Microglia are integral mediators of innate immunity within the mammalian central nervous system. Typical microglial responses are transient, intending to restore homeostasis by orchestrating the ...removal of pathogens and debris and the regeneration of damaged neurons. However, prolonged and persistent microglial activation can drive chronic neuroinflammation and is associated with neurodegenerative disease. Recent evidence has revealed that abnormalities in microglial signaling pathways involving phosphatidylinositol 3-kinase (PI3K) and protein kinase B (AKT) may contribute to altered microglial activity and exacerbated neuroimmune responses. In this scoping review, the known and suspected roles of PI3K-AKT signaling in microglia, both during health and pathological states, will be examined, and the key microglial receptors that induce PI3K-AKT signaling in microglia will be described. Since aberrant signaling is correlated with neurodegenerative disease onset, the relationship between maladapted PI3K-AKT signaling and the development of neurodegenerative disease will also be explored. Finally, studies in which microglial PI3K-AKT signaling has been modulated will be highlighted, as this may prove to be a promising therapeutic approach for the future treatment of a range of neuroinflammatory conditions.
Hypoxic-ischemic and traumatic brain injuries are leading causes of long-term mortality and disability in infants and children. Although several preclinical models using rodents of different ages ...have been developed, species differences in the timing of key brain maturation events can render comparisons of vulnerability and regenerative capacities difficult to interpret. Traditional models of developmental brain injury have utilized rodents at postnatal day 7-10 as being roughly equivalent to a term human infant, based historically on the measurement of post-mortem brain weights during the 1970s. Here we will examine fundamental brain development processes that occur in both rodents and humans, to delineate a comparable time course of postnatal brain development across species. We consider the timing of neurogenesis, synaptogenesis, gliogenesis, oligodendrocyte maturation and age-dependent behaviors that coincide with developmentally regulated molecular and biochemical changes. In general, while the time scale is considerably different, the sequence of key events in brain maturation is largely consistent between humans and rodents. Further, there are distinct parallels in regional vulnerability as well as functional consequences in response to brain injuries. With a focus on developmental hypoxic-ischemic encephalopathy and traumatic brain injury, this review offers guidelines for researchers when considering the most appropriate rodent age for the developmental stage or process of interest to approximate human brain development.
Chemokines and their receptors have crucial roles in the trafficking of leukocytes, and are of particular interest in the context of the unique immune responses elicited in the central nervous system ...(CNS). The chemokine system CC ligand 2 (CCL2) with its receptor CC receptor 2 (CCR2), as well as the receptor CXCR2 and its multiple ligands CXCL1, CXCL2 and CXCL8, have been implicated in a wide range of neuropathologies, including trauma, ischemic injury and multiple sclerosis. This review aims to overview the current understanding of chemokines as mediators of leukocyte migration into the CNS under neuroinflammatory conditions. We will specifically focus on the involvement of two chemokine networks, namely CCL2/CCR2 and CXCL8/CXCR2, in promoting macrophage and neutrophil infiltration, respectively, into the lesioned parenchyma after focal traumatic brain injury. The constitutive brain expression of these chemokines and their receptors, including their recently identified roles in the modulation of neuroprotection, neurogenesis, and neurotransmission, will be discussed. In conclusion, the value of evidence obtained from the use of Ccl2- and Cxcr2-deficient mice will be reported, in the context of potential therapeutics inhibiting chemokine activity which are currently in clinical trial for various inflammatory diseases.
This review recounts the definitions and research evidence supporting the multifaceted roles of neuroinflammation in the injured brain following trauma. We summarise the literature fluctuating from ...the protective and detrimental properties that cytokines, leukocytes and glial cells play in the acute and chronic stages of TBI, including the intrinsic factors that influence cytokine responses and microglial functions relative to genetics, sex, and age. We elaborate on the pros and cons that cytokines, chemokines, and microglia play in brain repair, specifically neurogenesis, and how such conflicting roles may be harnessed therapeutically to sustain the survival of new neurons. With a brief review of the clinical and experimental findings demonstrating early and chronic inflammation impacts on outcomes, we focus on the clinical conditions that may be amplified by neuroinflammation, ranging from acute seizures to chronic epilepsy, neuroendocrine dysfunction, dementia, depression, post-traumatic stress disorder and chronic traumatic encephalopathy. Finally, we provide an overview of the therapeutic agents that have been tested to reduce inflammation-driven secondary pathological cascades and speculate the future promise of alternative drugs.
Epilepsy is a common and debilitating consequence of traumatic brain injury (TBI). Seizures contribute to progressive neurodegeneration and poor functional and psychosocial outcomes for TBI ...survivors, and epilepsy after TBI is often resistant to existing anti-epileptic drugs. The development of post-traumatic epilepsy (PTE) occurs in a complex neurobiological environment characterized by ongoing TBI-induced secondary injury processes. Neuroinflammation is an important secondary injury process, though how it contributes to epileptogenesis, and the development of chronic, spontaneous seizure activity, remains poorly understood. A mechanistic understanding of how inflammation contributes to the development of epilepsy (epileptogenesis) after TBI is important to facilitate the identification of novel therapeutic strategies to reduce or prevent seizures. BODY: We reviewed previous clinical and pre-clinical data to evaluate the hypothesis that inflammation contributes to seizures and epilepsy after TBI. Increasing evidence indicates that neuroinflammation is a common consequence of epileptic seizure activity, and also contributes to epileptogenesis as well as seizure initiation (ictogenesis) and perpetuation. Three key signaling factors implicated in both seizure activity and TBI-induced secondary pathogenesis are highlighted in this review: high-mobility group box protein-1 interacting with toll-like receptors, interleukin-1β interacting with its receptors, and transforming growth factor-β signaling from extravascular albumin. Lastly, we consider age-dependent differences in seizure susceptibility and neuroinflammation as mechanisms which may contribute to a heightened vulnerability to epileptogenesis in young brain-injured patients.
Several inflammatory mediators exhibit epileptogenic and ictogenic properties, acting on glia and neurons both directly and indirectly influence neuronal excitability. Further research is required to establish causality between inflammatory signaling cascades and the development of epilepsy post-TBI, and to evaluate the therapeutic potential of pharmaceuticals targeting inflammatory pathways to prevent or mitigate the development of PTE.
Survivors of traumatic brain injury (TBI) often develop chronic neurological, neurocognitive, psychological, and psychosocial deficits that can have a profound impact on an individual’s wellbeing and ...quality of life. TBI is also a common cause of acquired epilepsy, which is itself associated with significant behavioral morbidity. This review considers the clinical and preclinical evidence that post-traumatic epilepsy (PTE) acts as a ‘second-hit’ insult to worsen chronic behavioral outcomes for brain-injured patients, across the domains of emotional, cognitive, and psychosocial functioning. Surprisingly, few well-designed studies have specifically examined the relationship between seizures and behavioral outcomes after TBI. The complex mechanisms underlying these comorbidities remain incompletely understood, although many of the biological processes that precipitate seizure occurrence and epileptogenesis may also contribute to the development of chronic behavioral deficits. Further, the relationship between PTE and behavioral dysfunction is increasingly recognized to be a bidirectional one, whereby premorbid conditions are a risk factor for PTE. Clinical studies in this arena are often challenged by the confounding effects of anti-seizure medications, while preclinical studies have rarely examined an adequately extended time course to fully capture the time course of epilepsy development after a TBI. To drive the field forward towards improved treatment strategies, it is imperative that both seizures and neurobehavioral outcomes are assessed in parallel after TBI, both in patient populations and preclinical models.
Traumatic brain injury (TBI) during early childhood is associated with a particularly high risk of developing social behavior impairments, including deficits in social cognition that manifest as ...reduced social interactions, with profound consequences for the individuals’ quality of life. A number of pre-injury, post-injury, and injury-related factors have been identified or hypothesized to determine the extent of social behavior problems after childhood TBI. These include variables associated with the individual themselves (e.g. age, genetics, the injury severity, and extent of white matter damage), proximal environmental factors (e.g. family functioning, parental mental health), and more distal environmental factors (e.g. socioeconomic status, access to resources). In this review, we synthesize the available evidence demonstrating which of these determinants influence risk versus resilience to social behavior deficits after pediatric TBI, drawing upon the available clinical and preclinical literature. Injury-related pathology in neuroanatomical regions associated with social cognition and behaviors will also be described, with a focus on findings from magnetic resonance imaging and diffusion tensor imaging. Finally, study limitations and suggested future directions are highlighted. In summary, while no single variable can alone accurately predict the manifestation of social behavior problems after TBI during early childhood, an increased understanding of how both injury and environmental factors can influence social outcomes provides a useful framework for the development of more effective rehabilitation strategies aiming to optimize recovery for young brain-injured patients.
Abstract Traumatic brain injury (TBI) elicits a complex secondary injury response, with neuroinflammation as a crucial central component. Long thought to be solely a deleterious factor, the ...neuroinflammatory response has recently been shown to be far more intricate, with both beneficial and detrimental consequences depending on the timing, magnitude and specific immune composition of the response post-injury. Despite extensive preclinical and clinical research into mechanisms of secondary injury after TBI, no effective neuroprotective therapy has been identified, with potential candidates repeatedly proving disappointing in the clinic. The neuroinflammatory response offers a promising avenue for therapeutic targeting, aiming to quell the deleterious consequences without influencing its function in providing a neurotrophic environment supportive of repair. The present review firstly describes the findings of recent clinical trials that aimed to modulate inflammation as a means of neuroprotection. Secondly, we discuss promising multifunctional and single-target anti-inflammatory candidates either currently in trial, or with ample experimental evidence supporting clinical application. This article is part of a Special Issue entitled SI:Brain injury and recovery.
Cerebral inflammation involves molecular cascades contributing to progressive damage after traumatic brain injury (TBI). The chemokine CC ligand-2 (CCL2) (formerly monocyte chemoattractant protein-1, ...MCP-1) is implicated in macrophage recruitment into damaged parenchyma after TBI. This study analyzed the presence of CCL2 in human TBI, and further investigated the role of CCL2 in physiological and cellular mechanisms of secondary brain damage after TBI. Sustained elevation of CCL2 was detected in the cerebrospinal fluid (CSF) of severe TBI patients for 10 days after trauma, and in cortical homogenates of C57Bl/6 mice, peaking at 4 to 12 h after closed head injury (CHI). Neurological outcome, lesion volume, macrophage/microglia infiltration, astrogliosis, and the cerebral cytokine network were thus examined in CCL2-deficient (−/−) mice subjected to CHI. We found that CCL2−/− mice showed altered production of multiple cytokines acutely (2 to 24 h); however, this did not affect lesion size or cell death within the first week after CHI. In contrast, by 2 and 4 weeks, a delayed reduction in lesion volume, macrophage accumulation, and astrogliosis were observed in the injured cortex and ipsilateral thalamus of CCL2−/− mice, corresponding to improved functional recovery as compared with wild-type mice after CHI. Our findings confirm the significant role of CCL2 in mediating post-traumatic secondary brain damage.
Epilepsy is a serious neurological condition exhibiting complex pathology and deserving of more serious attention. More than 30% of people with epilepsy are not responsive to more than 20 ...anti‐epileptic drugs currently available, reflecting an unmet clinical need for novel therapeutic strategies. Not much is known about the pathogenesis of epilepsy, but evidence indicates that neuroinflammation might contribute to the onset and progression of epilepsy following acquired brain insults. However, the molecular mechanisms underlying these pathophysiological processes are yet to be fully understood. The emerging research suggests that high‐mobility group box protein 1 (HMGB1), a DNA‐binding protein that is both actively secreted by inflammatory cells and released by necrotic cells, might contribute to the pathogenesis of epilepsy. HMGB1 as an initiator and amplifier of neuroinflammation, and its activation is implicated in the propagation of seizures in animal models. The current review will highlight the potential role of HMGB1 in the pathogenesis of epilepsy, and implications of HMGB1‐targeted therapies against epilepsy. HMGB1 in this context is an emerging concept deserving further exploration. Increased understanding of HMGB1 in seizures and epilepsy will pave the way in designing novel and innovative therapeutic strategies that could modify the disease course or prevent its development.
High‐mobility group box protein 1 (HMGB1) is an emerging target against epileptic seizures. HMGB1 is getting attention as an initiator and amplifier of neuroinflammation in epileptogenesis via TLR4 activation. This review highlighted the role of HMGB1 in epileptogenesis and argued on the challenges of HMGB1 as a therapy. HMGB1 targeted therapy has demonstrated admirable outcome in experimental epilepsy but clinical proofs are not yet registered. Disulphide form of HMGB1 is well studied and targeting HMGB1/TLR4 axis would represent a novel treatment option. Moreover, designing a disulphide‐HMGB1 antagonist is capable of preventing HMGB1 translocation and BBB disruption as a potential anti‐epileptic therapeutic strategy is a future need.
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