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


METHODS
Wistar 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).


RESULTS
Behavioral 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.


CONCLUSIONS
Overall, 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.
Clinical and Behavioral Neurology, IRCCS Fondazione Santa Lucia, Via Ardeatina 30600179, Rome, Italy. p.bossu@hsantalucia.it
Paola
P
Bossù
Debora
D
Cutuli
Ilaria
I
Palladino
Paola
P
Caporali
Francesco
F
Angelucci
Daniela
D
Laricchiuta
Francesca
F
Gelfo
Paola
P
De Bartolo
Carlo
C
Caltagirone
Laura
L
Petrosini
D000818:Animals; D001921:Brain / Q000378:metabolism*; D004731:Endotoxins / Q000633:toxicity*; D007274:Injections, Intraperitoneal; D020382:Interleukin-18 / Q000096:biosynthesis*; D008297:Male; D018782:Maze Learning / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D004731:Endotoxins; D020382:Interleukin-18; D014409:Tumor Necrosis Factor-alpha