Diffuse traumatic axonal injury in mice induces complex behavioural alterations that are normalized by neutralization of interleukin-1β

Abstract

Widespread traumatic axonal injury (TAI) results in brain network dysfunction, which commonly leads to persisting cognitive and behavioural impairments following traumatic brain injury (TBI). TBI induces a complex neuroinflammatory response, frequently located at sites of axonal pathology. The role of the pro-inflammatory cytokine interleukin (IL)-1β has not been established in TAI. An IL-1β-neutralizing or a control antibody was administered intraperitoneally at 30 min following central fluid percussion injury (cFPI), a mouse model of widespread TAI. Mice subjected to moderate cFPI (n = 41) were compared with sham-injured controls (n = 20) and untreated, naive mice (n = 9). The anti-IL-1β antibody reached the target brain regions in adequate therapeutic concentrations (up to ~30 μg/brain tissue) at 24 h post-injury in both cFPI (n = 5) and sham-injured (n = 3) mice, with lower concentrations at 72 h post-injury (up to ~18 μg/g brain tissue in three cFPI mice). Functional outcome was analysed with the multivariate concentric square field (MCSF) test at 2 and 9 days post-injury, and the Morris water maze (MWM) at 14-21 days post-injury. Following TAI, the IL-1β-neutralizing antibody resulted in an improved behavioural outcome, including normalized behavioural profiles in the MCSF test. The performance in the MWM probe (memory) trial was improved, although not in the learning trials. The IL-1β-neutralizing treatment did not influence cerebral ventricle size or the number of microglia/macrophages. These findings support the hypothesis that IL-1β is an important contributor to the processes causing complex cognitive and behavioural disturbances following TAI.

Early fine motor impairment and behavioral dysfunction in (Thy‐1)‐h[A30P] alpha‐synuclein mice

“…In order to measure locomotor activity and obtain a behavioral profile of the mice, the MCSF test was used (Meyerson, Augustsson, Berg, & Roman, ) on 8‐ and 11‐month‐old mice. This test has previously been adopted to study functional outcomes and treatment effects after traumatic brain injury (Ekmark‐Lewen, Lewen, Meyerson, & Hillered, ; Ekmark‐Lewen et al., , ). In the MCSF test, animals are placed in a novel arena, divided into different zones.…”

Interleukin-1 Beta Neutralization Attenuates Traumatic Brain Injury-Induced Microglia Activation and Neuronal Changes in the Globus Pallidus

“…Indeed, we previously showed that systemic administration of a neutralizing IL-1β antibody attenuated the inflammatory response, cerebral edema, and tissue loss and improved cognitive outcome in a focal TBI model in mice. Furthermore, neutralization of IL-1β attenuated the complex behavioral and cognitive dysfunction observed in mice subjected to the central fluid percussion model [10]. Similarly, systemic post-injury administration of a human recombinant interleukin-1 receptor antagonist resulted in attenuated neuronal loss and oligodendrocyte death after lateral fluid-percussion brain injury [11,12].…”

Neutralization of Interleukin-1β following Diffuse Traumatic Brain Injury in the Mouse Attenuates the Loss of Mature Oligodendrocytes

“… 27 , 28 Recently, neutralization of IL-1β normalized the complex behavioral changes observed in a diffuse TBI model, the central fluid percussion model, in mice. 29 The mechanisms explaining the behavioral improvements observed by IL-1β neutralization have not been established.…”