A single intraperitoneal injection of endotoxin in rats induces long-lasting modifications in behavior and brain protein levels of TNF-α and IL-18

Abstract

BackgroundSystemic inflammation might cause neuronal damage and sustain neurodegenerative diseases and behavior impairment, with the participation of pro-inflammatory cytokines, like tumor necrosis factor (TNF)-α and interleukin (IL)-18. However, the potential contribution of these cytokines to behavioral impairment in the long-term period has not been fully investigated.MethodsWistar rats were treated with a single intraperitoneal injection of LPS (5 mg/kg) or vehicle. After 7 days and 10 months, the animal behavior was evaluated by testing specific cognitive functions, as mnesic, discriminative, and attentional functions, as well as anxiety levels. Contextually, TNF-α and IL-18 protein levels were measured by ELISA in defined brain regions (that is, frontal cortex, hippocampus, striatum, cerebellum, and hypothalamus).ResultsBehavioral testing demonstrated a specific and persistent cognitive impairment characterized by marked deficits in reacting to environment modifications, possibly linked to reduced motivational or attentional deficits. Concomitantly, LPS induced a TNF-α increase in the hippocampus and frontal cortex (from 7 days onward) and cerebellum (only at 10 months). Interestingly, LPS treatment enhanced IL-18 expression in these same areas only at 10 months after injection.ConclusionsOverall, these results indicate that the chronic neuroinflammatory network elicited by systemic inflammation involves a persistent participation of TNF-α accompanied by a differently regulated contribution of IL-18. This leads to speculation that, though with still unclear mechanisms, both cytokines might take part in long-lasting modifications of brain functions, including behavioral alteration.

Effects of Centrally Administered Etanercept on Behavior, Microglia, and Astrocytes in Mice Following a Peripheral Immune Challenge

“…Supporting the present findings, that a single challenge with LPS systemically can increase central TNF-a expression, Bossu et al (2012), showed that a single dose of LPS (5 mg/kg) was effective in increasing TNF-a expression in the hippocampus and PFC from 7 days after LPS challenge, lasting up to 10 months after challenge and that these changes were associated with cognitive impairments. These results indicate that TNF-a, through systemic LPS, can have lasting neuroinflammatory effects in the brain and may lead to cognitive decline.…”

“…It is known that peripherally stimulated monocytes affect the CNS via the BBB and the blood-CSF barrier and express cytokines, such as TNF-a (Ubogu et al, 2006). Indeed, this peripheral-central immune cross-talk is further supported by a study that showed how a single high dose of LPS (5 mg/kg) given IP was effective in increasing cytokine expression, particularly TNF-a, in the hippocampus and prefrontal cortex even 7 days after administration (Bossu et al, 2012). Thus, activation of peripheral inflammation can promote central activation and proliferation of microglia and subsequent production of cytokines within the brain itself (Bossu et al, 2012;Qin et al, 2007), providing a potential mechanism to explain the increase in microglia numbers noted within this study only in the hippocampus but not in the PFC.…”

“…Indeed, this peripheral-central immune cross-talk is further supported by a study that showed how a single high dose of LPS (5 mg/kg) given IP was effective in increasing cytokine expression, particularly TNF-a, in the hippocampus and prefrontal cortex even 7 days after administration (Bossu et al, 2012). Thus, activation of peripheral inflammation can promote central activation and proliferation of microglia and subsequent production of cytokines within the brain itself (Bossu et al, 2012;Qin et al, 2007), providing a potential mechanism to explain the increase in microglia numbers noted within this study only in the hippocampus but not in the PFC. The differences in microglia findings in the hippocampus and the PFC between the present study and previous results by Bossu et al (2012) may be due to the relatively low dose of LPS used in this study.…”

“…Thus, activation of peripheral inflammation can promote central activation and proliferation of microglia and subsequent production of cytokines within the brain itself (Bossu et al, 2012;Qin et al, 2007), providing a potential mechanism to explain the increase in microglia numbers noted within this study only in the hippocampus but not in the PFC. The differences in microglia findings in the hippocampus and the PFC between the present study and previous results by Bossu et al (2012) may be due to the relatively low dose of LPS used in this study. It may be plausible that a higher dose of LPS is required to illicit a change in microglial numbers in the PFC, but the hippocampus is more susceptible to immune activation; however, these speculations will need to be clarified by further studies.…”

Increased Levels of Serum IL-18 Are Associated with the Long-Term Outcome of Severe Traumatic Brain Injury

“…Consistently, in a rodent model, IL-18 appears to be involved in the late stage of experimental neuroinflammation, possibly taking part in long-lasting modifications of brain functions, including progressive neurodegeneration and cognitive dysfunction [25]. Specifically regarding TBI, increased microglial activation can be present even several years after the trauma, triggering a long-lasting inflammatory response particularly in the subcortical regions of the brain [26].…”