Linda Noble-haeusslein | University of California, San Francisco (original) (raw)

Papers by Linda Noble-haeusslein

Journal of Neurotrauma, 2004

Heme oxygenase-1 (HO-1) has been shown to alter vascular function in part by attenuating inflamma... more Heme oxygenase-1 (HO-1) has been shown to alter vascular function in part by attenuating inflammation. We induced HO-1 in blood vessels in the spinal cord by systemic administration of hemin. Twenty-four hours later, immediately prior to euthanasia, fluorescence conjugated Lycopersicon esculentum (tomato) lectin was given intravenously to label the vasculature. HO-1 was induced in blood vessels, particularly in the white matter, as evidenced by the immunolocalization of HO-1 in lectin positive vessels. Western blots confirmed the hemin-mediated induction of HO-1 in the uninjured spinal cord. We next examined the extent to which treatment with hemin or vehicle, 24 h prior to a moderate contusion injury, influenced early vascular dysfunction in the injured cord. All animals were euthanized 24 h after injury. Luciferase, a marker of barrier integrity, was given intravenously 30 min prior to euthanasia. The spinal cord was either prepared for quantification of luciferase activity or fixed by vascular perfusion and prepared for the immunolocalization of neutrophils. There was a significant attenuation of barrier permeability to luciferase and a significant reduction in the number of neutrophils in hemin treated animals as compared to the vehicle treated group. Together, these findings demonstrate that vascular induction of HO-1 modulates barrier function and neutrophil infiltration and suggest that this protein may be useful for limiting the early vascular dysfunction and inflammation that occurs in the acutely injured spinal cord.

Frontiers in Neurology, 2015

Sports-related concussions are particularly common during adolescence, a time when even mild brai... more Sports-related concussions are particularly common during adolescence, a time when even mild brain injuries may disrupt ongoing brain maturation and result in long-term complications. A recent focus on the consequences of repetitive concussions among professional athletes has prompted the development of several new experimental models in rodents, as well as the revision of guidelines for best management of sports concussions. Here, we consider the utility of rodent models to understand the functional consequences and pathobiology of concussions in the developing brain, identifying the unique behavioral and pathological signatures of concussive brain injuries. The impact of repetitive concussions on behavioral consequences and injury progression is also addressed. In particular, we focus on the epidemiological, clinical, and experimental evidence underlying current recommendations for physical and cognitive rest after concussion, and highlight key areas in which further research is needed. Lastly, we consider how best to promote recovery after injury, recognizing that optimally timed, activity-based rehabilitative strategies may hold promise for the adolescent athlete who has sustained single or repetitive concussions. The purpose of this review is to inform the clinical research community as it strives to develop and optimize evidence-based guidelines for the concussed adolescent, in terms of both acute and long-term management.

Journal of neurotrauma, Jan 21, 2015

Traumatic brain injury (TBI) is a major public health issue exacting a substantial personal and e... more Traumatic brain injury (TBI) is a major public health issue exacting a substantial personal and economic burden globally. With the advent of "big data" approaches to understanding complex systems, there is the potential to greatly accelerate knowledge about mechanisms of injury, and how to detect and modify them to improve patient outcomes. High quality, well-defined data are critical to the success of bioinformatics platforms and a data dictionary of "common data elements" (CDEs), as well as…

Annals of Neurology, 1989

Combined phosphorus and proton magnetic resonance spectroscopy (MRS), using double-tuned surface ... more Combined phosphorus and proton magnetic resonance spectroscopy (MRS), using double-tuned surface coils, was used to monitor certain metabolic changes in the L-3 spinal segment of anesthetized rabbits prior to and following experimental spinal cord trauma. Following severe trauma, resulting in spastic paraplegia, there was a delayed and progressive accumulation of lactic acid, a decline in intracellular pH, and a loss of high-energy phosphates. Maximal alterations occurred between 2 and 3 hours after the trauma, with little further change by 4 hours. Histological examination 2 weeks after trauma showed tissue necrosis and cavitation. These findings support the concept of secondary tissue injury after spinal cord trauma and suggest that early changes in metabolism, as shown by MRS, may predict irreversible tissue damage. Vink R, Noble LJ, Knoblach SM, Bendall MR, Faden AI. Metabolic changes in rabbit spinal cord after trauma: magnetic resonance spectroscopy studies. Ann Neurol 1989;25:26-3 1

Clinical Neuroscience Research, 2006

The immune response that accompanies spinal cord injury contributes to both injury and reparative... more The immune response that accompanies spinal cord injury contributes to both injury and reparative processes. It is this duality that is the focus of this review. Here, we consider the complex cellular and molecular immune responses that lead to the infiltration of leukocytes and glial activation, promote oxidative stress and tissue damage, influence wound healing, and subsequently modulate locomotor recovery. Immunomodulatory strategies to improve outcomes are gaining momentum as ongoing research carefully dissects those pathways which likely mediate cell injury from those which favor recovery processes. Current therapeutic strategies address divergent approaches including early immunoblockade and vaccination with immune cells to prevent early tissue damage and support a wound-healing environment that favors plasticity. Despite these advances, there remain basic questions regarding how inflammatory cells interact in the injured spinal cord. Such questions likely arise as a result of our limited understanding of immune cell/neural interactions in a dynamic environment that culminates in progressive cell injury, demyelination, and regenerative failure.

MP1-12 A MURINE MODEL OF SPINAL CORD INJURY: EFFECT OF THE GENERAL MATRIX METALLOPROTEINASE INHIBITOR GM6001 ON LONG-TERM LOCOMOTOR AND BLADDER FUNCTION

The Journal of Urology, 2014

Annals of Neurology, 2009

Objective-Mice subjected to traumatic brain injury (TBI) at postnatal day (pnd) 21 show emerging ... more Objective-Mice subjected to traumatic brain injury (TBI) at postnatal day (pnd) 21 show emerging cognitive deficits that coincide with hippocampal neuronal loss. Here we consider glutathione peroxidase (GPx) activity as a determinant of recovery in the injured immature brain.

Neutrophil elastase mediates acute pathogenesis and is a determinant of long-term behavioral recovery after traumatic injury to the immature brain

Neurobiology of Disease, 2015

While neutrophil elastase (NE), released by activated neutrophils, is a key mediator of secondary... more While neutrophil elastase (NE), released by activated neutrophils, is a key mediator of secondary pathogenesis in adult models of brain ischemia and spinal cord injury, no studies to date have examined this protease in the context of the injured immature brain, where there is notable vulnerability resulting from inadequate antioxidant reserves and prolonged exposure to infiltrating neutrophils. We thus reasoned that NE may be a key determinant of secondary pathogenesis, and as such, adversely influence long-term neurological recovery. To address this hypothesis, wild-type (WT) and NE knockout (KO) mice were subjected to a controlled cortical impact at post-natal day 21, approximating a toddler-aged child. To determine if NE is required for neutrophil infiltration into the injured brain, and whether this protease contributes to vasogenic edema, we quantified neutrophil numbers and measured water content in the brains of each of these genotypes. While leukocyte trafficking was indistinguishable between genotypes, vasogenic edema was markedly attenuated in the NE KO. To determine if early pathogenesis is dependent on NE, indices of cell death (TUNEL and activated caspase-3) were quantified across genotypes. NE KO mice showed a reduction in these markers of cell death in the injured hippocampus, which corresponded to greater preservation of neuronal integrity as well as reduced expression of heme oxygenase-1, a marker of oxidative stress. WT mice, treated with a competitive inhibitor of NE at 2, 6 and 12h post-injury, likewise showed a reduction in cell death and oxidative stress compared to vehicle-treated controls. We next examined the long-term behavioral and structural consequences of NE deficiency. NE KO mice showed an improvement in long-term spatial memory retention and amelioration of injury-induced hyperactivity. However, volumetric and stereological analyses found comparable tissue loss in the injured cortex and hippocampus independent of genotype. Further, WT mice treated acutely with the NE inhibitor showed no long-term behavioral or structural improvements. Together, these findings validate the central role of NE in both acute pathogenesis and chronic functional recovery, and support future exploration of the therapeutic window, taking into account the prolonged period of neutrophil trafficking into the injured immature brain.

Neutrophils as Determinants of Vascular Stability in the Injured Spinal Cord

Vascular Mechanisms in CNS Trauma, 2013

Developmental Neuroscience, 2006

The immature brain may be particularly vulnerable to injury during critical periods of developmen... more The immature brain may be particularly vulnerable to injury during critical periods of development. To address the biologic basis for this vulnerability, mice were subjected to traumatic brain injury at postnatal day 21, a time point that approximates that of the toddler-aged child. After motor and cognitive testing at either 2 weeks (juveniles) or 3 months (adults) after injury, animals were euthanized and the brains prepared for quantitative histologic assessment. Brain-injured mice exhibited hyperactivity and age-dependent anxiolysis. Cortical lesion volume and subcortical neuronal loss were greater in brain-injured adults than in juveniles. Importantly, cognitive decline was delayed in onset and coincided with loss of neurons in the hippocampus. Our findings demonstrate that trauma to the developing brain results in a prolonged period of pathogenesis in both cortical and subcortical structures. Behavioral changes are a likely consequence of regional-specific neuronal degeneration.

Frontiers in Neurology, 2015

Sports-related concussions are particularly common during adolescence, a time when even mild brai... more Sports-related concussions are particularly common during adolescence, a time when even mild brain injuries may disrupt ongoing brain maturation and result in long-term complications. A recent focus on the consequences of repetitive concussions among professional athletes has prompted the development of several new experimental models in rodents, as well as the revision of guidelines for best management of sports concussions. Here, we consider the utility of rodent models to understand the functional consequences and pathobiology of concussions in the developing brain, identifying the unique behavioral and pathological signatures of concussive brain injuries. The impact of repetitive concussions on behavioral consequences and injury progression is also addressed. In particular, we focus on the epidemiological, clinical, and experimental evidence underlying current recommendations for physical and cognitive rest after concussion, and highlight key areas in which further research is needed. Lastly, we consider how best to promote recovery after injury, recognizing that optimally timed, activity-based rehabilitative strategies may hold promise for the adolescent athlete who has sustained single or repetitive concussions. The purpose of this review is to inform the clinical research community as it strives to develop and optimize evidence-based guidelines for the concussed adolescent, in terms of both acute and long-term management.

The Journal of neuroscience : the official journal of the Society for Neuroscience, 2003

After traumatic brain injury (TBI), substantial extracellular heme is released from hemoproteins ... more After traumatic brain injury (TBI), substantial extracellular heme is released from hemoproteins during hemorrhage and cell injury. Heme oxygenase (HO) isozymes are thought to detoxify the pro-oxidant heme to the potent antioxidant, bilirubin. HO-1, the inducible isozyme, is expressed in glial populations after injury and may play a protective role. However, the role of HO-2, the predominant and constitutively expressed isozyme in the brain, remains unclear after TBI. We used a controlled cortical impact injury model to determine the extent and mechanism of damage between HO-2 knock-out (KO) (-/-) and wild-type (WT) (+/+) mice. The specific cellular and temporal expressions of HO-2 and HO-1 were characterized by immunocytochemistry and Western blots. HO-2 was immunolocalized in neurons both before and after TBI, whereas HO-1 was highly upregulated in glia only after TBI. HO activity determined by gas chromatography using brain sonicates from injured HO-2 KO mice was significantly le...

Found in translation: Understanding the biology and behavior of experimental traumatic brain injury

Neuroscience & Biobehavioral Reviews, 2014

The aim of this review is to discuss in greater detail the topics covered in the recent symposium... more The aim of this review is to discuss in greater detail the topics covered in the recent symposium entitled "Traumatic brain injury: laboratory and clinical perspectives," presented at the 2014 International Behavioral Neuroscience Society annual meeting. Herein, we review contemporary laboratory models of traumatic brain injury (TBI) including common assays for sensorimotor and cognitive behavior. New modalities to evaluate social behavior after injury to the developing brain, as well as the attentional set-shifting test (AST) as a measure of executive function in TBI, will be highlighted. Environmental enrichment (EE) will be discussed as a preclinical model of neurorehabilitation, and finally, an evidence-based approach to sports-related concussion will be considered. The review consists predominantly of published data, but some discussion of ongoing or future directions is provided.

Sociosexual and communication deficits after traumatic injury to the developing murine brain

PloS one, 2014

Despite the life-long implications of social and communication dysfunction after pediatric trauma... more Despite the life-long implications of social and communication dysfunction after pediatric traumatic brain injury, there is a poor understanding of these deficits in terms of their developmental trajectory and underlying mechanisms. In a well-characterized murine model of pediatric brain injury, we recently demonstrated that pronounced deficits in social interactions emerge across maturation to adulthood after injury at postnatal day (p) 21, approximating a toddler-aged child. Extending these findings, we here hypothesized that these social deficits are dependent upon brain maturation at the time of injury, and coincide with abnormal sociosexual behaviors and communication. Age-dependent vulnerability of the developing brain to social deficits was addressed by comparing behavioral and neuroanatomical outcomes in mice injured at either a pediatric age (p21) or during adolescence (p35). Sociosexual behaviors including social investigation and mounting were evaluated in a resident-intr...

The Neuroscientist, 2010

Matrix metalloproteinases (MMPs) are involved in a wide range of proteolytic events in fetal deve... more Matrix metalloproteinases (MMPs) are involved in a wide range of proteolytic events in fetal development and normal tissue remodeling as well as wound healing and inflammation. In the CNS, they have been implicated in a variety of neurodegenerative diseases ranging from multiple sclerosis to Alzheimer disease and are integral to stroke-related cell damage. Although studies implicate increased activity of MMPs in pathogenesis in the CNS, there is also a growing literature to support their participation in events that support recovery processes. Here the authors provide a brief overview of MMPs and their regulation, address their complex roles following traumatic injuries to the adult and developing CNS, and consider their time-and contextdependent signatures that influence both injury and reparative processes.

Matrix Metalloproteinase-9 Facilitates Glial Scar Formation in the Injured Spinal Cord

Journal of Neuroscience, 2008

The Cerebellum, 2009

Traumatic brain injury (TBI) is a major cause of morbidity and mortality worldwide. Studies of hu... more Traumatic brain injury (TBI) is a major cause of morbidity and mortality worldwide. Studies of human TBI demonstrate that the cerebellum is sometimes affected even when the initial mechanical insult is directed to the cerebral cortex. Some of the components of TBI, including ataxia, postural instability, tremor, impairments in balance and fine motor skills, and even cognitive deficits, may be attributed in part to cerebellar damage. Animal models of TBI have begun to explore the vulnerability of the cerebellum. In this paper, we review the clinical presentation, pathogenesis, and putative mechanisms underlying cerebellar damage with an emphasis on experimental models that have been used to further elucidate this poorly understood but important aspect of TBI. Animal models of indirect (supratentorial) trauma to the cerebellum, including fluid percussion, controlled cortical impact, weight drop impact acceleration, and rotational acceleration injuries, are considered. In addition, we describe models that produce direct trauma to the cerebellum as well as those that reproduce specific components of TBI including axotomy, stab injury, in vitro stretch injury, and excitotoxicity. Overall, these models reveal robust characteristics of cerebellar damage including regionally specific Purkinje cell injury or loss, activation of glia in a distinct spatial pattern, and traumatic axonal injury. Further research is needed to better understand the mechanisms underlying the pathogenesis of cerebellar trauma, and the experimental models discussed here offer an important first step toward achieving that objective.

Progress in Neurobiology, 2013

PLoS ONE, 2014

Matrix metalloproteinase-9 is elevated within the acutely injured murine spinal cord and blockade... more 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. Citation: Levine JM, Cohen ND, Heller M, Fajt VR, Levine GJ, et al. (2014) Efficacy of a Metalloproteinase Inhibitor in Spinal Cord Injured Dogs. PLoS ONE 9(5): e96408.

Journal of Neurotrauma, 2004

Heme oxygenase-1 (HO-1) has been shown to alter vascular function in part by attenuating inflamma... more Heme oxygenase-1 (HO-1) has been shown to alter vascular function in part by attenuating inflammation. We induced HO-1 in blood vessels in the spinal cord by systemic administration of hemin. Twenty-four hours later, immediately prior to euthanasia, fluorescence conjugated Lycopersicon esculentum (tomato) lectin was given intravenously to label the vasculature. HO-1 was induced in blood vessels, particularly in the white matter, as evidenced by the immunolocalization of HO-1 in lectin positive vessels. Western blots confirmed the hemin-mediated induction of HO-1 in the uninjured spinal cord. We next examined the extent to which treatment with hemin or vehicle, 24 h prior to a moderate contusion injury, influenced early vascular dysfunction in the injured cord. All animals were euthanized 24 h after injury. Luciferase, a marker of barrier integrity, was given intravenously 30 min prior to euthanasia. The spinal cord was either prepared for quantification of luciferase activity or fixed by vascular perfusion and prepared for the immunolocalization of neutrophils. There was a significant attenuation of barrier permeability to luciferase and a significant reduction in the number of neutrophils in hemin treated animals as compared to the vehicle treated group. Together, these findings demonstrate that vascular induction of HO-1 modulates barrier function and neutrophil infiltration and suggest that this protein may be useful for limiting the early vascular dysfunction and inflammation that occurs in the acutely injured spinal cord.

Frontiers in Neurology, 2015

Sports-related concussions are particularly common during adolescence, a time when even mild brai... more Sports-related concussions are particularly common during adolescence, a time when even mild brain injuries may disrupt ongoing brain maturation and result in long-term complications. A recent focus on the consequences of repetitive concussions among professional athletes has prompted the development of several new experimental models in rodents, as well as the revision of guidelines for best management of sports concussions. Here, we consider the utility of rodent models to understand the functional consequences and pathobiology of concussions in the developing brain, identifying the unique behavioral and pathological signatures of concussive brain injuries. The impact of repetitive concussions on behavioral consequences and injury progression is also addressed. In particular, we focus on the epidemiological, clinical, and experimental evidence underlying current recommendations for physical and cognitive rest after concussion, and highlight key areas in which further research is needed. Lastly, we consider how best to promote recovery after injury, recognizing that optimally timed, activity-based rehabilitative strategies may hold promise for the adolescent athlete who has sustained single or repetitive concussions. The purpose of this review is to inform the clinical research community as it strives to develop and optimize evidence-based guidelines for the concussed adolescent, in terms of both acute and long-term management.

Journal of neurotrauma, Jan 21, 2015

Traumatic brain injury (TBI) is a major public health issue exacting a substantial personal and e... more Traumatic brain injury (TBI) is a major public health issue exacting a substantial personal and economic burden globally. With the advent of "big data" approaches to understanding complex systems, there is the potential to greatly accelerate knowledge about mechanisms of injury, and how to detect and modify them to improve patient outcomes. High quality, well-defined data are critical to the success of bioinformatics platforms and a data dictionary of "common data elements" (CDEs), as well as…

Annals of Neurology, 1989

Combined phosphorus and proton magnetic resonance spectroscopy (MRS), using double-tuned surface ... more Combined phosphorus and proton magnetic resonance spectroscopy (MRS), using double-tuned surface coils, was used to monitor certain metabolic changes in the L-3 spinal segment of anesthetized rabbits prior to and following experimental spinal cord trauma. Following severe trauma, resulting in spastic paraplegia, there was a delayed and progressive accumulation of lactic acid, a decline in intracellular pH, and a loss of high-energy phosphates. Maximal alterations occurred between 2 and 3 hours after the trauma, with little further change by 4 hours. Histological examination 2 weeks after trauma showed tissue necrosis and cavitation. These findings support the concept of secondary tissue injury after spinal cord trauma and suggest that early changes in metabolism, as shown by MRS, may predict irreversible tissue damage. Vink R, Noble LJ, Knoblach SM, Bendall MR, Faden AI. Metabolic changes in rabbit spinal cord after trauma: magnetic resonance spectroscopy studies. Ann Neurol 1989;25:26-3 1

Clinical Neuroscience Research, 2006

The immune response that accompanies spinal cord injury contributes to both injury and reparative... more The immune response that accompanies spinal cord injury contributes to both injury and reparative processes. It is this duality that is the focus of this review. Here, we consider the complex cellular and molecular immune responses that lead to the infiltration of leukocytes and glial activation, promote oxidative stress and tissue damage, influence wound healing, and subsequently modulate locomotor recovery. Immunomodulatory strategies to improve outcomes are gaining momentum as ongoing research carefully dissects those pathways which likely mediate cell injury from those which favor recovery processes. Current therapeutic strategies address divergent approaches including early immunoblockade and vaccination with immune cells to prevent early tissue damage and support a wound-healing environment that favors plasticity. Despite these advances, there remain basic questions regarding how inflammatory cells interact in the injured spinal cord. Such questions likely arise as a result of our limited understanding of immune cell/neural interactions in a dynamic environment that culminates in progressive cell injury, demyelination, and regenerative failure.

MP1-12 A MURINE MODEL OF SPINAL CORD INJURY: EFFECT OF THE GENERAL MATRIX METALLOPROTEINASE INHIBITOR GM6001 ON LONG-TERM LOCOMOTOR AND BLADDER FUNCTION

The Journal of Urology, 2014

Annals of Neurology, 2009

Objective-Mice subjected to traumatic brain injury (TBI) at postnatal day (pnd) 21 show emerging ... more Objective-Mice subjected to traumatic brain injury (TBI) at postnatal day (pnd) 21 show emerging cognitive deficits that coincide with hippocampal neuronal loss. Here we consider glutathione peroxidase (GPx) activity as a determinant of recovery in the injured immature brain.

Neutrophil elastase mediates acute pathogenesis and is a determinant of long-term behavioral recovery after traumatic injury to the immature brain

Neurobiology of Disease, 2015

While neutrophil elastase (NE), released by activated neutrophils, is a key mediator of secondary... more While neutrophil elastase (NE), released by activated neutrophils, is a key mediator of secondary pathogenesis in adult models of brain ischemia and spinal cord injury, no studies to date have examined this protease in the context of the injured immature brain, where there is notable vulnerability resulting from inadequate antioxidant reserves and prolonged exposure to infiltrating neutrophils. We thus reasoned that NE may be a key determinant of secondary pathogenesis, and as such, adversely influence long-term neurological recovery. To address this hypothesis, wild-type (WT) and NE knockout (KO) mice were subjected to a controlled cortical impact at post-natal day 21, approximating a toddler-aged child. To determine if NE is required for neutrophil infiltration into the injured brain, and whether this protease contributes to vasogenic edema, we quantified neutrophil numbers and measured water content in the brains of each of these genotypes. While leukocyte trafficking was indistinguishable between genotypes, vasogenic edema was markedly attenuated in the NE KO. To determine if early pathogenesis is dependent on NE, indices of cell death (TUNEL and activated caspase-3) were quantified across genotypes. NE KO mice showed a reduction in these markers of cell death in the injured hippocampus, which corresponded to greater preservation of neuronal integrity as well as reduced expression of heme oxygenase-1, a marker of oxidative stress. WT mice, treated with a competitive inhibitor of NE at 2, 6 and 12h post-injury, likewise showed a reduction in cell death and oxidative stress compared to vehicle-treated controls. We next examined the long-term behavioral and structural consequences of NE deficiency. NE KO mice showed an improvement in long-term spatial memory retention and amelioration of injury-induced hyperactivity. However, volumetric and stereological analyses found comparable tissue loss in the injured cortex and hippocampus independent of genotype. Further, WT mice treated acutely with the NE inhibitor showed no long-term behavioral or structural improvements. Together, these findings validate the central role of NE in both acute pathogenesis and chronic functional recovery, and support future exploration of the therapeutic window, taking into account the prolonged period of neutrophil trafficking into the injured immature brain.

Neutrophils as Determinants of Vascular Stability in the Injured Spinal Cord

Vascular Mechanisms in CNS Trauma, 2013

Developmental Neuroscience, 2006

The immature brain may be particularly vulnerable to injury during critical periods of developmen... more The immature brain may be particularly vulnerable to injury during critical periods of development. To address the biologic basis for this vulnerability, mice were subjected to traumatic brain injury at postnatal day 21, a time point that approximates that of the toddler-aged child. After motor and cognitive testing at either 2 weeks (juveniles) or 3 months (adults) after injury, animals were euthanized and the brains prepared for quantitative histologic assessment. Brain-injured mice exhibited hyperactivity and age-dependent anxiolysis. Cortical lesion volume and subcortical neuronal loss were greater in brain-injured adults than in juveniles. Importantly, cognitive decline was delayed in onset and coincided with loss of neurons in the hippocampus. Our findings demonstrate that trauma to the developing brain results in a prolonged period of pathogenesis in both cortical and subcortical structures. Behavioral changes are a likely consequence of regional-specific neuronal degeneration.

Frontiers in Neurology, 2015

Sports-related concussions are particularly common during adolescence, a time when even mild brai... more Sports-related concussions are particularly common during adolescence, a time when even mild brain injuries may disrupt ongoing brain maturation and result in long-term complications. A recent focus on the consequences of repetitive concussions among professional athletes has prompted the development of several new experimental models in rodents, as well as the revision of guidelines for best management of sports concussions. Here, we consider the utility of rodent models to understand the functional consequences and pathobiology of concussions in the developing brain, identifying the unique behavioral and pathological signatures of concussive brain injuries. The impact of repetitive concussions on behavioral consequences and injury progression is also addressed. In particular, we focus on the epidemiological, clinical, and experimental evidence underlying current recommendations for physical and cognitive rest after concussion, and highlight key areas in which further research is needed. Lastly, we consider how best to promote recovery after injury, recognizing that optimally timed, activity-based rehabilitative strategies may hold promise for the adolescent athlete who has sustained single or repetitive concussions. The purpose of this review is to inform the clinical research community as it strives to develop and optimize evidence-based guidelines for the concussed adolescent, in terms of both acute and long-term management.

The Journal of neuroscience : the official journal of the Society for Neuroscience, 2003

After traumatic brain injury (TBI), substantial extracellular heme is released from hemoproteins ... more After traumatic brain injury (TBI), substantial extracellular heme is released from hemoproteins during hemorrhage and cell injury. Heme oxygenase (HO) isozymes are thought to detoxify the pro-oxidant heme to the potent antioxidant, bilirubin. HO-1, the inducible isozyme, is expressed in glial populations after injury and may play a protective role. However, the role of HO-2, the predominant and constitutively expressed isozyme in the brain, remains unclear after TBI. We used a controlled cortical impact injury model to determine the extent and mechanism of damage between HO-2 knock-out (KO) (-/-) and wild-type (WT) (+/+) mice. The specific cellular and temporal expressions of HO-2 and HO-1 were characterized by immunocytochemistry and Western blots. HO-2 was immunolocalized in neurons both before and after TBI, whereas HO-1 was highly upregulated in glia only after TBI. HO activity determined by gas chromatography using brain sonicates from injured HO-2 KO mice was significantly le...

Found in translation: Understanding the biology and behavior of experimental traumatic brain injury

Neuroscience & Biobehavioral Reviews, 2014

The aim of this review is to discuss in greater detail the topics covered in the recent symposium... more The aim of this review is to discuss in greater detail the topics covered in the recent symposium entitled "Traumatic brain injury: laboratory and clinical perspectives," presented at the 2014 International Behavioral Neuroscience Society annual meeting. Herein, we review contemporary laboratory models of traumatic brain injury (TBI) including common assays for sensorimotor and cognitive behavior. New modalities to evaluate social behavior after injury to the developing brain, as well as the attentional set-shifting test (AST) as a measure of executive function in TBI, will be highlighted. Environmental enrichment (EE) will be discussed as a preclinical model of neurorehabilitation, and finally, an evidence-based approach to sports-related concussion will be considered. The review consists predominantly of published data, but some discussion of ongoing or future directions is provided.

Sociosexual and communication deficits after traumatic injury to the developing murine brain

PloS one, 2014

Despite the life-long implications of social and communication dysfunction after pediatric trauma... more Despite the life-long implications of social and communication dysfunction after pediatric traumatic brain injury, there is a poor understanding of these deficits in terms of their developmental trajectory and underlying mechanisms. In a well-characterized murine model of pediatric brain injury, we recently demonstrated that pronounced deficits in social interactions emerge across maturation to adulthood after injury at postnatal day (p) 21, approximating a toddler-aged child. Extending these findings, we here hypothesized that these social deficits are dependent upon brain maturation at the time of injury, and coincide with abnormal sociosexual behaviors and communication. Age-dependent vulnerability of the developing brain to social deficits was addressed by comparing behavioral and neuroanatomical outcomes in mice injured at either a pediatric age (p21) or during adolescence (p35). Sociosexual behaviors including social investigation and mounting were evaluated in a resident-intr...

The Neuroscientist, 2010

Matrix metalloproteinases (MMPs) are involved in a wide range of proteolytic events in fetal deve... more Matrix metalloproteinases (MMPs) are involved in a wide range of proteolytic events in fetal development and normal tissue remodeling as well as wound healing and inflammation. In the CNS, they have been implicated in a variety of neurodegenerative diseases ranging from multiple sclerosis to Alzheimer disease and are integral to stroke-related cell damage. Although studies implicate increased activity of MMPs in pathogenesis in the CNS, there is also a growing literature to support their participation in events that support recovery processes. Here the authors provide a brief overview of MMPs and their regulation, address their complex roles following traumatic injuries to the adult and developing CNS, and consider their time-and contextdependent signatures that influence both injury and reparative processes.

Matrix Metalloproteinase-9 Facilitates Glial Scar Formation in the Injured Spinal Cord

Journal of Neuroscience, 2008

The Cerebellum, 2009

Traumatic brain injury (TBI) is a major cause of morbidity and mortality worldwide. Studies of hu... more Traumatic brain injury (TBI) is a major cause of morbidity and mortality worldwide. Studies of human TBI demonstrate that the cerebellum is sometimes affected even when the initial mechanical insult is directed to the cerebral cortex. Some of the components of TBI, including ataxia, postural instability, tremor, impairments in balance and fine motor skills, and even cognitive deficits, may be attributed in part to cerebellar damage. Animal models of TBI have begun to explore the vulnerability of the cerebellum. In this paper, we review the clinical presentation, pathogenesis, and putative mechanisms underlying cerebellar damage with an emphasis on experimental models that have been used to further elucidate this poorly understood but important aspect of TBI. Animal models of indirect (supratentorial) trauma to the cerebellum, including fluid percussion, controlled cortical impact, weight drop impact acceleration, and rotational acceleration injuries, are considered. In addition, we describe models that produce direct trauma to the cerebellum as well as those that reproduce specific components of TBI including axotomy, stab injury, in vitro stretch injury, and excitotoxicity. Overall, these models reveal robust characteristics of cerebellar damage including regionally specific Purkinje cell injury or loss, activation of glia in a distinct spatial pattern, and traumatic axonal injury. Further research is needed to better understand the mechanisms underlying the pathogenesis of cerebellar trauma, and the experimental models discussed here offer an important first step toward achieving that objective.

Progress in Neurobiology, 2013

PLoS ONE, 2014

Matrix metalloproteinase-9 is elevated within the acutely injured murine spinal cord and blockade... more 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. Citation: Levine JM, Cohen ND, Heller M, Fajt VR, Levine GJ, et al. (2014) Efficacy of a Metalloproteinase Inhibitor in Spinal Cord Injured Dogs. PLoS ONE 9(5): e96408.