Publications by authors named "Krishnan M Dhandapani"

70 Publications

Cannabidiol Ameliorates Cognitive Function via Regulation of IL-33 and TREM2 Upregulation in a Murine Model of Alzheimer's Disease.

J Alzheimers Dis 2021 ;80(3):973-977

Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA, USA.

There is a dire need for due innovative therapeutic modalities to improve outcomes of AD patients. In this study, we tested whether cannabidiol (CBD) improves outcomes in a translational model of familial AD and to investigate if CBD regulates interleukin (IL)-33 and triggering receptor expressed on myeloid cells 2 (TREM2), which are associated with improved cognitive function. CBD was administered to 5xFAD mice, which recapitulate early onset, familial AD. Behavioral tests and immunoassays were used to evaluate cognitive and motor outcomes. Our findings suggest that CBD treatment enhanced IL-33 and TREM2 expression, ameliorated the symptoms of AD, and retarded cognitive decline.
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http://dx.doi.org/10.3233/JAD-210026DOI Listing
January 2021

AMPK induces regulatory innate lymphoid cells after traumatic brain injury.

JCI Insight 2021 01 11;6(1). Epub 2021 Jan 11.

Department of Neurosurgery, and.

The CNS is regarded as an immunoprivileged organ, evading routine immune surveillance; however, the coordinated development of immune responses profoundly influences outcomes after brain injury. Innate lymphoid cells (ILCs) are cytokine-producing cells that are critical for the initiation, modulation, and resolution of inflammation, but the functional relevance and mechanistic regulation of ILCs are unexplored after acute brain injury. We demonstrate increased proliferation of all ILC subtypes within the meninges for up to 1 year after experimental traumatic brain injury (TBI) while ILCs were present within resected dura and elevated within cerebrospinal fluid (CSF) of moderate-to-severe TBI patients. In line with energetic derangements after TBI, inhibition of the metabolic regulator, AMPK, increased meningeal ILC expansion, whereas AMPK activation suppressed proinflammatory ILC1/ILC3 and increased the frequency of IL-10-expressing ILC2 after TBI. Moreover, intracisternal administration of IL-33 activated AMPK, expanded ILC2, and suppressed ILC1 and ILC3 within the meninges of WT and Rag1-/- mice, but not Rag1-/- IL2rg-/- mice. Taken together, we identify AMPK as a brake on the expansion of proinflammatory, CNS-resident ILCs after brain injury. These findings establish a mechanistic framework whereby immunometabolic modulation of ILCs may direct the specificity, timing, and magnitude of cerebral immunity.
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http://dx.doi.org/10.1172/jci.insight.126766DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821592PMC
January 2021

Cannabidiol (CBD) modulation of apelin in acute respiratory distress syndrome.

J Cell Mol Med 2020 11 15;24(21):12869-12872. Epub 2020 Oct 15.

Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, University, Augusta, GA, USA.

Considering lack of target-specific antiviral treatment and vaccination for COVID-19, it is absolutely exigent to have an effective therapeutic modality to reduce hospitalization and mortality rate as well as to improve COVID-19-infected patient outcomes. In a follow-up study to our recent findings indicating the potential of Cannabidiol (CBD) in the treatment of acute respiratory distress syndrome (ARDS), here we show for the first time that CBD may ameliorate the symptoms of ARDS through up-regulation of apelin, a peptide with significant role in the central and peripheral regulation of immunity, CNS, metabolic and cardiovascular system. By administering intranasal Poly (I:C), a synthetic viral dsRNA, while we were able to mimic the symptoms of ARDS in a murine model, interestingly, there was a significant decrease in the expression of apelin in both blood and lung tissues. CBD treatment was able to reverse the symptoms of ARDS towards a normal level. Importantly, CBD treatment increased the apelin expression significantly, suggesting a potential crosstalk between apelinergic system and CBD may be the therapeutic target in the treatment of inflammatory diseases such as COVID-19 and many other pathologic conditions.
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http://dx.doi.org/10.1111/jcmm.15883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686987PMC
November 2020

Revisiting Traumatic Brain Injury: From Molecular Mechanisms to Therapeutic Interventions.

Biomedicines 2020 Sep 29;8(10). Epub 2020 Sep 29.

Department of Neurosurgery, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.

Studying the complex molecular mechanisms involved in traumatic brain injury (TBI) is crucial for developing new therapies for TBI. Current treatments for TBI are primarily focused on patient stabilization and symptom mitigation. However, the field lacks defined therapies to prevent cell death, oxidative stress, and inflammatory cascades which lead to chronic pathology. Little can be done to treat the mechanical damage that occurs during the primary insult of a TBI; however, secondary injury mechanisms, such as inflammation, blood-brain barrier (BBB) breakdown, edema formation, excitotoxicity, oxidative stress, and cell death, can be targeted by therapeutic interventions. Elucidating the many mechanisms underlying secondary injury and studying targets of neuroprotective therapeutic agents is critical for developing new treatments. Therefore, we present a review on the molecular events following TBI from inflammation to programmed cell death and discuss current research and the latest therapeutic strategies to help understand TBI-mediated secondary injury.
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http://dx.doi.org/10.3390/biomedicines8100389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7601301PMC
September 2020

Neurological consequences of COVID-19: what have we learned and where do we go from here?

J Neuroinflammation 2020 Sep 30;17(1):286. Epub 2020 Sep 30.

Department of Neurosurgery, Medical College of Georgia, Augusta University, 1120 15th Street, 30912, Augusta, Georgia.

The coronavirus disease-19 (COVID-19) pandemic is an unprecedented worldwide health crisis. COVID-19 is caused by SARS-CoV-2, a highly infectious pathogen that is genetically similar to SARS-CoV. Similar to other recent coronavirus outbreaks, including SARS and MERS, SARS-CoV-2 infected patients typically present with fever, dry cough, fatigue, and lower respiratory system dysfunction, including high rates of pneumonia and acute respiratory distress syndrome (ARDS); however, a rapidly accumulating set of clinical studies revealed atypical symptoms of COVID-19 that involve neurological signs, including headaches, anosmia, nausea, dysgeusia, damage to respiratory centers, and cerebral infarction. These unexpected findings may provide important clues regarding the pathological sequela of SARS-CoV-2 infection. Moreover, no efficacious therapies or vaccines are currently available, complicating the clinical management of COVID-19 patients and emphasizing the public health need for controlled, hypothesis-driven experimental studies to provide a framework for therapeutic development. In this mini-review, we summarize the current body of literature regarding the central nervous system (CNS) effects of SARS-CoV-2 and discuss several potential targets for therapeutic development to reduce neurological consequences in COVID-19 patients.
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http://dx.doi.org/10.1186/s12974-020-01957-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7525232PMC
September 2020

Cannabidiol Modulates Cytokine Storm in Acute Respiratory Distress Syndrome Induced by Simulated Viral Infection Using Synthetic RNA.

Cannabis Cannabinoid Res 2020 2;5(3):197-201. Epub 2020 Sep 2.

Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, Georgia, USA.

In the absence of effective antivirals and vaccination, the pandemic of COVID-19 remains the most significant challenge to our health care system in decades. There is an urgent need for definitive therapeutic intervention. Clinical reports indicate that the cytokine storm associated with acute respiratory distress syndrome (ARDS) is the leading cause of mortality in severe cases of some respiratory viral infections, including COVID-19. In recent years, cannabinoids have been investigated extensively due to their potential effects on the human body. Among all cannabinoids, cannabidiol (CBD) has demonstrated potent anti-inflammatory effects in a variety of pathological conditions. Therefore, it is logical to explore whether CBD can reduce the cytokine storm and treat ARDS. In this study, we show that intranasal application of Poly(I:C), a synthetic analogue of viral double-stranded RNA, simulated symptoms of severe viral infections inducing signs of ARDS and cytokine storm. The administration of CBD downregulated the level of proinflammatory cytokines and ameliorated the clinical symptoms of Poly I:C-induced ARDS. Our results suggest a potential protective role for CBD during ARDS that may extend CBD as part of the treatment of COVID-19 by reducing the cytokine storm, protecting pulmonary tissues, and re-establishing inflammatory homeostasis.
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http://dx.doi.org/10.1089/can.2020.0043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480719PMC
September 2020

Neutrophil extracellular traps exacerbate neurological deficits after traumatic brain injury.

Sci Adv 2020 May 29;6(22):eaax8847. Epub 2020 May 29.

Department of Neurosurgery, Medical College of Georgia, Augusta University, Augusta, GA, USA.

Traumatic brain injury (TBI) is a major cause of mortality and morbidity. Preventative measures reduce injury incidence and/or severity, yet one-third of hospitalized patients with TBI die from secondary pathological processes that develop during supervised care. Neutrophils, which orchestrate innate immune responses, worsen TBI outcomes via undefined mechanisms. We hypothesized that formation of neutrophil extracellular traps (NETs), a purported mechanism of microbial trapping, exacerbates acute neurological injury after TBI. NET formation coincided with cerebral hypoperfusion and tissue hypoxia after experimental TBI, while elevated circulating NETs correlated with reduced serum deoxyribonuclease-1 (DNase-I) activity in patients with TBI. Functionally, Toll-like receptor 4 (TLR4) and the downstream kinase peptidylarginine deiminase 4 (PAD4) mediated NET formation and cerebrovascular dysfunction after TBI. Last, recombinant human DNase-I degraded NETs and improved neurological function. Thus, therapeutically targeting NETs may provide a mechanistically innovative approach to improve TBI outcomes without the associated risks of global neutrophil depletion.
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http://dx.doi.org/10.1126/sciadv.aax8847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7259928PMC
May 2020

Bone Marrow Derived Extracellular Vesicles Activate Osteoclast Differentiation in Traumatic Brain Injury Induced Bone Loss.

Cells 2019 01 17;8(1). Epub 2019 Jan 17.

Departments of Orthopedic Surgery, Augusta University, Augusta, GA 30912, USA.

Traumatic brain injury (TBI) is a major source of worldwide morbidity and mortality. Patients suffering from TBI exhibit a higher susceptibility to bone loss and an increased rate of bone fractures; however, the underlying mechanisms remain poorly defined. Herein, we observed significantly lower bone quality and elevated levels of inflammation in bone and bone marrow niche after controlled cortical impact-induced TBI in in vivo CD-1 mice. Further, we identified dysregulated NF-κB signaling, an established mediator of osteoclast differentiation and bone loss, within the bone marrow niche of TBI mice. Ex vivo studies revealed increased osteoclast differentiation in bone marrow-derived cells from TBI mice, as compared to sham injured mice. We also found bone marrow derived extracellular vesicles (EVs) from TBI mice enhanced the colony forming ability and osteoclast differentiation efficacy and activated NF-κB signaling genes in bone marrow-derived cells. Additionally, we showed that miRNA-1224 up-regulated in bone marrow-derived EVs cargo of TBI. Taken together, we provide evidence that TBI-induced inflammatory stress on bone and the bone marrow niche may activate NF-κB leading to accelerated bone loss. Targeted inhibition of these signaling pathways may reverse TBI-induced bone loss and reduce fracture rates.
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http://dx.doi.org/10.3390/cells8010063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6356398PMC
January 2019

Remote ischemic post-conditioning promotes hematoma resolution via AMPK-dependent immune regulation.

J Exp Med 2018 10 6;215(10):2636-2654. Epub 2018 Sep 6.

Department of Neurosurgery, Medical College of Georgia, Augusta University, Augusta, GA

Spontaneous intracerebral hemorrhage (ICH) produces the highest acute mortality and worst outcomes of all stroke subtypes. Hematoma volume is an independent determinant of ICH patient outcomes, making clot resolution a primary goal of clinical management. Herein, remote-limb ischemic post-conditioning (RIC), the repetitive inflation-deflation of a blood pressure cuff on a limb, accelerated hematoma resolution and improved neurological outcomes after ICH in mice. Parabiosis studies revealed RIC accelerated clot resolution via a humoral-mediated mechanism. Whereas RIC increased anti-inflammatory macrophage activation, myeloid cell depletion eliminated the beneficial effects of RIC after ICH. Myeloid-specific inactivation of the metabolic regulator, AMPKα1, attenuated RIC-induced anti-inflammatory macrophage polarization and delayed hematoma resolution, providing a molecular link between RIC and immune activation. Finally, chimera studies implicated myeloid CD36 expression in RIC-mediated neurological recovery after ICH. Thus, RIC, a clinically well-tolerated therapy, noninvasively modulates innate immune responses to improve ICH outcomes. Moreover, immunometabolic changes may provide pharmacodynamic blood biomarkers to clinically monitor the therapeutic efficacy of RIC.
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http://dx.doi.org/10.1084/jem.20171905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6170180PMC
October 2018

NADPH oxidase 2 deletion enhances neurogenesis following traumatic brain injury.

Free Radic Biol Med 2018 08 18;123:62-71. Epub 2018 May 18.

Charlie Norwood Medical Center, One Freedom Way, Augusta, GA 30904, USA; Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30909, USA. Electronic address:

The NADPH oxidase (NOX) enzyme family is a major source of reactive oxygen species (ROS) and contributor to the secondary pathology underlying traumatic brain injury (TBI). However, little is known about how NOX-derived ROS influences the proliferation and cell-fate determination of neural stem/progenitor cells (NSCs/NPCs) following TBI. In the current study, we found that deletion of NOX2 (NOX2-KO) significantly decreases the population of radial glia-like NSCs and neuroblasts but maintains the population of non-radial Sox2 expressing stem cells under physiological (non-injury) conditions. Surprisingly, the brains of NOX2-KO mice demonstrated a robust increase in the number of neuroblasts during the first week after TBI, as compared to the wild-type group. This increase may result from an enhanced proliferation of NPCs in a lower ROS environment after brain injury, as further examination revealed a significant increase of dividing neuroblasts in both NOX2-KO and NOX inhibitor-treated mouse brain during the first week following TBI. Finally, 5-Bromo-2'-deoxyuridine (BrdU) lineage tracing demonstrated a significantly increased number of newborn neurons were present in the perilesional cortex of NOX2-KO mice at 5 weeks post TBI, indicating that deletion of NOX2 promotes long-term neurogenesis in the injured brain following TBI. Altogether, these findings suggest that targeting NOX through genetic deletion or inhibition enhances post-injury neurogenesis, which may be beneficial for recovery following TBI.
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http://dx.doi.org/10.1016/j.freeradbiomed.2018.05.069DOI Listing
August 2018

NADPH oxidases in traumatic brain injury - Promising therapeutic targets?

Redox Biol 2018 06 15;16:285-293. Epub 2018 Mar 15.

Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA. Electronic address:

Traumatic brain injury (TBI) is a major cause of death and disability worldwide. Despite intense investigation, no neuroprotective agents for TBI have yet translated to the clinic. Recent efforts have focused on identifying potential therapeutic targets that underlie the secondary TBI pathology that evolves minutes to years following the initial injury. Oxidative stress is a key player in this complex cascade of secondary injury mechanisms and prominently contributes to neurodegeneration and neuroinflammation. NADPH oxidase (NOX) is a family of enzymes whose unique function is to produce reactive oxygen species (ROS). Human post-mortem and animal studies have identified elevated NOX2 and NOX4 levels in the injured brain, suggesting that these two NOXs are involved in the pathogenesis of TBI. In support of this, NOX2 and NOX4 deletion studies have collectively revealed that targeting NOX enzymes can reduce oxidative stress, attenuate neuroinflammation, promote neuronal survival, and improve functional outcomes following TBI. In addition, NOX inhibitor studies have confirmed these findings and demonstrated an extended critical window of efficacious TBI treatment. Finally, the translational potential, caveats, and future directions of the field are highlighted and discussed throughout the review.
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http://dx.doi.org/10.1016/j.redox.2018.03.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5952873PMC
June 2018

Deletion of NADPH oxidase 4 reduces severity of traumatic brain injury.

Free Radic Biol Med 2018 03 31;117:66-75. Epub 2018 Jan 31.

Charlie Norwood VA Medical Center, One Freedom Way, Augusta, GA 30904, USA; Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA. Electronic address:

Traumatic brain injury (TBI) contributes to over 30% of injury-related deaths and is a major cause of disability without effective clinical therapies. Oxidative stress contributes to neurodegeneration, neuroinflammation, and neuronal death to amplify the primary injury after TBI. NADPH oxidase (NOX) is a major source of reactive oxygen species following brain injury. Our current study addresses the functional role of the NOX4 isoform in the damaged cortex following TBI. Adult male C57BL/6 J and NOX4 mice received a controlled cortical impact and lesion size, NOX4 expression, oxidative stress, neurodegeneration, and cell death were assessed in the injured cerebral cortex. The results revealed that NOX4 mRNA and protein expression were significantly upregulated at 1-7 days post-TBI in the injured cerebral cortex. Expression of the oxidative stress markers, 8-OHdG, 4-HNE, and nitrotyrosine was upregulated at 2 and 4 days post-TBI in the WT injured cerebral cortex, and nitrotyrosine primarily colocalized with neurons. In the NOX4 mice, expression of these oxidative stress markers, 8-OHdG, 4-HNE, and nitrotyrosine were significantly attenuated at both timepoints. In addition, examination of NOX4 mice revealed a reduced number of apoptotic (TUNEL) and degenerating (FJB) cells in the perilesional cortex after TBI, as well as a smaller lesion size compared with the WT group. The results of this study implicate a functional role for NOX4 in TBI induced oxidative damage and neurodegeneration and raise the possibility that targeting NOX4 may have therapeutic efficacy in TBI.
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http://dx.doi.org/10.1016/j.freeradbiomed.2018.01.031DOI Listing
March 2018

Human Neural Stem Cell Extracellular Vesicles Improve Tissue and Functional Recovery in the Murine Thromboembolic Stroke Model.

Transl Stroke Res 2018 10 28;9(5):530-539. Epub 2017 Dec 28.

ArunA Biomedical, Athens, GA, 30602, USA.

Over 700 drugs have failed in stroke clinical trials, an unprecedented rate thought to be attributed in part to limited and isolated testing often solely in "young" rodent models and focusing on a single secondary injury mechanism. Here, extracellular vesicles (EVs), nanometer-sized cell signaling particles, were tested in a mouse thromboembolic (TE) stroke model. Neural stem cell (NSC) and mesenchymal stem cell (MSC) EVs derived from the same pluripotent stem cell (PSC) line were evaluated for changes in infarct volume as well as sensorimotor function. NSC EVs improved cellular, tissue, and functional outcomes in middle-aged rodents, whereas MSC EVs were less effective. Acute differences in lesion volume following NSC EV treatment were corroborated by MRI in 18-month-old aged rodents. NSC EV treatment has a positive effect on motor function in the aged rodent as indicated by beam walk, instances of foot faults, and strength evaluated by hanging wire test. Increased time with a novel object also indicated that NSC EVs improved episodic memory formation in the rodent. The therapeutic effect of NSC EVs appears to be mediated by altering the systemic immune response. These data strongly support further preclinical development of a NSC EV-based stroke therapy and warrant their testing in combination with FDA-approved stroke therapies.
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http://dx.doi.org/10.1007/s12975-017-0599-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6132936PMC
October 2018

Selective activation of cannabinoid receptor-2 reduces neuroinflammation after traumatic brain injury via alternative macrophage polarization.

Brain Behav Immun 2018 02 24;68:224-237. Epub 2017 Oct 24.

Department of Neurosurgery, Medical College of Georgia, Augusta University, United States; Department of Medical Laboratory, Imaging, and Radiological Sciences, College of Allied Health Sciences, Augusta University, United States. Electronic address:

Inflammation is an important mediator of secondary neurological injury after traumatic brain injury (TBI). Endocannabinoids, endogenously produced arachidonate based lipids, have recently emerged as powerful anti-inflammatory compounds, yet the molecular and cellular mechanisms underlying these effects are poorly defined. Endocannabinoids are physiological ligands for two known cannabinoid receptors, CB1R and CB2R. In the present study, we hypothesized that selective activation of CB2R attenuates neuroinflammation and reduces neurovascular injury after TBI. Using a murine controlled cortical impact (CCI) model of TBI, we observed a dramatic upregulation of CB2R within infiltrating myeloid cells beginning at 72 h. Administration of the selective CB2R agonist, GP1a (1-5 mg/kg), attenuated pro-inflammatory M1 macrophage polarization, increased anti-inflammatory M2 polarization, reduced edema development, enhanced cerebral blood flow, and improved neurobehavioral outcomes after TBI. In contrast, the CB2R antagonist, AM630, worsened outcomes. Taken together, our findings support the development of selective CB2R agonists as a therapeutic strategy to improve TBI outcomes while avoiding the psychoactive effects of CB1R activation.
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http://dx.doi.org/10.1016/j.bbi.2017.10.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5767553PMC
February 2018

Regulatory role of NADPH oxidase 2 in the polarization dynamics and neurotoxicity of microglia/macrophages after traumatic brain injury.

Free Radic Biol Med 2017 12 21;113:119-131. Epub 2017 Sep 21.

Charlie Norwood Medical Center, One Freedom Way, Augusta, GA 30904, USA; Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, 1120 15th Street, CA-4004, Augusta, GA 30912, USA. Electronic address:

Traumatic brain injury (TBI) is a leading cause of death and disability. Secondary injuries that develop after the initial trauma contribute to long-lasting neurophysiological deficits. Polarization of microglia/macrophages toward a pro-inflammatory (M1) phenotype may increase the progression of secondary injury following TBI; however, the regulatory and functional mechanisms underlying these changes remain poorly defined. In the present study, we showed elevated expression of NADPH oxidase 2 (NOX2) and activation of nuclear factor-kappa B (NF-κB) predominantly in microglia/macrophages at 4- and 7-days after controlled cortical impact in mice. Delayed inhibition of NOX2, beginning one day after TBI, reduced reactive oxygen species production of myeloid cells and protected neurons from oxidative damage. Moreover, delayed NOX inhibition or global genetic NOX2 knockout suppressed the M1 "pro-inflammatory" profile of microglia/macrophages and simultaneously increased the M2 "anti-inflammatory" profile in the injured brain. These changes were associated with marked down-regulation of the classical NF-κB pathway in microglia/macrophages and reduced production of pro-inflammatory cytokines, tumor necrosis factor-α and interleukin-1β, after TBI. Finally, we demonstrated that wild-type microglia/macrophages isolated from the ipsilateral cortex at 7 days post-TBI were neurotoxic to co-cultured primary neurons, whereas this neurotoxicity was largely attenuated in microglia/macrophages from NOX2-KO mice. Taken together, our study shows a direct link between NOX2 and the NF-κB pathway in microglia/macrophages after TBI, and it provides a novel mechanism by which NOX2 activation leads to the enhanced inflammatory response and neuronal damage after brain injury. Our data also supports the therapeutic potential of targeting NOX2, which may provide efficacy with an extended therapeutic window after TBI.
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http://dx.doi.org/10.1016/j.freeradbiomed.2017.09.017DOI Listing
December 2017

Increased Innate Lymphoid Cells in Periodontal Tissue of the Murine Model of Periodontitis: The Role of AMP-Activated Protein Kinase and Relevance for the Human Condition.

Front Immunol 2017 15;8:922. Epub 2017 Aug 15.

Augusta University, Augusta, GA, United States.

Innate lymphoid cells (ILCs) are master regulators of immune and inflammatory responses, but their own regulatory mechanisms and functional roles of their subtypes (i.e., ILC1s-ILC3s) remain largely unresolved. Interestingly, AMP-activated protein kinase (AMPK), influences inflammatory responses, but its role in modulation of ILCs is not known. Periodontitis is a prevalent disorder with impairment of immune and inflammatory responses contributing importantly to its pathogenesis; however, neither the role of ILCs nor AMPK has been explored in this condition. We tested the hypotheses that (a) periodontitis increases ILCs and expression of relevant cytokines thereby contributing to inflammation and (b) knockdown of AMPK worsens indices of periodontitis in association with further increases in subtypes of ILCs and cytokine expression. The studies utilized wild-type (WT) and AMPK knockout (KO) mice, subjected to ligature-induced periodontitis or sham operation, in association with the use of micro-CT for assessment of bone loss, immunogold electron microscopy to show presence of ILCs in periodontal tissues, flow cytometry for quantitative assessment of subtypes of ILCs and RT-polymerase chain reaction analyses to measure mRNA expression of several relevant cytokines. The results for the first time show (a) presence of each subtype of ILCs in periodontal tissues of sham control and periodontitis animals, (b) that periodontitis is associated with increased frequencies of ILC1s-ILC3s with the effect more marked for ILC2s and differential phenotypic marker expression for ILC3s, (c) that AMPK KO mice display exacerbation of indices of periodontitis in association with further increases in the frequency of subtypes of ILCs with persistence of ILC2s effect, and (d) that periodontitis increased mRNA for interleukin (IL)-33, but not IL-5 or IL-13, in WT mice but expression of these cytokines was markedly increased in AMPK KO mice with periodontitis. Subsequently, we showed that human periodontitis is associated with increases in each ILCs subtype with the effect more marked for ILC2s and that mRNA expressions for IL-33 and IL-5 are markedly greater for sites affected by periodontitis than healthy sites. Collectively, these novel observations indicate a pivotal role for ILCs in pathogenesis of periodontitis and that AMPK is a regulator of their phenotype expression in this condition.
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http://dx.doi.org/10.3389/fimmu.2017.00922DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5559469PMC
August 2017

NADPH Oxidase 2 Regulates NLRP3 Inflammasome Activation in the Brain after Traumatic Brain Injury.

Oxid Med Cell Longev 2017 12;2017:6057609. Epub 2017 Jul 12.

Charlie Norwood VA Medical Center, One Freedom Way, Augusta, GA 30904, USA.

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. After the initial primary mechanical injury, a complex secondary injury cascade involving oxidative stress and neuroinflammation follows, which may exacerbate the injury and complicate the healing process. NADPH oxidase 2 (NOX2) is a major contributor to oxidative stress in TBI pathology, and inhibition of NOX2 is neuroprotective. The NLRP3 inflammasome can become activated in response to oxidative stress, but little is known about the role of NOX2 in regulating NLRP3 inflammasome activation following TBI. In this study, we utilized NOX2 knockout mice to study the role of NOX2 in mediating NLRP3 inflammasome expression and activation following a controlled cortical impact. Expression of NLRP3 inflammasome components NLRP3 and apoptosis-associated speck-like protein containing a CARD (ASC), as well as its downstream products cleaved caspase-1 and interleukin-1 (IL-1), was robustly increased in the injured cerebral cortex following TBI. Deletion of NOX2 attenuated the expression, assembly, and activity of the NLRP3 inflammasome via a mechanism that was associated with TXNIP, a sensor of oxidative stress. The results support the notion that NOX2-dependent inflammasome activation contributes to TBI pathology.
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http://dx.doi.org/10.1155/2017/6057609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5529650PMC
April 2018

White matter damage after traumatic brain injury: A role for damage associated molecular patterns.

Biochim Biophys Acta Mol Basis Dis 2017 10 19;1863(10 Pt B):2614-2626. Epub 2017 May 19.

Department of Neurosurgery, Medical College of Georgia, Augusta University, Augusta, GA, United States. Electronic address:

Traumatic brain injury (TBI) is a leading cause of mortality and long-term morbidity worldwide. Despite decades of pre-clinical investigation, therapeutic strategies focused on acute neuroprotection failed to improve TBI outcomes. This lack of translational success has necessitated a reassessment of the optimal targets for intervention, including a heightened focus on secondary injury mechanisms. Chronic immune activation correlates with progressive neurodegeneration for decades after TBI; however, significant challenges remain in functionally and mechanistically defining immune activation after TBI. In this review, we explore the burgeoning evidence implicating the acute release of damage associated molecular patterns (DAMPs), such as adenosine 5'-triphosphate (ATP), high mobility group box protein 1 (HMGB1), S100 proteins, and hyaluronic acid in the initiation of progressive neurological injury, including white matter loss after TBI. The role that pattern recognition receptors, including toll-like receptor and purinergic receptors, play in progressive neurological injury after TBI is detailed. Finally, we provide support for the notion that resident and infiltrating macrophages are critical cellular targets linking acute DAMP release with adaptive immune responses and chronic injury after TBI. The therapeutic potential of targeting DAMPs and barriers to clinical translational, in the context of TBI patient management, are discussed.
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http://dx.doi.org/10.1016/j.bbadis.2017.05.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5653450PMC
October 2017

Activation of Myeloid TLR4 Mediates T Lymphocyte Polarization after Traumatic Brain Injury.

J Immunol 2017 05 24;198(9):3615-3626. Epub 2017 Mar 24.

Department of Neurosurgery, Medical College of Georgia, Augusta University, Augusta, GA 30912;

Traumatic brain injury (TBI) is a major public health issue, producing significant patient mortality and poor long-term outcomes. Increasing evidence suggests an important, yet poorly defined, role for the immune system in the development of secondary neurologic injury over the days and weeks following a TBI. In this study, we tested the hypothesis that peripheral macrophage infiltration initiates long-lasting adaptive immune responses after TBI. Using a murine controlled cortical impact model, we used adoptive transfer, transgenic, and bone marrow chimera approaches to show increased infiltration and proinflammatory (classically activated [M1]) polarization of macrophages for up to 3 wk post-TBI. Monocytes purified from the injured brain stimulated the proliferation of naive T lymphocytes, enhanced the polarization of T effector cells (T1/T17), and decreased the production of regulatory T cells in an MLR. Similarly, elevated T effector cell polarization within blood and brain tissue was attenuated by myeloid cell depletion after TBI. Functionally, C3H/HeJ (TLR4 mutant) mice reversed M1 macrophage and T1/T17 polarization after TBI compared with C3H/OuJ (wild-type) mice. Moreover, brain monocytes isolated from C3H/HeJ mice were less potent stimulators of T lymphocyte proliferation and T1/T17 polarization compared with C3H/OuJ monocytes. Taken together, our data implicate TLR4-dependent, M1 macrophage trafficking/polarization into the CNS as a key mechanistic link between acute TBI and long-term, adaptive immune responses.
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http://dx.doi.org/10.4049/jimmunol.1601948DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5417078PMC
May 2017

Role of interleukin-10 in the neuroprotective effect of the Angiotensin Type 2 Receptor agonist, compound 21, after ischemia/reperfusion injury.

Eur J Pharmacol 2017 Mar 10;799:128-134. Epub 2017 Feb 10.

Charlie Norwood VA Medical Center, Center for Pharmacy and Experimental Therapeutics, University of Georgia, College of Pharmacy, Augusta, GA, USA. Electronic address:

Introduction: We and others have shown that the angiotensin type 2 (AT2) receptor agonist, compound 21 (C21), provides neuroprotection and enhances recovery in rodent stroke models yet the mechanism involved is not known. Moreover, C21 treatment is associated with an anti-inflammatory response. Here we tested the hypothesis that C21 mediates neuroprotection by upregulating the neuroprotective and anti-inflammatory cytokine, interleukin (IL)-10.

Methods: Wistar rats were subjected to 3h-middle cerebral artery suture occlusion and treated at reperfusion with C21 (0.03mg/kg)±IL-10 neutralizing antibody (0.1mg/kg) both given i.p. Infarct size, behavioral outcomes, and molecular analysis were performed at 24h post-injury. Primary rat neurons were used to test the direct neuroprotective effect of C21 in vitro.

Results: C21 treatment reduced infarct size, improved functional outcome and decreased the pro-inflammatory cytokine, tumor necrosis factor alpha (TNF-α) in the ischemic hemisphere compared to saline. Anti-IL-10 co-treatment blocked the C21-induced reduction in infarct size and inflammation, and the improvement in behavioral outcome. In vitro, C21 treatment increased neuron survival and reduced cell apoptosis after oxygen glucose deprivation (OGD) and OGD/reoxygenation. These effects were mediated through AT2R stimulation.

Conclusion: C21 provides direct neuroprotection as well as indirect protection through IL-10.
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http://dx.doi.org/10.1016/j.ejphar.2017.02.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5411859PMC
March 2017

NADPH oxidase in brain injury and neurodegenerative disorders.

Mol Neurodegener 2017 01 17;12(1). Epub 2017 Jan 17.

Charlie Norwood VA Medical Center, One Freedom Way, Augusta, GA, 30904, USA.

Oxidative stress is a common denominator in the pathology of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis, as well as in ischemic and traumatic brain injury. The brain is highly vulnerable to oxidative damage due to its high metabolic demand. However, therapies attempting to scavenge free radicals have shown little success. By shifting the focus to inhibit the generation of damaging free radicals, recent studies have identified NADPH oxidase as a major contributor to disease pathology. NADPH oxidase has the primary function to generate free radicals. In particular, there is growing evidence that the isoforms NOX1, NOX2, and NOX4 can be upregulated by a variety of neurodegenerative factors. The majority of recent studies have shown that genetic and pharmacological inhibition of NADPH oxidase enzymes are neuroprotective and able to reduce detrimental aspects of pathology following ischemic and traumatic brain injury, as well as in chronic neurodegenerative disorders. This review aims to summarize evidence supporting the role of NADPH oxidase in the pathology of these neurological disorders, explores pharmacological strategies of targeting this major oxidative stress pathway, and outlines obstacles that need to be overcome for successful translation of these therapies to the clinic.
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http://dx.doi.org/10.1186/s13024-017-0150-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5240251PMC
January 2017

The Histone Deacetylase Inhibitor Suberoylanilide Hydroxamic Acid (SAHA) Confers Acute Neuroprotection After Intracerebral Hemorrhage in Mice.

Transl Stroke Res 2016 Apr 4;7(2):141-8. Epub 2015 Sep 4.

Department of Neurosurgery, Georgia Regents University, 1120 15th Street CA1010, Augusta, GA, 30912, USA.

Spontaneous intracerebral hemorrhage (ICH) is a stroke subtype with no effective treatment. Though ICH is known to induce severe neurological damage, the molecular mechanisms of neurological injury after ICH remain largely unclear. Given the emerging role of epigenetic mechanisms in neurodegeneration, the present study evaluated whether suberoylanilide hydroxamic acid (SAHA: vorinostat), a clinically well-tolerated pan-histone deacetylase inhibitor (HDACi), would attenuate neurological injury and improve functional outcomes in a preclinical model of ICH. Mice were administered with SAHA or vehicle after an induction of ICH and acute neuronal death, glial activation, and neurological outcomes were assessed. SAHA-treated mice exhibited less neurodegeneration with concomitant improvement in neurological outcomes than vehicle-treated mice. Furthermore, SAHA downregulated glial activation and the expression of heme oxygenase-1, a stress-inducible enzyme that plays critical roles in neurological damage after ICH. Altogether, the data strongly suggest the role of epigenetic mechanisms in inducing neurological injury after ICH and raise the possible clinical utility of SAHA for therapeutic intervention after ICH.
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http://dx.doi.org/10.1007/s12975-015-0421-yDOI Listing
April 2016

Overexpression of Nrf2 attenuates Carmustine-induced cytotoxicity in U87MG human glioma cells.

BMC Cancer 2015 Mar 13;15:118. Epub 2015 Mar 13.

Background: Malignant glioma is one of the most devastating tumors in adults with poor patient prognosis. Notably, glioma often exhibits resistance to conventional chemotherapeutic approaches, complicating patient treatments. However, the molecular mediators involved in tumor chemoresistance remain poorly defined, creating a barrier to the successful management of glioma. In the present study, we hypothesized that the antioxidant transcription factor, Nrf2 (nuclear factor erythroid-derived 2 like 2), attenuates glioma cytotoxicity to Carmustine (BCNU), a widely used chemotherapeutic agent known to modulate cellular oxidative balance.

Methods: To test the hypothesis, we employed human malignant glioma cell line, U87MG and overexpression of Nrf2 in glioma cells was achieved using both pharmacological and genetic approaches.

Results: Notably, induction of Nrf2 was associated with increased expression of heme oxygenase-1 (HO-1), a stress inducible enzyme involved in anti-oxidant defense. In addition, over expression of Nrf2 in U87MG cells significantly attenuated the cytotoxicity of Carmustine as evidenced by both cellular viability assay and flow cytometry analysis. Consistent with this, antioxidants such as glutathione and N-acetyl cysteine significantly reduced Carmustine mediated glioma cytotoxicity.

Conclusions: Taken together, these data strongly implicate an unexplored role of Nrf2 in glioma resistance to Carmustine and raise the possible use of Nrf2 inhibitors as adjunct to Carmustine for the treatment of malignant glioma.
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http://dx.doi.org/10.1186/s12885-015-1134-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4365816PMC
March 2015

Remote ischemic postconditioning: harnessing endogenous protection in a murine model of vascular cognitive impairment.

Transl Stroke Res 2015 Feb 29;6(1):69-77. Epub 2014 Oct 29.

Departments of Neurology, Georgia Regents University, 1120 15th St, CA 1014, Augusta, GA, 30912, USA.

We previously reported that remote limb ischemic conditioning (RLIC; PERconditioning) during acute stroke confers neuroprotection, possibly due to increased cerebral blood flow (CBF). Vascular cognitive impairment (VCI) is a growing threat to public health without any known treatment. The bilateral common carotid artery stenosis (BCAS) mouse model is regarded as the most valid model for VCI. We hypothesized that RLIC (postconditioning; RIPostC) will augment CBF during chronic cerebral hypoperfusion (CCH) and prevent cognitive impairment in the BCAS model. BCAS using customized microcoil was performed in C57/B6 male mice to establish CCH. A week after the BCAS surgery, mice were treated with RIPostC-therapy once daily for 2 weeks. CBF was measured with laser speckle contrast imager at different time points. Cognitive testing was performed at 4-week post-BCAS, and brain tissue was harvested for biochemistry. BCAS led to chronic hypoperfusion resulting into impaired cognitive function as tested by novel object recognition (NOR). Histological examinations revealed that BCAS triggered inflammatory responses and caused frequent vacuolization and cell death. BCAS also increased the generation and accumulation of amyloid beta protein (Aβ), resulting into the loss of white matter (WM) and myelin basic protein (MBP). RIPostC-therapy showed both acute increase as well as sustained improvement in CBF even after the cessation of therapy for a week. RIPostC improved cognitive function, inhibited inflammatory responses, prevented the cell death, reduced the generation and accumulation of Aβ, and protected WM integrity. RIPostC is effective in the BCAS model and could be an attractive low-cost conventional therapy for aged individuals with VCI. The mechanisms by which RIPostC improves CBF and attenuates tissue damage need to be investigated in the future.
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http://dx.doi.org/10.1007/s12975-014-0374-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4297613PMC
February 2015

A 2 × 2 factorial design for the combination therapy of minocycline and remote ischemic perconditioning: efficacy in a preclinical trial in murine thromboembolic stroke model.

Exp Transl Stroke Med 2014 9;6:10. Epub 2014 Oct 9.

Department of Neurology, Georgia Regents University, Augusta, GA 30912, USA ; Program in Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, Augusta, USA.

Background: After the failure of so many drugs and therapies for acute ischemic stroke, innovative approaches are needed to develop new treatments. One promising strategy is to test combinations of agents in the pre-hospital setting prior to the administration of intravenous tissue plasminogen activator (IV-tPA) and/ or the use of mechanical reperfusion devices in the hospital.

Methods: We performed a 2 × 2 factorial design preclinical trial where we tested minocycline (MINO), remote ischemic perconditioning (RIPerC) and their combination treatment in a thromboembolic clot model of stroke in mice, without IV-tPA or later treated with IV-tPA at 4 hours post-stroke. Cerebral blood flow (CBF) was measured by laser speckle contrast imaging (LSCI), behavioral outcomes as neurological deficit score (NDS) and adhesive tape removal test, and infarct size measurement were performed at 48 hours post-stroke. Mice within the experimental sets were randomized for the different treatments, and all outcome measures were blinded.

Results: RIPerC significantly improved CBF as measured by LSCI in both with and without tPA treated mice (P < 0.001). MINO and RIPerC treatment were effective alone at reducing infarct size (p < 0.0001) and improving short-term functional outcomes (p < 0.001) in the tPA and non-tPA treated animals. The combination treatment of MINO and RIPerC significantly reduced the infarct size greater than either intervention alone (p < 0.05). There were trends in favor of improving functional outcomes after combination treatment of MINO and RIPerC; however combination treatment group was not significantly different than the individual treatments of MINO and RIPerC. There was no "statistical" interaction between minocycline and RIPerC treatments indicating that the effects of RIPerC and MINO were additive and not synergistic on the outcome measures.

Conclusion: In the future, combining these two safe and low cost interventions in the ambulance has the potential to "freeze" the penumbra and improve outcomes in stroke patients. This pre-clinical 2 × 2 design can be easily translated into a pre-hospital clinical trial.
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http://dx.doi.org/10.1186/2040-7378-6-10DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4204390PMC
October 2014

Activation of the endothelin system mediates pathological angiogenesis during ischemic retinopathy.

Am J Pathol 2014 Nov 6;184(11):3040-51. Epub 2014 Sep 6.

Vascular Biology Center, Georgia Regents University, Augusta, Georgia; Vision Discovery Institute, Georgia Regents University, Augusta, Georgia; Charlie Norwood VA Medical Center, Augusta, Georgia; Department of Cellular Biology and Anatomy, Georgia Regents University, Augusta, Georgia. Electronic address:

Retinopathy of prematurity adversely affects premature infants because of oxygen-induced damage of the immature retinal vasculature, resulting in pathological neovascularization (NV). Our pilot studies using the mouse model of oxygen-induced retinopathy (OIR) showed marked increases in angiogenic mediators, including endothelins and endothelin receptor (EDNR) A. We hypothesized that activation of the endothelin system via EDNRA plays a causal role in pathological angiogenesis and up-regulation of angiogenic mediators, including vascular endothelial growth factor A (VEGFA) in OIR. Mice were exposed to 75% oxygen from post-natal day P7 to P12, treated with either vehicle or EDNRA antagonist BQ-123 or EDNRB antagonist BQ-788 on P12, and kept at room air from P12 to P17 (ischemic phase). RT-PCR analysis revealed increased levels of EDN2 and EDNRA mRNA, and Western blot analysis revealed increased EDN2 expression during the ischemic phase. EDNRA inhibition significantly increased vessel sprouting, resulting in enhanced physiological angiogenesis and decreased pathological NV, whereas EDNRB inhibition modestly improved vascular repair. OIR triggered significant increases in VEGFA protein and mRNA for delta-like ligand 4, apelin, angiopoietin-2, and monocyte chemoattractant protein-1. BQ-123 treatment significantly reduced these alterations. EDN2 expression was localized to retinal glia and pathological NV tufts of the OIR retinas. EDN2 also induced VEGFA protein expression in cultured astrocytes. In conclusion, inhibition of the EDNRA during OIR suppresses pathological NV and promotes physiological angiogenesis.
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http://dx.doi.org/10.1016/j.ajpath.2014.07.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4215027PMC
November 2014

Therapeutic inducers of the HSP70/HSP110 protect mice against traumatic brain injury.

J Neurochem 2014 Sep 4;130(5):626-41. Epub 2014 Jul 4.

Charlie Norwood VA Medical Center (CNVAMC), Augusta, Georgia, USA; Molecular Chaperone Biology, Georgia Regents University, Augusta, Georgia, USA; Cancer Center, Georgia Regents University, Augusta, Georgia, USA; Georgia Regents University (GRU) and Medical College of Georgia, Augusta, Georgia, USA.

Traumatic brain injury (TBI) induces severe harm and disability in many accident victims and combat-related activities. The heat-shock proteins Hsp70/Hsp110 protect cells against death and ischemic damage. In this study, we used mice deficient in Hsp110 or Hsp70 to examine their potential requirement following TBI. Data indicate that loss of Hsp110 or Hsp70 increases brain injury and death of neurons. One of the mechanisms underlying the increased cell death observed in the absence of Hsp110 and Hsp70 following TBI is the increased expression of reactive oxygen species-induced p53 target genes Pig1, Pig8, and Pig12. To examine whether drugs that increase the levels of Hsp70/Hsp110 can protect cells against TBI, we subjected mice to TBI and administered Celastrol or BGP-15. In contrast to Hsp110- or Hsp70i-deficient mice that were not protected following TBI and Celastrol treatment, there was a significant improvement of wild-type mice following administration of these drugs during the first week following TBI. In addition, assessment of neurological injury shows significant improvement in contextual and cued fear conditioning tests and beam balance in wild-type mice that were treated with Celastrol or BGP-15 following TBI compared to TBI-treated mice. These studies indicate a significant role of Hsp70/Hsp110 in neuronal survival following TBI and the beneficial effects of Hsp70/Hsp110 inducers toward reducing the pathological consequences of TBI. Our data indicate that loss of Hsp110 or Hsp70 in mice increases brain injury following TBI. (a) One of the mechanisms underlying the increased cell death observed in the absence of these Hsps following TBI is the increased expression of ROS-induced p53 target genes known as Pigs. In addition, (b) using drugs (Celastrol or BGP-15) to increase Hsp70/Hsp110 levels protect cells against TBI, suggesting the beneficial effects of Hsp70/Hsp110 inducers to reduce the pathological consequences of TBI.
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http://dx.doi.org/10.1111/jnc.12781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4237206PMC
September 2014

Perispinal etanercept for post-stroke neurological and cognitive dysfunction: scientific rationale and current evidence.

CNS Drugs 2014 Aug;28(8):679-97

Department of Pathology and Anatomical Sciences and Program for Neuroscience, School of Medicine and Biomedical Sciences, The State University of New York, Buffalo, NY, USA.

There is increasing recognition of the involvement of the immune signaling molecule, tumor necrosis factor (TNF), in the pathophysiology of stroke and chronic brain dysfunction. TNF plays an important role both in modulating synaptic function and in the pathogenesis of neuropathic pain. Etanercept is a recombinant therapeutic that neutralizes pathologic levels of TNF. Brain imaging has demonstrated chronic intracerebral microglial activation and neuroinflammation following stroke and other forms of acute brain injury. Activated microglia release TNF, which mediates neurotoxicity in the stroke penumbra. Recent observational studies have reported rapid and sustained improvement in chronic post-stroke neurological and cognitive dysfunction following perispinal administration of etanercept. The biological plausibility of these results is supported by independent evidence demonstrating reduction in cognitive dysfunction, neuropathic pain, and microglial activation following the use of etanercept, as well as multiple studies reporting improvement in stroke outcome and cognitive impairment following therapeutic strategies designed to inhibit TNF. The causal association between etanercept treatment and reduction in post-stroke disability satisfy all of the Bradford Hill Criteria: strength of the association; consistency; specificity; temporality; biological gradient; biological plausibility; coherence; experimental evidence; and analogy. Recognition that chronic microglial activation and pathologic TNF concentration are targets that may be therapeutically addressed for years following stroke and other forms of acute brain injury provides an exciting new direction for research and treatment.
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http://dx.doi.org/10.1007/s40263-014-0174-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4110406PMC
August 2014

Necrostatin-1 reduces neurovascular injury after intracerebral hemorrhage.

Int J Cell Biol 2014 6;2014:495817. Epub 2014 Mar 6.

Department of Neurosurgery, Medical College of Georgia, Georgia Regents University, 1120 15th Street, Augusta, GA 30912, USA.

Intracerebral hemorrhage (ICH) is the most common form of hemorrhagic stroke, accounting for 15% of all strokes. ICH has the highest acute mortality and the worst long-term prognosis of all stroke subtypes. Unfortunately, the dearth of clinically effective treatment options makes ICH the least treatable form of stroke, emphasizing the need for novel therapeutic targets. Recent work by our laboratory identified a novel role for the necroptosis inhibitor, necrostatin-1, in limiting neurovascular injury in tissue culture models of hemorrhagic injury. In the present study, we tested the hypothesis that necrostatin-1 reduces neurovascular injury after collagenase-induced ICH in mice. Necrostatin-1 significantly reduced hematoma volume by 54% at 72 h after-ICH, as compared to either sham-injured mice or mice administered an inactive, structural analogue of necrostatin-1. Necrostatin-1 also limited cell death by 48%, reduced blood-brain barrier opening by 51%, attenuated edema development to sham levels, and improved neurobehavioral outcomes after ICH. These data suggest a potential clinical utility for necrostatin-1 and/or novel necroptosis inhibitors as an adjunct therapy to reduce neurological injury and improve patient outcomes after ICH.
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http://dx.doi.org/10.1155/2014/495817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3963111PMC
April 2014

High mobility group box protein-1 promotes cerebral edema after traumatic brain injury via activation of toll-like receptor 4.

Glia 2014 Jan 28;62(1):26-38. Epub 2013 Oct 28.

Department of Neurosurgery, Medical College of Georgia, Georgia Regents University, Augusta, Georgia.

Traumatic brain injury (TBI) is a major cause of mortality and morbidity worldwide. Cerebral edema, a life-threatening medical complication, contributes to elevated intracranial pressure (ICP) and a poor clinical prognosis after TBI. Unfortunately, treatment options to reduce post-traumatic edema remain suboptimal, due in part, to a dearth of viable therapeutic targets. Herein, we tested the hypothesis that cerebral innate immune responses contribute to edema development after TBI. Our results demonstrate that high-mobility group box protein 1 (HMGB1) was released from necrotic neurons via a NR2B-mediated mechanism. HMGB1 was clinically associated with elevated ICP in patients and functionally promoted cerebral edema after TBI in mice. The detrimental effects of HMGB1 were mediated, at least in part, via activation of microglial toll-like receptor 4 (TLR4) and the subsequent expression of the astrocytic water channel, aquaporin-4 (AQP4). Genetic or pharmacological (VGX-1027) TLR4 inhibition attenuated the neuroinflammatory response and limited post-traumatic edema with a delayed, clinically implementable therapeutic window. Human and rodent tissue culture studies further defined the cellular mechanisms demonstrating neuronal HMGB1 initiates the microglial release of interleukin-6 (IL-6) in a TLR4 dependent mechanism. In turn, microglial IL-6 increased the astrocytic expression of AQP4. Taken together, these data implicate microglia as key mediators of post-traumatic brain edema and suggest HMGB1-TLR4 signaling promotes neurovascular dysfunction after TBI.
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http://dx.doi.org/10.1002/glia.22581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4503251PMC
January 2014