Exosome Treatment Improves Functional Recovery After Traumatic Brain Injury in Rats: A Dose-Response and Therapeutic Window Study
Zhang Y, Zhang Y, Chopp M, Lu M, Zhang ZG, Mahmood A, and Xiong Y. Exosome Treatment Improves Functional Recovery After Traumatic Brain Injury in Rats: A Dose-Response and Therapeutic Window Study. J Neurotrauma 2019; 36(13):A76-A77.
We have previously demonstrated that treatment of traumatic brain injury (TBI) 24h post injury, with exosomes harvested from bone marrow mesenchymal stem cells, significantly improved functional recovery. The present study was designed to determine the dose-response and therapeutic window of exosomes for treatment of TBI (n = 8 rats/group). In Experiment 1: male rats subjected to moderate TBI induced by controlled cortical impact randomly received phosphate-buffered solution (PBS) or one dose of exosomes (50, 100, 200 μg/rat) 24h after injury. In Experiment 2: TBI rats randomly received PBS or 100 μg exosomes starting at 1, 4, and 7 days after injury. Neurological functional tests were performed 1 day and weekly after TBI for 5 weeks. Spatial learning was measured on days 31-35 after TBI using the Morris water maze test. Analysis of variance (ANOVA) followed by post hoc Tukey's tests was used for data analyses. In Experiment 1, all the doses of exosomes significantly improved sensorimotor and cognitive function (p< 0.05). However, the exosome treatment at 100 μg/rat resulted in a more rapid and significantly greater reduction of these deficits compared with rats treated with the 50 μg or 200lg exosomes (p < 0.05). In Experiment 2, treatment with exosomes at 100 μg/rat starting 1, 4, and 7 days post TBI significantly reduced neurological deficits and improved cognitive function (p< 0.05). However, the exosome treatment starting at 1 day post TBI resulted in a significantly greater reduction of these deficits compared with TBI rats treated with exosomes at the two later time points (p < 0.05). In summary, exosome therapy for male rats with therapy initiated 24h post TBI at 100 μg/rat provides a superior therapeutic window of treatment compared with treatment initiated at 4d or 7d time points. Exosome treatment at 100 μg/rat provides a robust therapeutic effect for treatment initiated at 24h post TBI in male rats, indicating that cell-free exosomes may have potential as a novel treatment of TBI.