More than 6.5 million patients are burdened by the physical, cognitive, and psychosocial deficits associated with traumatic brain injury (TBI) in the U.S. Despite extensive efforts to develop neuroprotective therapies for this devastating disorder, there have been no successful outcomes in human clinical trials to date. Retrospective studies have shown that b-adrenergic receptor blockers, specifically propranolol, significantly decrease mortality of TBI through mechanisms not yet fully elucidated but are thought to counterbalance a hyperadrenergic state resulting from a TBI. Conversely, cellular therapies have been shown to improve long-term behavior following TBI, likely by reducing inflammation. Given the nonredundancy in their therapeutic mechanisms, we hypothesized that a combination of acute propranolol followed by mesenchymal stem cells (MSCs) isolated from human bone marrow would have additive effects in treating a rodent model of TBI. We have found that the treatments are well-tolerated individually and in combination with no adverse events. MSCs decrease BBB permeability at 96 hours after injury, inhibit a significant accumulation of activated microglia/ macrophage in the thalamic region of the brain both short and long term, and enhance neurogenesis short term. Propranolol decreases edema and reduces the number of fully activated microglia at 7 days and the number of semiactivated microglia at 120 days. Combinatory treatment improved cognitive and memory functions 120 days following TBI. Therefore, the results here suggest a new, efficacious sequential treatment for TBI may be achieved using the b-blocker propranolol followed by MSC treatment. STEM CELLS TRANSLATIONAL MEDICINE 2016;5:33-44 SIGNIFICANCEDespite continuous efforts, traumatic brain injury (TBI) remains the leading cause of death and disability worldwide in patients under the age of 44. In this study, an animal model of moderatesevere TBI was treated with an acute dose of propranolol followed by a delayed dose of human mesenchymal stem cells (MSCs), resulting in improved short-and long-term measurements. These results have direct translational application. They reinforce the inevitable clinical trial of MSCs to treat TBI by demonstrating, among other benefits, a notable decrease in chronic neuroinflammation. More importantly, these results demonstrate that MSCs and propranolol, which is increasingly being used clinically for TBI, are compatible treatments that improve overall outcome.

Spinal cord injury causes neuronal death, limiting subsequent regeneration and recovery. Thus, there is a need to develop strategies for improving neuronal survival after injury. Relative to our understanding of axon regeneration, comparatively little is known about the mechanisms that promote the survival of damaged neurons. To address this, we took advantage of lamprey giant reticulospinal neurons whose large size permits detailed examination of post-injury molecular responses at the level of individual, identified cells. We report here that spinal cord injury caused a select subset of giant reticulospinal neurons to accumulate synuclein, a synaptic vesicle-associated protein best known for its atypical aggregation and causal role in neurodegeneration in Parkinson’s and other diseases. Post-injury synuclein accumulation took the form of punctate aggregates throughout the somata and occurred selectively in dying neurons, but not in those that survived. In contrast, another synaptic vesicle protein, synaptotagmin, did not accumulate in response to injury. We further show that the post-injury synuclein accumulation was greatly attenuated after single dose application of either the “molecular tweezer” inhibitor, CLR01, or a translation-blocking synuclein morpholino. Consequently, reduction of synuclein accumulation not only improved neuronal survival, but also increased the number of axons in the spinal cord proximal and distal to the lesion. This study is the first to reveal that reducing synuclein accumulation is a novel strategy for improving neuronal survival after spinal cord injury.

Patients with orbital compartment syndrome may see visual recovery after lateral canthotomy and cantholysis, even if performed outside of the previously accepted 3-hour window. Purpose: Evaluate visual outcomes in relation to time from injury to intervention in patients who undergo lateral canthotomy with cantholysis (LCC) for retrobulbar hemorrhage (RBH). Methods: Retrospective study of patients with orbital compartment syndrome (OCS) secondary to RBH who underwent LCC. OCS due to RBH was defined by a combination of decreased vision, proptosis, resistance to retropulsion, increased intraocular pressure, and relative afferent pupillary defect. Time from injury to intervention and change in visual acuity were calculated, with regression analysis identifying predictors of vision recovery. Results: Fifteen participants were included. Three (20%) participants presented with no light perception, 7 (47%) with count fingers (CF) to light perception, and 5 (33%) with better than count fingers vision. All 5 participants who had LCC within 3 hours (twice the standard 90 minutes) gained some vision, and 6 of 10 participants who had LCC after 3 hours recovered some vision. The latest intervention with visual acuity improvement was performed 9 hours postinjury. Of 3 participants who presented with no light perception vision, 1 regained vision to 20/40 (intervention 1.7 hours postinjury), and 2 did not regain any vision (interventions at 5 and 8.7 hours postinjury). Duration from injury to intervention was associated with decreased amount of vision recovery (P = 0.03). Conclusions: Increased time to intervention with LCC was associated with less vision recovery after OCS from RBH. However, over half of participants with intervention more than 90 minutes after injury still showed visual acuity improvement. The authors recommend LCC in all patients who present with OCS regardless of the time since injury.