increase the resistance of neurons to injury and disease by stimulating adaptive cellular stress responses. However, the impact of IF on the cognitive sequelae of systemic and brain inflammation is unknown.MethodsRats on IF for 30 days received 1 mg/kg of lipopolysaccharide (LPS) or saline intravenously. Half of the rats were subjected to behavioral tests and the other half were euthanized two hours after LPS administration and the hippocampus was dissected and frozen for analyses.ResultsHere, we report that IF ameliorates cognitive deficits in a rat model of sepsis by a mechanism involving NF-κB activation, suppression of the expression of pro-inflammatory cytokines, and enhancement of neurotrophic support. Treatment of rats with LPS resulted in deficits in cognitive performance in the Barnes maze and inhibitory avoidance tests, without changing locomotor activity, that were ameliorated in rats that had been maintained on the IF diet. IF also resulted in reduced levels of mRNAs encoding the LPS receptor TLR4 and inducible nitric oxide synthase (iNOS) in the hippocampus. Moreover, IF prevented LPS-induced elevation of IL-1α, IL-1β and TNF-α levels, and prevented the LPS-induced reduction of BDNF levels in the hippocampus. IF also significantly attenuated LPS-induced elevations of serum IL-1β, IFN-γ, RANTES, TNF-α and IL-6 levels.ConclusionsTaken together, our results suggest that IF induces adaptive responses in the brain and periphery that can suppress inflammation and preserve cognitive function in an animal model of systemic bacterial infection.

TLR4-activated microglia require IFN-γ to induce severe neuronal dysfunction and death in situ

“…We did not observe direct toxic effects in situ as has been described for primary cortical neuron cultures (46). The decreased frequency of gamma oscillations might contribute to cognitive deficits and sickness behavior during systemic infections, multiple sclerosis, and Alzheimer's disease featuring increased IFN-γ levels (7,(48)(49)(50).…”

Biochemical Studies of Hippocampal Gene Expression of Brain-Derived Neurotropic Factor and Toll-Like Receptor-4 in Diabetic Rats Exposed to Chronic Stress: Effects of Antidepressant Drugs

“…The chronic IMIP treatment produced a significant increase in BDNF in both non-diabetic (p<0.001) and diabetic rats (p<0.01). IMIP produced a significant decline in TLR-4 gene expression only in diabetic rats as compared to vehicle-treated group (p<0.001) (F (3,40) =47.57, p<0.0001; F (3,40) =9.49, p<0.0001).…”

“…Figs. 2a and b, 3a and b, diabetic rats showed a significant decrease in hippocampal BDNF with an increase in TLR-4 gene expression (F (1,40) =84.57, p<0.0001; F (1,40) =41.29, p<0.0001, respectively). CRS induced a significant decrease in BDNF (p<0.001, p<0.05) and increase in TLR-4 (p<0.05, p<0.001) gene expression in both non-diabetic and diabetic rats, respectively, in contrast to control groups.…”

“…4a and b, diabetic rats showed a significant decrease in hippocampal BDNF with an increase in TLR-4 protein (F (1,40) =6.47, p<0.05; F (1,40) =31.95, p<0.0001). Exposure to CRS in non-diabetic and diabetic rats induced a significant decrease in BDNF protein (p<0.01, p<0.05) and increase in TLR-4 protein (p<0.001, p<0.001) in contrast to control groups.…”

Toxoplasma gondii and Schizophrenia: A Relationship That Is Not Ruled Out

“…Among other effects, an increase is produced in the expression of NADPH oxidase enzyme (NOX2) and inducible nitric oxide synthase (iNOS). These enzymes are responsible for the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS), which assist the destruction of foreign pathogens [110,111] but have been linked to seizures, stroke, neurodegenerative diseases, and schizophrenia [111,112] as a consequence of their toxic effect on neurons [113]. Scientific evidence points to ROS-mediated oxidative damage as a key pathogenic pathway involved in infection-mediated neuropathy.…”