Introduction: Traumatic brain injury (TBI) is a major cause of death and disability worldwide. To date, there are no pharmacologic agents proven to improve outcomes from TBI because all the Phase I...

Exosomes play an important role in intercellular communication by delivering microribonucleic acids (miRNAs) to recipient cells. Previous studies have demonstrated that multi-potent mesenchymal stromal cell (MSC)-derived exosomes improve functional recovery after experimental traumatic brain injury (TBI). This study was performed to determine efficacy of miR-17-92 cluster-enriched exosomes (Exo-17-92) harvested from human bone marrow MSCs transfected with a miR-17-92 cluster plasmid in enhancing tissue and neurological recovery compared with exosomes derived from MSCs transfected with an empty plasmid vector (Exo-empty) for treatment of TBI. Adult male rats underwent a unilateral moderate cortical contusion. Animals received a single intravenous injection of miR-17-92 cluster-enriched exosomes (100 μg/rat, approximately 3.75x10 ¹¹ particles, Exo-17-92) or control exosomes (100 μg/rat, Exo-empty) or Vehicle (phosphate-buffered solution) one day after injury. A battery of neurological functional tests was performed weekly after TBI for five weeks. Spatial learning and memory were measured on days 31–35 after TBI using the Morris water maze test. All animals were sacrificed five weeks after injury. Their brains were processed for histopathological and immunohistochemical analyses of lesion volume, cell loss, angiogenesis, neurogenesis, and neuroinflammation. Compared with Vehicle, both Exo-17-92 and Exo-empty treatments significantly improved sensorimotor and cognitive function, reduced neuroinflammation and hippocampal neuronal cell loss, promoted angiogenesis and neurogenesis without altering the lesion volume. Moreover, Exo-17-92 treatment exhibited a significantly more robust therapeutic effect on improvement in functional recovery by reducing neuroinflammation and cell loss, enhancing angiogenesis and neurogenesis than did Exo-empty treatment. Exosomes enriched with miR-17-92 cluster have a significantly better effect on improving functional recovery after TBI compared with Exo-empty, likely by reducing neuroinflammation and enhancing endogenous angiogenesis and neurogenesis. Engineering specific miRNA in exosomes may provide a novel therapeutic strategy for management of unilateral moderate cortical contusion TBI.

Traumatic brain injury (TBI) and stroke stand as prominent causes of global disability and mortality. Treatment strategies for stroke and TBI are shifting from targeting neuroprotection toward cell-based neurorestorative strategy, aiming to augment endogenous brain remodeling, which holds considerable promise for the treatment of TBI and stroke. Compelling evidence underscores that the therapeutic effects of cell-based therapy are mediated by the active generation and release of exosomes from administered cells. Exosomes, endosomal derived and nano-sized extracellular vesicles, play a pivotal role in intercellular communication. Thus, we may independently employ exosomes to treat stroke and TBI. Systemic administration of mesenchymal stem cell (MSC) derived exosomes promotes neuroplasticity and neurological functional recovery in preclinical animal models of TBI and stroke. In this mini review, we describe the properties of exosomes and recent exosome-based therapies of TBI and stroke. It is noteworthy that the microRNA cargo within exosomes contributes to their therapeutic effects. Thus, we provide a brief introduction to microRNAs and insight into their key roles in mediating therapeutic effects. With the increasing knowledge of exosomes, researchers have “engineered” exosome microRNA content to amplify their therapeutic benefits. We therefore focus our discussion on the therapeutic benefits of recently employed microRNA-enriched engineered exosomes. We also discuss the current opportunities and challenges in translating exosome-based therapy to clinical applications.

Traumatic brain injury (TBI) is a major cause of death and disability worldwide. There are no effective therapies available for TBI patients. Vepoloxamer is an amphiphilic polyethylene-polypropylene-polyethylene tri-block copolymer that seals membranes and restores plasma membrane integrity in damaged cells. We previously demonstrated that treatment of TBI rats with Vepoloxamer improves functional recovery. However, additional studies are needed to potentially translate Vepoloxamer treatment from preclinical studies into clinical applications. We thus conducted a study to investigate dose-response and therapeutic window of Vepoloxamer on functional recovery of adult rats after TBI. To identify the most effective dose of Vepoloxamer, male Wistar adult rats with controlled cortical impact (CCI) injury were randomly treated with 0 (vehicle), 100, 300, or 600 mg/kg of Vepoloxamer, administered intravenously (IV) at 2 h after TBI. We then performed a therapeutic window study in which the rats were treated IV with the most effective single dose of Vepoloxamer at different time points of 2 h, 4 h, 1 day, or 3 days after TBI. A battery of cognitive and neurological tests was performed. Animals were killed 35 days after TBI for histopathological analysis. Dose-response experiments showed that Vepoloxamer at all three tested doses (100, 300, 600 mg/kg) administered 2 h post injury significantly improved cognitive functional recovery, whereas Vepoloxamer at doses of 300 and 600 mg/kg, but not the 100 mg/kg dose, significantly reduced lesion volume compared to saline treatment. However, Vepoloxamer at 300 mg/kg showed significantly improved neurological and cognitive outcomes than treatment with a dose of 600 mg/kg. In addition, our data demonstrated that the dose of 300 mg/kg of Vepoloxamer administered at 2 h, 4 h, 1 day, or 3 days post injury significantly improved neurological function compared with vehicle, whereas Vepoloxamer administered at 2 h or 4 h post injury significantly improved cognitive function compared with the 1-day and 3-day treatments, with the most robust effect administered at 2 h post injury. The present study demonstrated that Vepoloxamer improves functional recovery in a dose-and time-dependent manner, with therapeutic efficacy compared with vehicle evident even when the treatment is initiated 3 days post TBI in the rat.