Abstract
Traumatic brain injury (TBI) increases the risk of delayed neurodegenerative processes, including Parkinson’s disease (PD). Interleukin-1beta (IL-1β), a key pro-inflammatory cytokine, may promote secondary injury development after TBI. Conversely, neutralizing IL-1β was found to improve functional recovery following experimental TBI. However, the mechanisms underlying the behavioral improvements observed by IL-1β neutralization are still poorly understood. The present study investigated the role of IL-1β on the microglia response and neuronal changes in the globus pallidus in response to diffuse TBI. Mice were subjected to sham injury or the central fluid percussion injury (cFPI) (a model of traumatic axonal injury), and were randomly administered an IL-1β neutralizing or a control antibody at 30 min post-injury. The animals were analyzed at 2, 7, or 14 days post-injury. When compared to controls, mice subjected to cFPI TBI had increased microglia activation and dopaminergic innervation in the globus pallidus, and a decreased number of parvalbumin (PV) positive interneurons in the globus pallidus. Neutralization of IL-1β attenuated the microglia activation, prevented the loss of PV+ interneurons and normalized dopaminergic fiber density in the globus pallidus of brain-injured animals. These findings argue for an important role for neuro-inflammation in the PD-like pathology observed in TBI.
Highlights
Traumatic brain injury (TBI) is a common cause of disability and death, in patients < 40 years of age [1]
The number of Iba1+ cells in the central fluid percussion injury (cFPI) IL-1β group was significantly lower when compared to the cFPI cyclosporin A mlgG2a (CsA) group, and neutralizing IL-1β treatment normalized the number of Iba1+ cells to levels similar to the sham CsA group (Figure 1C,D)
We used the cFPI model of diffuse TBI in mice and observed microglia activation and neuronal changes in the globus pallidus (GP) that may contribute to the development of Parkinson’s disease (PD)-like pathology
Summary
Traumatic brain injury (TBI) is a common cause of disability and death, in patients < 40 years of age [1]. Key contributors to the secondary injury process are microglia cell activation and elevated pro-inflammatory cytokines that persist for many years post-injury in both experimental and human TBI [2,3]. The cytokine Interleukin-1β (IL-1β) is one of the most important pro-inflammatory cytokines, increased early following experimental and human TBI, and mainly secreted by activated microglia, and by damaged endothelial cells, and astrocytes [4,5]. The production of IL-1β is closely associated with injury severity Both moderate and severe TBI increase IL-1β mRNA and protein levels in the cortex and deep central brain structures as early as 1 h after the injury [7]. 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]. The effects of IL-1β neutralization on TBI-induced microglia response in midbrain regions have not been established
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