Jason H. Huang

Blood–brain barrier dysfunction following traumatic brain injury

Traumatic brain injury is a serious cause of morbidity and mortality worldwide. After traumatic brain injury, the blood–brain barrier, the protective barrier between the brain and the intravascular compartment, becomes dysfunctional, leading to leakage of proteins, fluid, and transmigration of immune cells. As this leakage has profound clinical implications, including edema formation, elevated intracranial pressure and decreased perfusion pressure, much interest has been paid to better understanding the mechanisms responsible for these events. Various molecular pathways and numerous mediators have been found to be involved in the intricate process of regulating blood–brain barrier permeability following traumatic brain injury. This review provides an update to the existing knowledge about the various pathophysiological pathways and advancements in the field of blood–brain barrier dysfunction and hyperpermeability following traumatic brain injury, including the role of various tight junction proteins involved in blood–brain barrier integrity and regulation. We also address pitfalls of existing systems and propose strategies to improve the various debilitating functional deficits caused by this progressive epidemic.

Melatonin Preserves Blood-Brain Barrier Integrity and Permeability via Matrix Metalloproteinase-9 Inhibition.

Microvascular hyperpermeability that occurs at the level of the blood-brain barrier (BBB) often leads to vasogenic brain edema and elevated intracranial pressure following traumatic brain injury (TBI). At a cellular level, tight junction proteins (TJPs) between neighboring endothelial cells maintain the integrity of the BBB via TJ associated proteins particularly, zonula occludens-1 (ZO-1) that binds to the transmembrane TJPs and actin cytoskeleton intracellularly. The pro-inflammatory cytokine, interleukin-1β (IL-1β) as well as the proteolytic enzymes, matrix metalloproteinase-9 (MMP-9) are key mediators of trauma-associated brain edema. Recent studies indicate that melatonin a pineal hormone directly binds to MMP-9 and also might act as its endogenous inhibitor. We hypothesized that melatonin treatment will provide protection against TBI-induced BBB hyperpermeability via MMP-9 inhibition. Rat brain microvascular endothelial cells grown as monolayers were used as an in vitro model of the BBB and a mouse model of TBI using a controlled cortical impactor was used for all in vivo studies. IL-1β (10 ng/mL; 2 hours)-induced endothelial monolayer hyperpermeability was significantly attenuated by melatonin (10 μg/mL; 1 hour), GM6001 (broad spectrum MMP inhibitor; 10 μM; 1 hour), MMP-9 inhibitor-1 (MMP-9 specific inhibitor; 5 nM; 1 hour) or MMP-9 siRNA transfection (48 hours) in vitro. Melatonin and MMP-9 inhibitor-1 pretreatment attenuated IL-1β-induced MMP-9 activity, loss of ZO-1 junctional integrity and f-actin stress fiber formation. IL-1β treatment neither affected ZO-1 protein or mRNA expression or cell viability. Acute melatonin treatment attenuated BBB hyperpermeability in a mouse controlled cortical impact model of TBI in vivo. In conclusion, one of the protective effects of melatonin against BBB hyperpermeability occurs due to enhanced BBB integrity via MMP-9 inhibition. In addition, acute melatonin treatment provides protection against BBB hyperpermeability in a mouse model of TBI indicating its potential as a therapeutic agent for brain edema when established in humans.

Imaging chronic traumatic brain injury as a risk factor for neurodegeneration

Population‐based studies have supported the hypothesis that a positive history of traumatic brain injury (TBI) is associated with an increased incidence of neurological disease and psychiatric comorbidities, including chronic traumatic encephalopathy, Alzheimers disease, Parkinsons disease, and amyotrophic lateral sclerosis. These epidemiologic studies, however, do not offer a clear definition of that risk, and leave unanswered the bounding criteria for greater lifetime risk of neurodegeneration. Key factors that likely mediate the degree of risk of neurodegeneration include genetic factors, significant premorbid and comorbid medical history (e.g. depression, multiple head injuries and repetitive subconcussive impact to the brain, occupational risk, age at injury, and severity of brain injury). However, given the often‐described concerns in self‐report accuracy as it relates to history of multiple TBIs, low frequency of patient presentation to a physician in the case of mild brain injuries, and challenges with creating clear distinctions between injury severities, disentangling the true risk for neurodegeneration based solely on population‐based studies will likely remain elusive. Given this reality, multiple modalities and approaches must be combined to characterize who are at risk so that appropriate interventions to alter progression of neurodegeneration can be evaluated. This article presents data from a study that highlights uses of neuroimaging and areas of needed research in the link between TBI and neurodegenerative disease.

NKCC1 up-regulation contributes to early post-traumatic seizures and increased post-traumatic seizure susceptibility

Traumatic brain injury (TBI) is not only a leading cause for morbidity and mortality in young adults (Bruns and Hauser, Epilepsia 44(Suppl 10):210, 2003), but also a leading cause of seizures. Understanding the seizure-inducing mechanisms of TBI is of the utmost importance, because these seizures are often resistant to traditional first- and second-line anti-seizure treatments. The early post-traumatic seizures, in turn, are a contributing factor to ongoing neuropathology, and it is critically important to control these seizures. Many of the available anti-seizure drugs target gamma-aminobutyric acid (GABAA) receptors. The inhibitory activity of GABAA receptor activation depends on low intracellular Cl−, which is achieved by the opposing regulation of Na+–K+–Cl− cotransporter 1 (NKCC1) and K+–Cl−–cotransporter 2 (KCC2). Up-regulation of NKCC1 in neurons has been shown to be involved in neonatal seizures and in ammonia toxicity-induced seizures. Here, we report that TBI-induced up-regulation of NKCC1 and increased intracellular Cl− concentration. Genetic deletion of NKCC1 or pharmacological inhibition of NKCC1 with bumetanide suppresses TBI-induced seizures. TGFβ expression was also increased after TBI and competitive antagonism of TGFβ reduced NKKC1 expression, ameliorated reactive astrocytosis, and inhibited seizures. Thus, TGFβ might be an important pathway involved in NKCC1 up-regulation after TBI. Our findings identify neuronal up-regulation of NKCC1 and its mediation by TGFβ, as a potential and important mechanism in the early post-traumatic seizures, and demonstrate the therapeutic potential of blocking this pathway.

Neuromodulator and Emotion Biomarker for Stress Induced Mental Disorders

Affective disorders are a leading cause of disabilities worldwide, and the etiology of these many affective disorders such as depression and posttraumatic stress disorder is due to hormone changes, which includes hypothalamus-pituitary-adrenal axis in the peripheral nervous system and neuromodulators in the central nervous system. Consistent with pharmacological studies indicating that medical treatment acts by increasing the concentration of catecholamine, the locus coeruleus (LC)/norepinephrine (NE) system is regarded as a critical part of the central “stress circuitry,” whose major function is to induce “fight or flight” behavior and fear and anger emotion. Despite the intensive studies, there is still controversy about NE with fear and anger. For example, the rats with LC ablation were more reluctant to leave a familiar place and took longer to consume the food pellets in an unfamiliar place (neophobia, i.e., fear in response to novelty). The reason for this discrepancy might be that NE is not only for flight (fear), but also for fight (anger). Here, we try to review recent literatures about NE with stress induced emotions and their relations with mental disorders. We propose that stress induced NE release can induce both fear and anger. “Adrenaline rush or norepinephrine rush” and fear and anger emotion might act as biomarkers for mental disorders.

Attenuation of Blood-Brain Barrier Breakdown and Hyperpermeability by Calpain Inhibition

Blood-brain barrier (BBB) breakdown and the associated microvascular hyperpermeability followed by brain edema are hallmark features of several brain pathologies, including traumatic brain injuries (TBI). Recent studies indicate that pro-inflammatory cytokine interleukin-1β (IL-1β) that is up-regulated following traumatic injuries also promotes BBB dysfunction and hyperpermeability, but the underlying mechanisms are not clearly known. The objective of this study was to determine the role of calpains in mediating BBB dysfunction and hyperpermeability and to test the effect of calpain inhibition on the BBB following traumatic insults to the brain. In these studies, rat brain microvascular endothelial cell monolayers exposed to calpain inhibitors (calpain inhibitor III and calpastatin) or transfected with calpain-1 siRNA demonstrated attenuation of IL-1β-induced monolayer hyperpermeability. Calpain inhibition led to protection against IL-1β-induced loss of zonula occludens-1 (ZO-1) at the tight junctions and alterations in F-actin cytoskeletal assembly. IL-1β treatment had no effect on ZO-1 gene (tjp1) or protein expression. Calpain inhibition via calpain inhibitor III and calpastatin decreased IL-1β-induced calpain activity significantly (p < 0.05). IL-1β had no detectable effect on intracellular calcium mobilization or endothelial cell viability. Furthermore, calpain inhibition preserved BBB integrity/permeability in a mouse controlled cortical impact model of TBI when studied using Evans blue assay and intravital microscopy. These studies demonstrate that calpain-1 acts as a mediator of IL-1β-induced loss of BBB integrity and permeability by altering tight junction integrity, promoting the displacement of ZO-1, and disorganization of cytoskeletal assembly. IL-1β-mediated alterations in permeability are neither due to the changes in ZO-1 expression nor cell viability. Calpain inhibition has beneficial effects against TBI-induced BBB hyperpermeability.

Stress Induced Hormone and Neuromodulator Changes in Menopausal Depressive Rats

Objective: Previously, we showed that neuromodulators are important factors involved in depression, here we aim to further investigate the interactions between neuromodulators and sex hormone involved in menopause related depression in rats. Methods: Menopausal depression was made with bilateral ovariectomies in female SD rats followed by chronic mild unpredictable stress treatment for 21 days. Thirty six rats were randomly divided into four groups: sham surgery group, sham/stress group, surgery group, surgery/stress group. Then open-field locomotor scores and sucrose intake were employed to observe behavior changes. The levels of norepinephrine (NE), dopamine (DA), serotonin (5-HT) in the cerebral spinal fluid and serum adrenocorticotropic hormone (ACTH), cortisone were determined with High-performance liquid chromatography (HPLC). Serum estradiol (E2), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) were measured with radioimmunoassay. Results: The open-field locomotor scores and sucrose intake were significantly decreased after the surgery and stress treatment (p < 0.01). The Serum E2 level decreased significantly after the surgery (p < 0.01), but serum LH, FSH levels increased significantly in the surgery group than the sham surgery group (p < 0.01). The cortisone levels increased significantly in sham/stress group than that in the sham surgery group during the first 2 weeks at stressful treatment, but decrease afterwards. The monoamine levels in the surgery/stress group were much lower than those in the sham surgery group (p < 0.01). The correlation analysis found that LH and FSH are related more to the neurotransmitter release than E2. Conclusion: Ovary removal rats showed depression-like behaviors, with LH and FSH increase and monoamine decrease, and the levels of these monoamines in the stress treated groups changed only after the stressful treatment. The LH, FSH hormone increasing might be the reason for the lower monoamine release, which in turn might be the reason for depressed syndromes in the menopause. The cortisone and ACTH in the serum in the surgery/stress group were much higher than that in the sham surgery group.

Glial Cells and Synaptic Plasticity

Neuroglia are composed of highly heterogeneous cellular populations of neural (astrocytes, oligodendrocytes, and NG2 glial cells) and nonneural (microglia) origin that are essential for maintaining efficient neurotransmission, homeostatic cascades, supply of energy metabolites, turnover of neurotransmitters, and establishment of the blood-brain barrier [1]. Astrocytes shape synaptic networks through essential roles in synaptogenesis, synaptic maturation, and synaptic extinction [2, 3]. Furthermore, astroglial cells secrete neurotransmitters (such as glutamate, ATP, and GABA), neuromodulators (such as adenosine and D-serine), neurohormones (such as atrial natriuretic peptide), and other humoral factors (such as eicosanoids) that modulate synaptic networks and affect information processing [4]. The concept of “multipartite synapse” formalizes the multicomponent nature of the synaptic concept that includes astroglial perisynaptic processes, microglial processes, and extracellular matrix [5, 6]. n nPotentiation and depression of synaptic connections are critical for learning, memory formation, and emotions [7, 8]. Long-term potentiation (LTP) and long-term depression (LTD) are triggered by patterned and repeated synaptic activities, depending on the complex dynamics of neurotransmitters (especially glutamate) in the synaptic cleft. Both the temporal course and spatial distribution of glutamate contribute to the coordinated activation of intracellular signaling cascades affecting synaptic strength [9]. The multipartite synapse concept has defined astrocyte as the key regulator of glutamate homeostasis (mediated through release and uptake) [10]. Astrocytes, for example, are capable of releasing D-serine to enhance the function of NMDA receptors [11]. In addition, astrocytes can change the buffering ability to take up extracellular K+, thus modulating synaptic plasticity [12]. Calcium dynamics in astrocytes determine the release of glutamate and ATP molecules. At the synaptic level, the astroglial calcium signaling is activated in response to synaptic activities, such as repeated synaptic stimulation, through purinergic, glutamatergic, and cholinergic pathways. The hyperactivity of neural circuits (e.g., in epilepsy) results in altered calcium dynamics in astrocytes. These changes, in turn, contribute to the differential modulation of synaptic efficacy under physiological or pathological circumstances [13, 14]. n nThe papers collected in this special issue focus on glial cells and synaptic plasticity. The reviews and experimental papers present the evidence that glial cells indeed affect long-term synaptic changes. n nIn “Housing Complexity Alters GFAP-Immunoreactive Astrocyte Morphology in the Rat Dentate Gyrus,” G. Salois and J. S. Smith [15] demonstrate that the housing environment can affect neural plasticity. They found that an enriched environment results in considerable neuroplasticity in the rodent brain. They used confocal microscopy and found that astrocytes play a key role in the process and induce changes in synaptic spines. These findings offer a hallmark feature for the understanding of numerous diseases, including the neurodegenerative ones. n nIn “Recent Advance in the Relationship between Excitatory Amino Acid Transporters and Parkinsons Disease,” Y. Zhang et al. [16] reviewed their studies and also recent discoveries about the excitatory amino acid transporters (EAATs). Glutamate is the major excitatory neurotransmitter in the central nervous system, and it is mostly removed by astrocytes, where it is converted into glutamine. Impairment of astroglial glutamate uptake leads to the accumulation of glutamate in the synaptic cleft, which may contribute to various pathologies such as Parkinsons disease (PD). n nConsistent with recent studies about astrocytic function in emotions, the paper “Anger Emotional Stress Influences VEGF/VEGFR2 and Its Induced PI3K/AKT/mTOR Signaling Pathway,” by P. Sun et al. [17], reported changes of VEGR/VEGFR2 in both astrocytes and neurons, induced by the anger emotion; these changes, in turn, can stimulate neurogenesis. n nIn the review article “The Plastic Glial-Synaptic Dynamics within the Neuropil: A Self-Organizing System Composed of Polyelectrolytes in Phase Transition,” V. M. F. de Lima and A. Pereira Jr. [18] reported another pathway for neuronal-glial interaction: the plastic nonlinear dynamics between glial and synaptic terminals; they also offered a model based on hydroionic waves within the neuropil. n nIn the paper “Glia and TRPM2 Channels in Plasticity of Central Nervous System and Alzheimers Diseases,” J. Wang et al. [19] review recent findings about synaptic plasticity in neurodegenerative diseases, mainly focusing on the transient receptor potential melastatin 2 (TRPM2) channels. The TRPM2 is a nonselective Ca2+ permeable channel expressed in both glial cells and neurons, which regulates synaptic plasticity and also the glial cells. In this review, authors summarized recent discoveries about the contribution of TRPM2 in physiological and pathological conditions. n nIn “Dynamic Alterations of miR-34c Expression in the Hypothalamus of Male Rats after Early Adolescent Traumatic Stress,” C. Li et al. [20] reported experimental findings about neural plasticity under stress. They found that stress induces the overexpression of several types of microRNA notably including corticotrophin releasing factor 1 (CRFR1 mRNA) and miR-34c. Expression levels of the miR-34c in the hypothalamus represent an important factor involved in susceptibility to posttraumatic stress disorders. n nIn the subsequent paper “Role of MicroRNA in Governing Synaptic Plasticity,” Y. Ye et al. reviewed the role of microRNA in neural plasticity. They explored recent findings demonstrating that miRNA exerts widespread regulation over the translation and degradation of target genes in the nervous systems and contributes to the pathophysiology of plasticity-related diseases. n nIn “Astrocyte Hypertrophy Contributes to Aberrant Neurogenesis after Traumatic Brain Injury,” C. Robinson et al. reported their recent findings about astrocytic changes after traumatic brain injury (TBI). They analyzed the immunohistochemistry of glial fibrillary acidic protein and doublecortin and found a loss of radial glial-like processes extending through the granule cell layer after TBI. They further suggested that hypertrophied astrocytic processes form an ectopic glial scaffold that might facilitate the aberrant development of immature neurons in the dentate gyrus. n nIn “Modulation of Synaptic Plasticity by Glutamatergic Gliotransmission: A Modeling Study,” M. De Pitta and N. Brunel reported a computational model about gliotransmitter releasing pathways related to modulation of synaptic release and postsynaptic slow inward currents. This model predicts that both pathways could profoundly affect synaptic plasticity. n nCollectively, these studies demonstrate that glial cells play an important role in neural plasticity under physiological and pathological conditions. We hope that this special issue will stimulate interest in the field of glial cells modulating synaptic activities and will help to achieve a deeper understanding of the role of glial cells in neural plasticity.

Neuroinflammation and blood-brain barrier disruption following traumatic brain injury: Pathophysiology and potential therapeutic targets

Traumatic Brain Injury (TBI) is the most frequent cause of death and disability in young adults and children in the developed world, occurring in over 1.7 million persons and resulting in 50,000 deaths in the United States alone. The Centers for Disease Control and Prevention estimate that between 3.2 and 5.3 million persons in the United States live with a TBI‐related disability, including several neurocognitive disorders and functional limitations. Following the primary mechanical injury in TBI, literature suggests the presence of a delayed secondary injury involving a variety of neuroinflammatory changes. In the hours to days following a TBI, several signaling molecules and metabolic derangements result in disruption of the blood–brain barrier, leading to an extravasation of immune cells and cerebral edema. The primary, sudden injury in TBI occurs as a direct result of impact and therefore cannot be treated, but the timeline and pathophysiology of the delayed, secondary injury allows for a window of possible therapeutic options. The goal of this review is to discuss the pathophysiology of the primary and delayed injury in TBI as well as present several preclinical studies that identify molecular targets in the potential treatment of TBI. Additionally, certain recent clinical trials are briefly discussed to demonstrate the current state of TBI investigation.

Management of autoimmune status epilepticus

Status epilepticus is a neurological emergency with increased morbidity and mortality. Urgent diagnosis and treatment are crucial to prevent irreversible brain damage. In this mini review, we will discuss the recent advances in the diagnosis and treatment of autoimmune status epilepticus (ASE), a rare form of the disorder encountered in the intensive care unit. ASE can be refractory to anticonvulsant therapy and the symptoms include subacute onset of short-term memory loss with rapidly progressive encephalopathy, psychiatric symptoms with unexplained new-onset seizures, imaging findings, CSF pleocytosis, and availability of antibody testing makes an earlier diagnosis of ASE possible. Neuroimmunomodulatory therapies are the mainstay in the treatment of ASE. The goal is to maximize the effectiveness of anticonvulsant agents and find an optimal combination of therapies while undergoing immunomodulatory therapy to reduce morbidity and mortality.