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Pharmacological Strategies for Neuroinflammation in Brain Injury

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: closed (31 October 2022) | Viewed by 22209

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Special Issue Editors

Dr. Vijay Kumar

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Guest Editor

Johns Hopkins University School of Medicine, Baltimore, MD, USA
Interests: neuroscience; bone biology; clinical trial; pharmacovigilance
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Anna-Leena Sirén

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Guest Editor

Department Neurosurgery, University Clinic of Würzburg, Würzburg, Germany
Interests: mechanisms of neuroprotection and -regeneration after brain injury; presynaptic structural plasticity; cell culture; transgenic animals; experimental models of brain trauma; behavioural testing; microscopy and imaging

Special Issue Information

Dear Colleagues,

Brain injury is a widespread and devastating problem that affects all ages. Only incremental improvements in treatment have been made over the past century. Brain injury management lacks effective pharmacological treatment. Persisting neuroinflammation is a significant component of secondary brain injury that can progressively worsen brain damage over time, thus allowing for opportunities to pharmacologically intervene. The management of neuroinflammation may be a promising target for improving patient outcomes. Substantial evidence suggests that therapies targeting the cytokine pathway may limit neuroinflammation. A better understanding of microglia heterogeneity may lead to more effective and precise therapeutic approaches and help to identify biomarkers for brain injury.

The effects of brain injury can be severe, including neurocognitive, physical, and psychosocial impairment. A significant unmet need to develop strategies to avoid long-term damage as a result of brain injury remains. The primary phase of brain injury describes immediate neuronal damage from contusions or oxygen deprivation caused by the global mass effect. The secondary injury occurs later via mechanisms such as reperfusion injury, delayed cortical edema, blood–brain barrier breakdown, and local electrolyte imbalance. These disturbances result in increased reactive oxygen species (ROS), calcium release, glutamate toxicity, lipid peroxidation (LP), and mitochondrial dysfunction, which lead to a vicious positive feedback loop of progressive oxidative stress-mediated neurodegeneration and neuroinflammation. Such a secondary injury may occur in the brain adjacent to the site of the initial injury, yielding an unexpected spread of cellular damage months after post-injury. ROS scavengers and LP product inhibitors have become candidate compounds to treat secondary brain injury. However, there are still no effective treatment options demonstrating improved outcomes in large, multi-center phase III trials. This may be partially attributed to a poor delivery to and an insufficient retention in the brain of the potential therapeutic agents.

Dr. Vijay Kumar
Prof. Dr. Anna-Leena Sirén
Guest Editors

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Keywords

Neuroinflammation in brain injury
Oxidative stress in brain injury
Blood–brain barrier and brain injury
Calcium and brain injury
Glutamate and brain injury
Lipid peroxidation and brain injury
Mitochondrial dysfunction and brain injury
Microglia and brain injury
Proteotoxicity and brain injury

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Published Papers (7 papers)

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Research

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16 pages, 22267 KiB

Open AccessArticle

Multifaceted Benefits of GDF11 Treatment in Spinal Cord Injury: In Vitro and In Vivo Studies

by May-Jywan Tsai, Li-Yu Fay, Dann-Ying Liou, Yi Chen, Ya-Tzu Chen, Meng-Jen Lee, Tsung-Hsi Tu, Wen-Cheng Huang and Henrich Cheng

Int. J. Mol. Sci. 2023, 24(1), 421; https://doi.org/10.3390/ijms24010421 - 27 Dec 2022

Cited by 2 | Viewed by 2727

Abstract

Traumatic spinal cord injury (SCI) initiates a series of cellular and molecular events that include both primary and secondary injury cascades. This secondary cascade provides opportunities for the delivery of therapeutic intervention. Growth differentiation factor 11 (GDF11), a member of the transforming growth factor-β (TGF-β) superfamily, regulates various biological processes in mammals. The effects of GDF11 in the nervous system were not fully elucidated. Here, we perform extensive in vitro and in vivo studies to unravel the effects of GDF11 on spinal cord after injury. In vitro culture studies showed that GDF11 increased the survival of both neuronal and oligodendroglial cells but decreased microglial cells. In stressed cultures, GDF11 effectively inhibited LPS stimulation and also protected neurons from ischemic damage. Intravenous GDF11 administration to rat after eliciting SCI significantly improved hindlimb functional restoration of SCI rats. Reduced neuronal connectivity was evident at 6 weeks post-injury and these deficits were markedly attenuated by GDF11 treatment. Furthermore, SCI-associated oligodendroglial alteration were more preserved by GDF11 treatment. Taken together, GDF11 infusion via intravenous route to SCI rats is beneficial, facilitating its therapeutic application in the future. Full article

(This article belongs to the Special Issue Pharmacological Strategies for Neuroinflammation in Brain Injury)

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19 pages, 4042 KiB

Open AccessArticle

Novel Hydroxypyridine Compound Protects Brain Cells against Ischemic Damage In Vitro and In Vivo

by Ekaterina Blinova, Egor Turovsky, Elena Eliseikina, Alexandra Igrunkova, Elena Semeleva, Grigorii Golodnev, Rita Termulaeva, Olga Vasilkina, Sofia Skachilova, Yan Mazov, Kirill Zhandarov, Ekaterina Simakina, Konstantin Belanov, Saveliy Zalogin and Dmitrii Blinov

Int. J. Mol. Sci. 2022, 23(21), 12953; https://doi.org/10.3390/ijms232112953 - 26 Oct 2022

Cited by 5 | Viewed by 2099

Abstract

A non-surgical pharmacological approach to control cellular vitality and functionality during ischemic and/or reperfusion-induced phases of strokes remains extremely important. The synthesis of 2-ethyl-6-methyl-3-hydroxypyridinium gammalactone-2,3-dehydro-L-gulonate (3-EA) was performed using a topochemical reaction. The cell-protective effects of 3-EA were studied on a model of glutamate excitotoxicity (GluTox) and glucose-oxygen deprivation (OGD) in a culture of NMRI mice cortical cells. Ca²⁺ dynamics was studied using fluorescent bioimaging and a Fura-2 probe, cell viability was assessed using cytochemical staining with propidium iodide, and gene expression was assessed by a real-time polymerase chain reaction. The compound anti-ischemic efficacy in vivo was evaluated on a model of irreversible middle cerebral artery (MCA) occlusion in Sprague-Dawley male rats. Brain morphological changes and antioxidant capacity were assessed one week after the pathology onset. The severity of neurological disorder was evaluated dynamically. 3-EA suppressed cortical cell death in a dose-dependent manner under the excitotoxic effect of glutamate and ischemia/reoxygenation. Pre-incubation of cerebral cortex cells with 10–100 µM 3-EA led to significant stagnation in Ca²⁺ concentration in a cytosol ([Ca2+]i) of neurons and astrocytes suffering GluTox and OGD. Decreasing intracellular Ca²⁺ and establishing a lower [Ca2+]i baseline inhibited necrotic cell death in an acute experiment. The mechanism of 3-EA cytoprotective action involved changes in the baseline and ischemia/reoxygenation-induced expression of genes encoding anti-apoptotic proteins and proteins of the oxidative status; this led to inhibition of the late irreversible stages of apoptosis. Incubation of brain cortex cells with 3-EA induced an overexpression of the anti-apoptotic genes BCL-2, STAT3, and SOCS3, whereas the expression of genes regulating necrosis and inflammation (TRAIL, MLKL, Cas-1, Cas-3, IL-1β and TNFa) were suppressed. 3-EA 18.0 mg/kg intravenous daily administration for 7 days following MCA occlusion preserved rats’ cortex neuron population, decreased the severity of neurological deficit, and spared antioxidant capacity of damaged tissues. 3-EA demonstrated proven short-term anti-ischemic activity in vivo and in vitro, which can be associated with antioxidant activity and the ability to target necrotic and apoptotic death. The compound may be considered a potential neuroprotective molecule for further pre-clinical investigation. Full article

(This article belongs to the Special Issue Pharmacological Strategies for Neuroinflammation in Brain Injury)

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21 pages, 6361 KiB

Open AccessArticle

Lupeol Treatment Attenuates Activation of Glial Cells and Oxidative-Stress-Mediated Neuropathology in Mouse Model of Traumatic Brain Injury

by Riaz Ahmad, Amjad Khan, Inayat Ur Rehman, Hyeon Jin Lee, Ibrahim Khan and Myeong Ok Kim

Int. J. Mol. Sci. 2022, 23(11), 6086; https://doi.org/10.3390/ijms23116086 - 29 May 2022

Cited by 18 | Viewed by 3879

Abstract

Traumatic brain injury (TBI) signifies a major cause of death and disability. TBI causes central nervous system (CNS) damage under a variety of mechanisms, including protein aggregation, mitochondrial dysfunction, oxidative stress, and neuroinflammation. Astrocytes and microglia, cells of the CNS, are considered the key players in initiating an inflammatory response after injury. Several evidence suggests that activation of astrocytes/microglia and ROS/LPO have the potential to cause more harmful effects in the pathological processes following traumatic brain injury (TBI). Previous studies have established that lupeol provides neuroprotection through modulation of inflammation, oxidative stress, and apoptosis in Aβ and LPS model and neurodegenerative disease. However, the effects of lupeol on apoptosis caused by inflammation and oxidative stress in TBI have not yet been investigated. Therefore, we explored the role of Lupeol on antiapoptosis, anti-inflammatory, and antioxidative stress and its potential mechanism following TBI. In these experiments, adult male mice were randomly divided into four groups: control, TBI, TBI+ Lupeol, and Sham group. Western blotting, immunofluorescence staining, and ROS/LPO assays were performed to investigate the role of lupeol against neuroinflammation, oxidative stress, and apoptosis. Lupeol treatment reversed TBI-induced behavioral and memory disturbances. Lupeol attenuated TBI-induced generation of reactive oxygen species/lipid per oxidation (ROS/LPO) and improved the antioxidant protein level, such as nuclear factor erythroid 2-related factor 2 (Nrf2) and heme-oxygenase 1 (HO-1) in the mouse brain. Similarly, our results indicated that lupeol treatment inhibited glial cell activation, p-NF-κB, and downstream signaling molecules, such as TNF-α, COX-2, and IL-1β, in the mouse cortex and hippocampus. Moreover, lupeol treatment also inhibited mitochondrial apoptotic signaling molecules, such as caspase-3, Bax, cytochrome-C, and reversed deregulated Bcl2 in TBI-treated mice. Overall, our study demonstrated that lupeol inhibits the activation of astrocytes/microglia and ROS/LPO that lead to oxidative stress, neuroinflammation, and apoptosis followed by TBI. Full article

(This article belongs to the Special Issue Pharmacological Strategies for Neuroinflammation in Brain Injury)

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18 pages, 6112 KiB

Open AccessArticle

Anti-Inflammatory Effect of IKK-Activated GSK-3β Inhibitory Peptide Prevented Nigrostriatal Neurodegeneration in the Rodent Model of Parkinson’s Disease

by Seulah Lee, Dong Geun Hong, Seonguk Yang, Jaehoon Kim, Minwoo Baek, Seoyeong Kim, Dinakaran Thirumalai, Hae Young Chung, Seung-Cheol Chang and Jaewon Lee

Int. J. Mol. Sci. 2022, 23(2), 998; https://doi.org/10.3390/ijms23020998 - 17 Jan 2022

Cited by 7 | Viewed by 3479

Abstract

Parkinson’s disease (PD) is a progressive movement disorder caused by nigrostriatal neurodegeneration. Since chronically activated neuroinflammation accelerates neurodegeneration in PD, we considered that modulating chronic neuroinflammatory response might provide a novel therapeutic approach. Glycogen synthase kinase 3 (GSK-3) is a multifunctional serine/threonine protein kinase with two isoforms, GSK-3α and GSK-3β, and GSK-3β plays crucial roles in inflammatory response, which include microglial migration and peripheral immune cell activation. GSK-3β inhibitory peptide (IAGIP) is specifically activated by activated inhibitory kappa B kinase (IKK), and its therapeutic effects have been demonstrated in a mouse model of colitis. Here, we investigated whether the anti-inflammatory effects of IAGIP prevent neurodegeneration in the rodent model of PD. IAGIP significantly reduced MPP⁺-induced astrocyte activation and inflammatory response in primary astrocytes without affecting the phosphorylations of ERK or JNK. In addition, IAGIP inhibited LPS-induced cell migration and p65 activation in BV-2 microglial cells. In vivo study using an MPTP-induced mouse model of PD revealed that intravenous IAGIP effectively prevented motor dysfunction and nigrostriatal neurodegeneration. Our findings suggest that IAGIP has a curative potential in PD models and could offer new therapeutic possibilities for targeting PD. Full article

(This article belongs to the Special Issue Pharmacological Strategies for Neuroinflammation in Brain Injury)

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10 pages, 1057 KiB

Open AccessArticle

FosL1 Is a Novel Target of Levetiracetam for Suppressing the Microglial Inflammatory Reaction

by Kouji Niidome, Ruri Taniguchi, Takeshi Yamazaki, Mayumi Tsuji, Kouichi Itoh and Yasuhiro Ishihara

Int. J. Mol. Sci. 2021, 22(20), 10962; https://doi.org/10.3390/ijms222010962 - 11 Oct 2021

Cited by 12 | Viewed by 3025

Abstract

We previously showed that the antiepileptic drug levetiracetam (LEV) inhibits microglial activation, but the mechanism remains unclear. The purpose of this study was to identify the target of LEV in microglial activity suppression. The mouse microglial BV-2 cell line, cultured in a ramified form, was pretreated with LEV and then treated with lipopolysaccharide (LPS). A comprehensive analysis of LEV targets was performed by cap analysis gene expression sequencing using BV-2 cells, indicating the transcription factors BATF, Nrf-2, FosL1 (Fra1), MAFF, and Spic as candidates. LPS increased AP-1 and Spic transcriptional activity, and LEV only suppressed AP-1 activity. FosL1, MAFF, and Spic mRNA levels were increased by LPS, and LEV only attenuated FosL1 mRNA expression, suggesting FosL1 as an LEV target. FosL1 protein levels were increased by LPS treatment and decreased by LEV pretreatment, similar to FosL1 mRNA levels. The FosL1 siRNA clearly suppressed the expression of TNFα and IL-1β. Pilocarpine-induced status epilepticus increased hippocampus FosL1 expression, along with inflammation. LEV treatment significantly suppressed FosL1 expression. Together, LEV reduces FosL1 expression and AP-1 activity in activated microglia, thereby suppressing neuroinflammation. LEV might be a candidate for the treatment of several neurological diseases involving microglial activation. Full article

(This article belongs to the Special Issue Pharmacological Strategies for Neuroinflammation in Brain Injury)

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Review

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16 pages, 1024 KiB

Open AccessReview

Cerebrospinal Fluid Biomarkers for Diagnosis and the Prognostication of Acute Ischemic Stroke: A Systematic Review

by Anant Naik, Olufunmilola Adeleye, Stefan W. Koester, Ethan A. Winkler, Joelle N. Hartke, Katherine Karahalios, Sandra Mihaljevic, Anupama Rani, Sudhanshu Raikwar, Jarrod D. Rulney, Shashvat M. Desai, Lea Scherschinski, Andrew F. Ducruet, Felipe C. Albuquerque, Michael T. Lawton, Joshua S. Catapano, Ashutosh P. Jadhav and Ruchira M. Jha

Int. J. Mol. Sci. 2023, 24(13), 10902; https://doi.org/10.3390/ijms241310902 - 30 Jun 2023

Cited by 7 | Viewed by 3011

Abstract

Despite the high incidence and burden of stroke, biological biomarkers are not used routinely in clinical practice to diagnose, determine progression, or prognosticate outcomes of acute ischemic stroke (AIS). Because of its direct interface with neural tissue, cerebrospinal fluid (CSF) is a potentially valuable source for biomarker development. This systematic review was conducted using three databases. All trials investigating clinical and preclinical models for CSF biomarkers for AIS diagnosis, prognostication, and severity grading were included, yielding 22 human trials and five animal studies for analysis. In total, 21 biomarkers and other multiomic proteomic markers were identified. S100B, inflammatory markers (including tumor necrosis factor-alpha and interleukin 6), and free fatty acids were the most frequently studied biomarkers. The review showed that CSF is an effective medium for biomarker acquisition for AIS. Although CSF is not routinely clinically obtained, a potential benefit of CSF studies is identifying valuable biomarkers from the pathophysiologic microenvironment that ultimately inform optimization of targeted low-abundance assays from peripheral biofluid samples (e.g., plasma). Several important catabolic and anabolic markers can serve as effective measures of diagnosis, etiology identification, prognostication, and severity grading. Trials with large cohorts studying the efficacy of biomarkers in altering clinical management are still needed. Full article

(This article belongs to the Special Issue Pharmacological Strategies for Neuroinflammation in Brain Injury)

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17 pages, 5890 KiB

Open AccessReview

Anti-Inflammatory Drug Therapy in Chronic Subdural Hematoma: A Systematic Review and Meta-Analysis of Prospective Randomized, Double-Blind and Placebo-Controlled Trials

by Martin Vychopen, Erdem Güresir and Johannes Wach

Int. J. Mol. Sci. 2022, 23(24), 16198; https://doi.org/10.3390/ijms232416198 - 19 Dec 2022

Cited by 4 | Viewed by 2607

Abstract

Althoughanti-inflammatory drug therapy has been identified as potentially beneficial for patients suffering from chronic subdural hematoma (cSDH), contemporary literature presents contradictory results. In this meta-analysis, we aimed to investigate the impact of anti-inflammatory drug therapy on mortality and outcome. We searched for eligible randomized, placebo-controlled prospective trials (RTCs) on PubMed, Embase and Medline until July 2022. From 97 initially identified articles, five RTCs met the criteria and were included in our meta-analysis. Our results illustrate significantly lower rates of recurrent cSDH (OR: 0.35; 95% CI: 0.21–0.58, p = 0.0001) in patients undergoing anti-inflammatory therapy. In the subgroup of patients undergoing primary conservative treatment, anti-inflammatory therapy was associated with lower rates of “switch to surgery” cases (OR: 0.30; 95% CI: 0.14–0.63, p = 0.002). Despite these findings, anti-inflammatory drugs seemed to be associated with higher mortality rates in patients undergoing surgery (OR: 1.76; 95% CI: 1.03–3.01, p = 0.04), although in the case of primary conservative treatment, no effect on mortality has been observed (OR: 2.45; 95% CI: 0.35–17.15, p = 0.37). Further multicentric prospective randomized trials are needed to evaluate anti-inflammatory drugs as potentially suitable therapy for asymptomatic patients with cSDH to avoid the necessity of surgical hematoma evacuation on what are predominantly elderly, vulnerable, patients. Full article

(This article belongs to the Special Issue Pharmacological Strategies for Neuroinflammation in Brain Injury)

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