Rodent Models Of Traumatic Brain Injury Research Articles

VX-765 Alleviates Circadian Rhythm Disorder in a Rodent Model of Traumatic Brain Injury Plus Hemorrhagic Shock and Resuscitation.

Severe traumatic brain injury (TBI) can result in persistent complications, including circadian rhythm disorder, that substantially affect not only the injured people, but also the mood and social interactions with the family and the community. Pyroptosis in GFAP-positive astrocytes plays a vital role in inflammatory changes post-TBI. We determined whether VX-765, a low molecular weight caspase-1 inhibitor, has potential therapeutic value against astrocytic inflammation and pyroptosis in a rodent model of TBI plus hemorrhagic shock and resuscitation (HSR). A weight-drop plus bleeding and refusion model was used to establish traumatic exposure in rats. VX-765 (50mg/kg) was injected via the femoral vein after resuscitation. Wheel-running activity was assessed, brain magnetic resonance images were evaluated, the expression of pyroptosis-associated molecules including cleaved caspase-1, gasdermin D (GSDMD), and interleukin-18 (IL-18) in astrocytes in the region of anterior hypothalamus, were explored 30days post-trauma. VX-765-treated rats had significant improvement in circadian rhythm disorder, decreased mean diffusivity (MD) and mean kurtosis (MK), increased fractional anisotropy (FA), an elevated number and branches of astrocytes, and lower cleaved caspase-1, GSDMD, and IL-18 expression in astrocytes than TBI + HSR-treated rats. These results demonstrated that inhibition of pyroptosis-associated astrocytic activations in the anterior hypothalamus using VX-765 may ameliorate circadian rhythm disorder after trauma. In conclusion, we suggest that interventions targeting caspase-1-induced astrocytic pyroptosis by VX-765 are promising strategies to alleviate circadian rhythm disorder post-TBI.

Traumatic brain injury disrupts state-dependent functional cortical connectivity in a mouse model.

Traumatic brain injury (TBI) is the leading cause of death in young people and can cause cognitive and motor dysfunction and disruptions in functional connectivity between brain regions. In human TBI patients and rodent models of TBI, functional connectivity is decreased after injury. Recovery of connectivity after TBI is associated with improved cognition and memory, suggesting an important link between connectivity and functional outcome. We examined widespread alterations in functional connectivity following TBI using simultaneous widefield mesoscale GCaMP7c calcium imaging and electrocorticography (ECoG) in mice injured using the controlled cortical impact (CCI) model of TBI. Combining CCI with widefield cortical imaging provides us with unprecedented access to characterize network connectivity changes throughout the entire injured cortex over time. Our data demonstrate that CCI profoundly disrupts functional connectivity immediately after injury, followed by partial recovery over 3weeks. Examining discrete periods of locomotion and stillness reveals that CCI alters functional connectivity and reduces theta power only during periods of behavioral stillness. Together, these findings demonstrate that TBI causes dynamic, behavioral state-dependent changes in functional connectivity and ECoG activity across the cortex.

Multiplexed Quantitative Proteomics Reveals Proteomic Alterations in Two Rodent Traumatic Brain Injury Models.

In many cases of traumatic brain injury (TBI), conspicuous abnormalities, such as scalp wounds and intracranial hemorrhages, abate over time. However, many unnoticeable symptoms, including cognitive, emotional, and behavioral dysfunction, often last from several weeks to years after trauma, even for mild injuries. Moreover, the cause of such persistence of symptoms has not been examined extensively. Recent studies have implicated the dysregulation of the molecular system in the injured brain, necessitating an in-depth analysis of the proteome and signaling pathways that mediate the consequences of TBI. Thus, in this study, the brain proteomes of two TBI models were examined by quantitative proteomics during the recovery period to determine the molecular mechanisms of TBI. Our results show that the proteomes in both TBI models undergo distinct changes. A bioinformatics analysis demonstrated robust activation and inhibition of signaling pathways and core proteins that mediate biological processes after brain injury. These findings can help determine the molecular mechanisms that underlie the persistent effects of TBI and identify novel targets for drug interventions.

Dexamethasone-Enhanced Continuous Online Microdialysis for Neuromonitoring of O2 after Brain Injury.

Traumatic brain injury (TBI) is a major public health crisis in many regions of the world. Severe TBI may cause a primary brain lesion with a surrounding penumbra of tissue that is vulnerable to secondary injury. Secondary injury presents as progressive expansion of the lesion, possibly leading to severe disability, a persistent vegetive state, or death. Real time neuromonitoring to detect and monitor secondary injury is urgently needed. Dexamethasone-enhanced continuous online microdialysis (Dex-enhanced coMD) is an emerging paradigm for chronic neuromonitoring after brain injury. The present study employed Dex-enhanced coMD to monitor brain K+ and O2 during manually induced spreading depolarization in the cortex of anesthetized rats and after controlled cortical impact, a widely used rodent model of TBI, in behaving rats. Consistent with prior reports on glucose, O2 exhibited a variety of responses to spreading depolarization and a prolonged, essentially permanent decline in the days after controlled cortical impact. These findings confirm that Dex-enhanced coMD delivers valuable information regarding the impact of spreading depolarization and controlled cortical impact on O2 levels in the rat cortex.

Effect of Voluntary Exercise on Endogenous Pain Control Systems and Post-traumatic Headache in Mice

Traumatic brain injury (TBI) can cause acute and chronic pain along with motor, cognitive, and emotional problems. Although the mechanisms are poorly understood, previous studies suggest disruptions in endogenous pain modulation may be involved. Voluntary exercise after a TBI has been shown to reduce some consequences of injury including cognitive impairment. We hypothesized, therefore, that voluntary exercise could augment endogenous pain control systems in a rodent model of TBI. For these studies, we used a closed-head impact procedure in male mice modeling mild TBI. We investigated the effect of voluntary exercise on TBI-induced hindpaw nociceptive sensitization, diffuse noxious inhibitory control failure, and periorbital sensitization after bright light stress, a model of post-traumatic headache. Furthermore, we investigated the effects of exercise on memory, circulating markers of brain injury, neuroinflammation, and spinal cord gene expression. We observed that exercise significantly reduced TBI-induced hindpaw allodynia and periorbital allodynia in the first week following TBI. We also showed that exercise improved the deficits associated with diffuse noxious inhibitory control and reduced bright light stress-induced allodynia up to 2 months after TBI. In addition, exercise preserved memory and reduced TBI-induced increases in spinal BDNF, CXCL1, CXCL2, and prodynorphin expression, all genes previously linked to TBI-induced nociceptive sensitization. Taken together, our observations suggest that voluntary exercise may reduce pain after TBI by reducing TBI-induced changes in nociceptive signaling and preserving endogenous pain control systems. PerspectiveThis article evaluates the effects of exercise on pain-related behaviors in a preclinical model of traumatic brain injury (TBI). The findings show that exercise reduces nociceptive sensitization, loss of diffuse noxious inhibitory control, memory deficits, and spinal nociception-related gene expression after TBI. Exercise may reduce or prevent pain after TBI.

333 Intraventricular Ziconotide Improves Cognitive Outcomes following Lateral Fluid Percussion Injury in a Rat Model

INTRODUCTION: Traumatic brain injury (TBI) is a major source of morbidity and mortality worldwide. In previous studies, intravenous ziconotide, a selective N-type voltage-gated calcium channel blocker, reduced brain calcium accumulation, improved brain mitochondrial respiration, and improved cognitive and motor outcomes in rodent models of TBI. Attempts to translate intravenous ziconotide therapy to humans were halted due to peripheral side-effects. However, ziconotide is now FDA-approved for treatment of severe pain syndromes when administered intrathecally instead of intravenously. We hypothesize that following TBI intraventricular ziconotide will improve cognitive function in the absence of significant side effects. METHODS: Seventy-seven Sprague-Dawley rats underwent sham (n = 11 males, n = 11 females) or lateral fluid percussion (LFP) injury (n = 21 males, n = 23 females). One-hour post-injury, rats received either an intraventricular injection of saline (n = 22 sham, n = 23 LFP) or ziconotide (n = 21 LFP). A catheter was implanted in the left lateral ventricle and connected to an Alzet micro-osmotic pump to allow for 72 hours of continuous infusion. Cognitive outcomes were evaluated using Morris water maze (MWM; days 10-15). RESULTS: TBI-saline rats performed significantly worse than shams on MWM (p < 0.01). Ziconotide treated rats had an intermediate phenotype on MWM. TBI-saline rats swam a less efficient path than sham animals (p < 0.01); ziconotide path efficiency was not significantly different from shams. Performance on the MWM was likely not related to motor deficits as there was no significant effect of group on mean swimming speed in either males or females. Female sham animals performed significantly better on probe trials compared to TBI-saline (p < 0.05); ziconotide animals were not different from shams. CONCLUSIONS: These findings support centrally delivered Ziconotide as a potential neuroprotective agent to improve cognitive performance following TBI. Further studies are required to characterize the neuroprotective effects of Ziconotide therapy.

STING mediates neuroinflammatory response by activating NLRP3-related pyroptosis in severe traumatic brain injury.

Long-term neurological deficits after severe traumatic brain injury (TBI), including cognitive dysfunction and emotional impairments, can significantly impair rehabilitation. Glial activation induced by inflammatory response is involved in the neurological deficits post-TBI. This study aimed to investigate the role of the stimulator of interferon genes (STING)-nucleotide-binding oligomerization domain-like receptor pyrin domain-containing-3 (NLRP3) signaling in a rodent model of severe TBI. Severe TBI models were established using weight-drop plus blood loss reinfusion model. Selective STING agonist ADU-S100 or antagonist C-176 was given as a single dose after modeling. Further, NLRP3 inhibitor MCC950 or activator nigericin, or caspase-1 inhibitor VX765, was given as an intracerebroventricular injection 30 min before modeling. After that, a novel object recognition test, open field test, force swimming test, western blot, and immunofluorescence assays were used to assess behavioral and pathological changes in severe TBI. Administration of C-176 alleviated TBI-induced cognitive dysfunction and emotional impairments, neuronal loss, and inflammatory activation of glia cells. However, the administration of STING agonist ADU-S100 exacerbated TBI-induced behavioral and pathological changes. In addition, STING activation exacerbated pyroptosis-associated neuroinflammation via promoting glial activation, as evidenced by increased cleaved caspase-1 and GSDMD N-terminal expression. In contrast, the administration of C-176 showed anti-pyroptotic effects. The neuroprotective effects of C-176 were partially reversed by the NLRP3 activator, nigericin. Collectively, glial STING is responsible for neuroinflammation post-TBI. However, pharmacologic inhibition of STING led to a remarkable improvement of neuroinflammation partly through suppressing NLRP3 signaling. The STING-NLRP3 signaling is a potential therapeutic target in TBI-induced neurological dysfunction.

Deficits in Acoustic Startle Reactivity and Auditory Temporal Processing after Traumatic Brain Injury.

Traumatic brain injury (TBI) exacts significant neurological and financial costs on patients and their families. In adult patients with moderate-to-severe TBI, central auditory impairments have been reported. These auditory impairments may interfere with language receptivity, as observed in children with developmental brain injury. Although rodent models of TBI have been widely used to examine behavioral outcomes, few studies have evaluated how TBI affects higher-order central auditory processing across a range of cue complexities. Here, auditory processing was assessed using a modified acoustic startle paradigm. We used a battery of progressively complex stimuli (single-tone, silent gaps in white noise, and frequency-modulated [FM] sweeps) in adult rats that received unilateral controlled cortical impact injury. TBI subjects showed significant reductions in acoustic startle absolute responses across nearly all stimuli, regardless of cue, duration of stimuli, or cue complexity. Despite this overall reduction of startle magnitudes in injured animals, the detection of single-tone stimuli was comparable between TBI and sham-injured subjects, indicating intact hearing after TBI. TBI subjects showed deficits in rapid gap (5 ms) and FM sweep (175 ms) detection, and, in contrast to shams, they did not improve on detecting silent gaps and FM sweeps across days of testing. Our findings provide evidence for both low-level (brainstem-mediated) and higher-order central auditory processing deficits in a rodent model of TBI, which parallel sensory impairments observed in TBI patients. The present findings support the use of modified pre-pule auditory detection paradigms to investigate clinically relevant processes in TBI.

Phasic stimulation in the nucleus accumbens enhances learning after traumatic brain injury.

Traumatic brain injury (TBI) is a significant cause of morbidity and mortality worldwide. Despite improvements in survival, treatments that improve functional outcome remain lacking. There is, therefore, a pressing need to develop novel treatments to improve functional recovery. Here, we investigated task-matched deep-brain stimulation of the nucleus accumbens (NAc) to augment reinforcement learning in a rodent model of TBI. We demonstrate that task-matched deep brain stimulation (DBS) of the NAc can enhance learning following TBI. We further demonstrate that animals receiving DBS exhibited greater behavioral improvement and enhanced neural proliferation. Treated animals recovered to an uninjured behavioral baseline and showed retention of improved performance even after stimulation was stopped. These results provide encouraging early evidence for the potential of NAc DBS to improve functional outcomes following TBI and that its effects may be broad, with alterations in neurogenesis and synaptogenesis.

Melatonin alleviates traumatic brain injury-induced anxiety-like behaviors in rats: Roles of the protein kinase A/cAMP-response element binding signaling pathway.

Melatonin is a hormone produced by the pineal gland. Given its capabilities of neuroprotection and low neurotoxicity, melatonin could be a therapeutic strategy for traumatic brain injury (TBI). The present study was conducted to determine the neuroprotective effects of melatonin on TBI-induced anxiety and the possible molecular mechanism. Rats were randomly divided into seven groups. The rodent model of TBI was established using the weight-drop method. Melatonin was administered by intraperitoneal injection at a dose of 10 mg/kg after TBI. H89 (0.02 mg/kg), a special protein kinase A (PKA) inhibitor, or dibutyryl-cyclic adenosine monophosphate (cAMP; 0.1 mg/kg), an activator of PKA, were administered by stereotactic injection of the brain to evaluate the roles of PKA and cAMP-response element-binding protein (CREB) in melatonin-related mood regulation, respectively. At 30 days post-TBI, the changes in anxiety-like behaviors in rats were measured using the open field and elevated plus maze tests. At 24 h post-TBI, the number of activated astrocytes and neuronal apoptosis were evaluated using immunofluorescence assay. The expression levels of inflammatory cytokines (TNF-α and IL-6) in the amygdala were measured using an enzyme-linked immunosorbent assay. The expression levels of PKA, phosphorylated (p)-PKA, CREB, p-CREB, NF-κB and p-NF-κB in the amygdala were detected using western blotting. It was revealed that melatonin partially reversed TBI-induced anxiety-like behavior in rats, and decreased the number of activated astrocytes and neuronal apoptosis in the amygdala induced by TBI. H89 partially blocked the neuroprotective effects of melatonin; while dibutyryl-cAMP not only reduced the H89-induced emotional disturbance but also enhanced the protective effects of melatonin against TBI. Overall, melatonin can alleviate TBI-induced anxiety-like behaviors in rats. Moreover, the underlying mechanism may be associated with the activation of the PKA/CREB signaling pathway.

Early life stress-induced neuroinflammation and neurological disorders: a novel perspective for research.

Early life stress-induced neuroinflammation and neurological disorders: a novel perspective for research.

A role for insulin-like growth factor-1 in hippocampal plasticity following traumatic brain injury.

Traumatic brain injury (TBI) initiates a constellation of secondary injury cascades, leading to neuronal damage and dysfunction that is often beyond the scope of endogenous repair mechanisms. Cognitive deficits are among the most persistent morbidities resulting from TBI, necessitating a greater understanding of mechanisms of posttraumatic hippocampal damage and neuroplasticity and identification of therapies that improve recovery by enhancing repair pathways. Focusing here on hippocampal neuropathology associated with contusion-type TBIs, the impact of brain trauma on synaptic structure and function and the process of adult neurogenesis is discussed, reviewing initial patterns of damage as well as evidence for spontaneous recovery. A case is made that insulin-like growth factor-1 (IGF-1), a growth-promoting peptide synthesized in both the brain and the periphery, is well suited to augment neuroplasticity in the injured brain. Essential during brain development, multiple lines of evidence delineate roles in the adult brain for IGF-1 in the maintenance of synapses, regulation of neurotransmission, and modulation of forms of synaptic plasticity such as long-term potentiation. Further, IGF-1 enhances adult hippocampal neurogenesis though effects on proliferation and neuronal differentiation of neural progenitor cells and on dendritic growth of newly born neurons. Post-injury administration of IGF-1 has been effective in rodent models of TBI in improving learning and memory, attenuating death of mature hippocampal neurons and promoting neurogenesis, providing critical proof-of-concept data. More studies are needed to explore the effects of IGF-1-based therapies on synaptogenesis and synaptic plasticity following TBI and to optimize strategies in order to stimulate only appropriate, functional neuroplasticity.

Propofol effects in rodent models of traumatic brain injury: a systematic review.

Traumatic brain injury (TBI) causes high mortality and disability worldwide. Animal models have been developed to explore the complex processes in TBI. Propofol is used to manage head injuries during surgical intervention and mechanical ventilation in patients with TBI. Many studies have investigated the neuroprotective effect of propofol on TBI. However, other studies have shown neurotoxic effects. To review systematically the literature regarding the neuroprotective and neurotoxic effects of propofol in rodent models of TBI. Data from rodents as models of TBI with propofol as one of the intervention agents, and/or comparing the neuroprotective effects of propofol with the other substances in rodent models of TBI, were obtained from PubMed, EBSCO Host, and ProQuest databases. The PRISMA 2020 statement recommendations were followed and research questions were developed based on PICOS guidelines. Data was extracted from the literature using a standardized Cochrane method. We analyzed data from 12 articles on physiological changes of experimental animals before and after trauma, the effects of propofol administration, and the observed neurotoxic effects. The effects of propofol administration were observed in terms of changes in traumatic lesion volume, the release of antioxidants and inflammatory factors, and the neurological function of rodent models of TBI. Propofol has neuroprotective and neurotoxic effects via several mechanisms, and various doses have been used in research to determine its effects. The timing of administration, the dose administered, and the duration of administration contribute to determine the effect of propofol in rodent models of TBI. However, the doses that produce neuroprotective and neurotoxic effects are not yet clear and further research is needed to determine them.

Androgen is responsible for enhanced susceptibility of melatonin against traumatic brain injury in females

BackgroundNumerous publications have demonstrated that melatonin administration is associated with mortality reduction and improvement in neurological outcomes after traumatic brain injury (TBI). However, there are significant sex differences in several diseases associated with melatonin. We aimed to determine whether androgen was responsible for enhanced susceptibility of melatonin against TBI in females, as well as potential molecular mechanisms. MethodsWeight-drop was used to establish a rodent model of TBI. Melatonin (10 mg/kg) and testosterone (1 mg/kg) were administered three times every day for three days after TBI using subcutaneous injection, respectively. Seven days after TBI, an open field assay was used to evaluate locomotor and exploratory activities. Neuronal amount, neuronal apoptosis, and expression of phosphorylated extracellularly regulated protein kinases 1/2 (ERK1/2), c-jun N-terminal kinase 1/2 (JNK1/2), and p38 mitogen-activated protein kinase (p38MAPK) in neurons were assessed using immunofluorescence assay seven days after TBI. The expression of caspase-3, Bax, and Bcl-2 in the frontal cortex was detected using western blot. ResultsCompared with female rats, melatonin administration exhibited more neuroprotective effects (including improved locomotor and exploratory activities, elevated neuronal amount, and reduced neuronal apoptosis) in male rats exposed to TBI. Moreover, testosterone significantly improved locomotor and exploratory activities, elevated neuronal amount, decreased neuronal apoptosis, downregulated phosphorylation of JNK1/2- and p38MAPK-positive neurons, but upregulated phosphorylation of ERK1/2-positive neurons in the frontal cortex, and reduced the expressions of cleaved caspase-3, Bax, but increased Bcl-2 expressions in female rats exposed to TBI. ConclusionsAndrogen was responsible for the enhanced susceptibility to TBI under melatonin supplementation in females through a mechanism that may be associated with MAPK pathway regulation.

Contusion Rodent Model of Traumatic Brain Injury: Controlled Cortical Impact.

Traumatic brain injury (TBI) is a heterogeneous brain injury which represents one of the leading causes of mortality and disability worldwide. Rodent TBI models are helpful to examine the cellular and molecular mechanisms after injury. Controlled cortical impact (CCI) is one of the most commonly used TBI models in rats and mice, based on its consistency of injury and ease of implementation. Here, we describe a CCI protocol to induce a moderate contusion to the somatosensory motor cortex. We provide additional protocols for monitoring animals after CCI induction.

Human cord blood-derived regulatory T-cell therapy modulates the central and peripheral immune response after traumatic brain injury.

Traumatic brain injury (TBI) causes a profound inflammatory response within the central nervous system and peripheral immune system, which contributes to secondary brain injury and further morbidity and mortality. Preclinical investigations have demonstrated that treatments that downregulate microglia activation and polarize them toward a reparative/anti‐inflammatory phenotype have improved outcomes in preclinical models. However, no therapy to date has translated into proven benefits in human patients. Regulatory T cells (Treg) have been shown to downregulate pathologic immune responses of the innate and adaptive immune system across a variety of pathologies. Furthermore, cellular therapy has been shown to augment host Treg responses in preclinical models; yet, studies investigating the use of Treg as a therapeutic for TBI are lacking. In a rodent TBI model, we demonstrate that human umbilical cord blood Treg modulate the central and peripheral immune response after injury in vitro and in vivo.

Abstracts from The 37th Annual National Neurotrauma Symposium June 29–July 3, 2019 Pittsburgh, Pennsylvania

Abstracts from The 37^th Annual National Neurotrauma Symposium June 29–July 3, 2019 Pittsburgh, Pennsylvania

OR10-6 Thyroid Hormone Protects Primary Cortical Neurons Exposed to Hypoxia by Reducing DNA Methylation and Apoptosis

Traumatic Brain Injury (TBI) is associated with disruption of cerebral blood flow leading to localized brain hypoxia. Thyroid hormone (TH) treatment, when administered shortly after injury, has been shown to promote neural survival in rodent TBI models. The mechanism of TH protection, however, is not established. We used mouse primary cortical neurons, to investigate the effectiveness and mechanism of T3 promoted cell survival after exposure to hypoxic injury. Cultured primary cortical neurons were exposed to hypoxia (0.2% oxygen) for 7 hours, in either the presence or absence of T3 (5 nM). T3 treatment enhanced DNA 5-hydroxymethylcytosin (5-hmc) levels compared to the conditions without T3, and attenuated the hypoxia-induced increase in DNA 5-methylcytosin (5-mc). In the presence of T3, mRNA expression of Tet family genes was increased and DNA methyltransferase, (Dnmt) 3a and Dnmt3b, were downregulated, compared to conditions in the absence of T3. These T3-induced changes may reduce hypoxia-induced DNA de novo methylation. We utilized RNA-seq to characterize T3-regulated genes in cortical neurons under hypoxic conditions, and identified 23 genes that were upregulated and 15 genes that were downregulated. KLF9, krupple-like factor 9, a multifunctional transcription factor that plays a key role in CNS development, was highly upregulated by T3 treatment in hypoxic conditions. We show that knockdown of the KLF9 gene induced early apoptosis and abolished the beneficial role of T3 in neuronal survival. KLF9 mediates, in part, the neuronal protective role of T3. T3 treatment reduces hypoxic damage and acts through pathways that reduce DNA methylation and apoptosis.

Synthetic Corticotropin Therapy Reduces Microglial Activation in a Rodent TBI Model

Traumatic brain injury (TBI) is a leading cause of mortality/morbidity and is associated with chronic neuroinflammation. Melanocortin receptor (MCR) agonists (e.g., ACTH or adrenocorticotropic hormone) that target MC3R/4R ameliorate inflammation and provide a novel therapeutic approach. Following TBI, quiescent microglia become activated resulting in anti and pro‐inflammatory responses and morphological changes. We examined the effect of Cosyntropin (synthetic ACTH) administration on microglial activation through quantification of microglia morphology in a rodent TBI model. We hypothesized that Cosyntropin administration would reduce injury‐induced microglia morphological changes following experimental TBI in rats. We used CCI in adult Sprague‐Dawley rats, randomized to 4 groups: sham‐vehicle (N = 2), sham‐Cosyntropin (N = 2), CCI‐vehicle (N = 4), and CCI‐Cosyntropin (N = 4). Subcutaneous injections of Cosyntropin (120U/kg/day; West Therapeutic Development; Grayslake, IL) were given 30 minutes after CCI and every 12 hours for 7 days thereafter. Microglia activation was quantified based on morphology. Sectioned brains were immunostained (Iba1) and visualized with diaminobenzidine. Image processing and quantification were conducted with FIJI and FracLac for ImageJ resulting in 15 morphological values/cell. Parameters included cell area, fractal dimension, circularity, and cell perimeter and density. CCI animals exhibited increased microglia in the lesion site with no difference in cell count between vehicle and treated. Microglia from CCI animals exhibited no change in cell area, decreased cell perimeter and increased density and circularity compared to sham animals. Cosyntropin treatment altered CCI‐induced microglia changes in cell area, cell perimeter, and cell density. Cosyntropin‐treated CCI animals showed reduced morphological changes in microglia suggesting a reduced activation state. Decreased activation may decrease long‐term deleterious neuroinflammatory effects and may be mediated by Cosyntropin effects on melanocortin receptor signaling.Support or Funding InformationSupported in part by the Pediatric Epilepsy Research Foundation. Cosyntropin was supplied by West Therapeutic Development (Grayslake, IL).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Stimulation of N-methyl-D-aspartate receptors by exogenous and endogenous ligands improves outcome of brain injury.

The failure of N-methyl-D-aspartate receptor (NMDAR) antagonists as a treatment for human traumatic brain injury (TBI) and stroke, along with preclinical findings of a persistent hypofunctional state of these receptors after brain injury, resulted in a new focus on NMDAR agonists, specifically those acting via the glycine site of the NMDAR. This article reviews the recent literature on positive modulators of the glycine site as a new modality for improving cognitive function in central nervous system pathology, including traumatic and ischemic brain injuries, neuroinflammation, and neuropsychiatric disorders. A sustained cognitive decline and NMDAR downregulation were reported in rodent models of TBI, developmental TBI, stroke, and lipopolysaccharide-induced neuroinflammation. Activation of the glycine/serine site by D-cycloserine (DCS) or D-serine ameliorated these cognitive deficits. Recent reviews and reports on the use of DCS and D-serine to modify memory function in a wide range of psychiatric conditions are generally positive. Taken together, the preclinical and clinical studies provide new, additional support for the notion that activation of the glycine/serine site should be considered a novel therapeutic approach to cognitive impairments. Specifically, as DCS is an approved drug, its translation into clinical practice should be advocated.