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Blood vessels in the CNS form a specialized and critical structure, the blood–brain barrier (BBB). We present a resource to understand the molecular mechanisms that regulate BBB function in health and dysfunction during disease. Using endothelial cell enrichment and RNA sequencing, we analyzed the gene expression of endothelial cells in mice, comparing brain endothelial cells with peripheral endothelial cells. We also assessed the regulation of CNS endothelial gene expression in models of stroke, multiple sclerosis, traumatic brain injury and seizure, each having profound BBB disruption. We found that although each is caused by a distinct trigger, they exhibit strikingly similar endothelial gene expression changes during BBB disruption, comprising a core BBB dysfunction module that shifts the CNS endothelial cells into a peripheral endothelial cell-like state. The identification of a common pathway for BBB dysfunction suggests that targeting therapeutic agents to limit it may be effective across multiple neurological disorders.

Despite the large number of promising neuroprotective agents identified in experimental traumatic brain injury (TBI) studies, none has yet shown meaningful improvements in long-term outcome in clinical trials. To develop recommendations and guidelines for pre-clinical testing of pharmacological or biological therapies for TBI, the Moody Project for Translational Traumatic Brain Injury Research hosted a symposium attended by investigators with extensive experience in pre-clinical TBI testing. The symposium participants discussed issues related to pre-clinical TBI testing including experimental models, therapy and outcome selection, study design, data analysis, and dissemination. Consensus recommendations included the creation of a manual of standard operating procedures with sufficiently detailed descriptions of modeling and outcome measurement procedures to permit replication. The importance of the selection of clinically relevant outcome variables, especially related to behavior testing, was noted. Considering the heterogeneous nature of human TBI, evidence of therapeutic efficacy in multiple, diverse (e.g., diffuse vs. focused) rodent models and a species with a gyrencephalic brain prior to clinical testing was encouraged. Basing drug doses, times, and routes of administration on pharmacokinetic and pharmacodynamic data in the test species was recommended. Symposium participants agreed that the publication of negative results would reduce costly and unnecessary duplication of unsuccessful experiments. Although some of the recommendations are more relevant to multi-center, multi-investigator collaborations, most are applicable to pre-clinical therapy testing in general. The goal of these consensus guidelines is to increase the likelihood that therapies that improve outcomes in pre-clinical studies will also improve outcomes in TBI patients.

Mild traumatic brain injuries can lead to long-lasting cognitive and motor deficits, increasing the risk of future behavioral, neurological, and affective disorders. Our study focused on long-term behavioral deficits after repeated injury in which mice received either a single mild CHI (mCHI), a repeated mild CHI (rmCHI) consisting of one impact to each hemisphere separated by 3 days, or a moderate controlled cortical impact injury (CCI). Shams received only anesthesia. Behavioral tests were administered at 1, 3, 5, 7, and 90 days post-injury (dpi). CCI animals showed significant motor and sensory deficits in the early (1-7 dpi) and long-term (90 dpi) stages of testing. Interestingly, sensory and subtle motor deficits in rmCHI animals were found at 90 dpi. Most importantly, depression-like behaviors and social passiveness were observed in rmCHI animals at 90 dpi. These data suggest that mild concussive injuries lead to motor and sensory deficits and affective disorders that are not observed after moderate TBI.

Strategies that block infiltration of leukocytes into the injured spinal cord improve sparing of white matter and neurological recovery. In this article, we examine the dependency of recovery on hematogenous depletion of neutrophils and monocytes. Mice were depleted of neutrophils or monocytes by systemic administration of anti-Ly6G or clodronate-liposomes. A third group was depleted of both subsets. Neurological improvement, based on a battery of tests of performance, and white matter sparing, occurred only in animals depleted of both neutrophils and monocytes. We also attempted to define the nature of the environment that was favorable to recovery. Hemeoxygenase-1 and malondialdehyde, markers of oxidative stress and lipid peroxidation, respectively, were reduced to similar levels in animals depleted of both neutrophils and monocytes, or only monocytes, but remained elevated in the group only depleted of neutrophils. Matrix metalloproteinase-9, a protease involved in early damage, was most strongly reduced in animals depleted of both leukocyte subsets. Finally, disruption of the blood–spinal cord barrier and abnormal nonheme iron accumulation were reduced only in animals depleted of both neutrophils and monocytes. Together, these findings indicate cooperation between neutrophils and monocytes in mediating early pathogenesis in the contused spinal cord and defining long-term neurological recovery.

Traumatic spinal cord injury results in the disruption of neural and vascular structures (primary injury) and is characterized by an evolution of secondary pathogenic events that collectively define the extent of functional recovery. This article reviews the vascular responses to spinal cord injury, focusing on both early and delayed events, including intraparenchymal hemorrhage, inflammation, disruption of the blood-spinal cord barrier, and angiogenesis. These vascular-related events not only influence the evolution of secondary tissue damage but also define an environment that fosters neural plasticity in the chronically injured spinal cord.

Thrombin-induced secondary injury is mediated through its receptor, protease activated receptor-1 (PAR-1), by \"biased agonism.\" Activated protein C (APC) acts through the same PAR-1 receptor but functions as an anti-coagulant and anti-inflammatory protein, which counteracts many of the effects of thrombin. Although the working mechanism of PAR-1 is becoming clear, the functional role of PAR-1 and its correlation with APC in the injured spinal cord remains to be elucidated. Here we investigated if PAR-1 and APC are determinants of long-term functional recovery after a spinal cord contusive injury using PAR-1 null and wild-type mice. We found that neutrophil infiltration and disruption of the blood-spinal cord barrier were significantly reduced in spinal cord injured PAR-1 null mice relative to the wild-type group. Both locomotor recovery and ability to descend an inclined grid were significantly improved in the PAR-1 null group 42 days after injury and this improvement was associated with greater long-term sparing of white matter and a reduction in glial scarring. Wild-type mice treated with APC acutely after injury showed a similar level of improved locomotor recovery to that of PAR-1 null mice. However, improvement of APC-treated PAR-1 null mice was indistinguishable from that of vehicle-treated PAR-1 null mice, suggesting that APC acts through PAR-1. Collectively, our findings define a detrimental role of thrombin-activated PAR-1 in wound healing and further validate APC, also acting through the PAR-1 by biased agonism, as a promising therapeutic target for spinal cord injury.

Deficiencies in methods reporting in animal experimentation lead to difficulties in reproducing experiments; the authors propose a set of reporting standards to improve scientific communication and study design. Making the most of animal studies Animal studies have contributed immensely to our understanding of diseases and assist the development of new therapies, but inadequate experimental reporting can sometimes render such studies difficult to reproduce and to translate into the clinic. This year, a US National Institute of Neurological Disorders and Stroke workshop addressed this issue, and its conclusions are discussed in a Perspective piece in this issue of Nature . The main workshop recommendation is that at a minimum, studies should report on randomization, blinding, sample-size estimation and how the data were handled. The US National Institute of Neurological Disorders and Stroke convened major stakeholders in June 2012 to discuss how to improve the methodological reporting of animal studies in grant applications and publications. The main workshop recommendation is that at a minimum studies should report on sample-size estimation, whether and how animals were randomized, whether investigators were blind to the treatment, and the handling of data. We recognize that achieving a meaningful improvement in the quality of reporting will require a concerted effort by investigators, reviewers, funding agencies and journal editors. Requiring better reporting of animal studies will raise awareness of the importance of rigorous study design to accelerate scientific progress.

This review considers the pathobiology of non-impact blast-induced neurotrauma (BINT). The pathobiology of traumatic brain injury (TBI) has been historically studied in experimental models mimicking features seen in the civilian population. These brain injuries are characterized by primary damage to both gray and white matter and subsequent evolution of secondary pathogenic events at the cellular, biochemical, and molecular levels, which collectively mediate widespread neurodegeneration. An emerging field of research addresses brain injuries related to the military, in particular blast-induced brain injuries. What is clear from the effort to date is that the pathobiology of military TBIs, particularly BINT, has characteristics not seen in other types of brain injury, despite similar secondary injury cascades. The pathobiology of primary BINT is extremely complex. It comprises systemic, local, and cerebral responses interacting and often occurring in parallel. Activation of the autonomous nervous system, sudden pressure-increase in vital organs such as lungs and liver, and activation of neuroendocrine-immune system are among the most important mechanisms significantly contributing to molecular changes and cascading injury mechanisms in the brain.

Spinal cord injury (SCI) damages neural circuits and triggers pro-inflammatory responses, resulting in locomotor impairment. The carbohydrate sulfotransferases GlcNAc6ST1 and GlcNAc6ST4 modulate the function of blood monocytes and microglia. However, their specific roles and enzymatic relationships in neuroinflammation and functional recovery after SCI remain unclear. In this study, we demonstrate that mice deficient in both GlcNAc6ST1 and GlcNAc6ST4 (DKO) exhibit improved locomotor recovery compared with mice with a single deficiency. DKO mice exhibit reduced levels of monocytes and activated macrophages/microglia at the injury site alongside increased serotonergic neural fibers, indicating enhanced neural plasticity. RNA sequencing reveals down-regulation of collagen I genes and up-regulation of genes encoding synaptic membrane components in the injured DKO spinal cord. In addition, GALAXY glycomic analysis shows an absence of GlcNAc-6-sulfated N -glycans in the DKO spinal cord. These results suggest that GlcNAc6ST1 and GlcNAc6ST4 play complementary roles in promoting detrimental inflammatory responses post-SCI. Targeting these sulfotransferases could offer a novel therapeutic strategy to improve locomotor recovery after SCI.

Matrix metalloproteinase-9 is elevated within the acutely injured murine spinal cord and blockade of this early proteolytic activity with GM6001, a broad-spectrum matrix metalloproteinase inhibitor, results in improved recovery after spinal cord injury. As matrix metalloproteinase-9 is likewise acutely elevated in dogs with naturally occurring spinal cord injuries, we evaluated efficacy of GM6001 solubilized in dimethyl sulfoxide in this second species. Safety and pharmacokinetic studies were conducted in naïve dogs. After confirming safety, subsequent pharmacokinetic analyses demonstrated that a 100 mg/kg subcutaneous dose of GM6001 resulted in plasma concentrations that peaked shortly after administration and were sustained for at least 4 days at levels that produced robust in vitro inhibition of matrix metalloproteinase-9. A randomized, blinded, placebo-controlled study was then conducted to assess efficacy of GM6001 given within 48 hours of spinal cord injury. Dogs were enrolled in 3 groups: GM6001 dissolved in dimethyl sulfoxide (n = 35), dimethyl sulfoxide (n = 37), or saline (n = 41). Matrix metalloproteinase activity was increased in the serum of injured dogs and GM6001 reduced this serum protease activity compared to the other two groups. To assess recovery, dogs were a priori stratified into a severely injured group and a mild-to-moderate injured group, using a Modified Frankel Scale. The Texas Spinal Cord Injury Score was then used to assess long-term motor/sensory function. In dogs with severe spinal cord injuries, those treated with saline had a mean motor score of 2 (95% CI 0-4.0) that was significantly (P<0.05; generalized linear model) less than the estimated mean motor score for dogs receiving dimethyl sulfoxide (mean, 5; 95% CI 2.0-8.0) or GM6001 (mean, 5; 95% CI 2.0-8.0). As there was no independent effect of GM6001, we attribute improved neurological outcomes to dimethyl sulfoxide, a pleotropic agent that may target diverse secondary pathogenic events that emerge in the acutely injured cord.