The Single-Dose Application of Interleukin-4 Ameliorates Secondary Brain Damage in the Early Phase after Moderate Experimental Traumatic Brain Injury in Mice.

Activation of the interleukin-4 (IL-4) pathway ameliorates secondary injury mechanisms after experimental traumatic brain injury (TBI); therefore, we assessed the effect of a therapeutic IL-4 administration on secondary brain damage after experimental TBI. We subjected 100 C57/Bl6 wildtype mice to controlled cortical impact (CCI) and administered IL-4 or a placebo control subcutaneously 15 min thereafter. Contusion volume (Nissl staining), neurological function (hole board, video open field, and CatWalkXT®), and the immune response (immunofluorescent staining) were analyzed up to 28 days post injury (dpi). Contusion volumes were significantly reduced after IL-4 treatment up to 14 dpi (e.g., 6.47 ± 0.41 mm3 vs. 3.80 ± 0.85 mm3, p = 0.011 3 dpi). Macrophage invasion and microglial response were significantly attenuated in the IL-4 group in the acute phase after CCI (e.g., 1.79 ± 0.15 Iba-1+/CD86+ cells/sROI vs. 1.06 ± 0.21 Iba-1/CD86+ cells/sROI, p = 0.030 in the penumbra 3 dpi), whereas we observed an increased neuroinflammation thereafter (e.g., mean GFAP intensity of 3296.04 ± 354.21 U vs. 6408.65 ± 999.54 U, p = 0.026 in the ipsilateral hippocampus 7 dpi). In terms of functional outcome, several gait parameters were improved in the acute phase following IL-4 treatment (e.g., a difference in max intensity of -7.58 ± 2.00 U vs. -2.71 ± 2.44 U, p = 0.041 3 dpi). In conclusion, the early single-dose administration of IL-4 significantly reduces secondary brain damage in the acute phase after experimental TBI in mice, which seems to be mediated by attenuation of macrophage and microglial invasion.

Focal lesion size poorly correlates with motor function after experimental traumatic brain injury in mice.

BACKGROUND: It remains unclear whether neurobehavioral testing adds significant information to histologic assessment of experimental traumatic brain injury (TBI) and if automated gait assessment using the CatWalk XT®, while shown to be effective in in the acute phase, is also effective in the chronic phase after experimental TBI. Therefore, we evaluated the correlation of CatWalk XT® parameters with histologic lesion volume and analyzed their temporal and spatial patterns over four weeks after trauma induction. METHODS: C57Bl/6 mice were subjected to controlled cortical impact (CCI). CatWalk XT® analysis was performed one day prior to surgery and together with the histological evaluation of lesion volume on postoperative days one, three, seven, 14 and 28. Temporal and spatial profiles of gait impairment were analyzed and a total of 100 CatWalk XT® parameters were correlated to lesion size. RESULTS: While in the first week after CCI, there was significant impairment of nearly all CatWalk XT® parameters, impairment of paw prints, intensities and dynamic movement parameters resolved thereafter; however, impairment of dynamic single paw parameters persisted up to four weeks. Correlation of the CatWalk XT® parameters with lesion volume was poor at all timepoints. CONCLUSION: As CatWalk XT® parameters do not correlate with focal lesion size after CCI, gait assessment using the CatWalk XT® might add valuable information to solitary histologic evaluation of the injury site. While all CatWalk XT® parameters can be used for gait assessments in the first week after CCI, dynamic single paw parameters might be more relevant in the chronic phase after experimental TBI.