IL-12 sensing in neurons induces neuroprotective CNS tissue adaptation and attenuates neuroinflammation in mice DOI Creative Commons
Myrto Andreadou, Florian Ingelfinger, Donatella De Feo

et al.

Nature Neuroscience, Journal Year: 2023, Volume and Issue: 26(10), P. 1701 - 1712

Published: Sept. 25, 2023

Abstract Interleukin-12 (IL-12) is a potent driver of type 1 immunity. Paradoxically, in autoimmune conditions, including the CNS, IL-12 reduces inflammation. The underlying mechanism behind these opposing properties and involved cellular players remain elusive. Here we map receptor (IL-12R) expression to NK T cells as well neurons oligodendrocytes. Conditionally ablating IL-12R across cell types adult mice assessing their susceptibility experimental encephalomyelitis revealed that neuroprotective role mediated by neuroectoderm-derived cells, specifically neurons, not immune cells. In human brain tissue from donors with multiple sclerosis, observe an distribution comparable mice, suggesting similar mechanisms humans. Combining flow cytometry, bulk single-nucleus RNA sequencing, reveal IL-12-induced adaption preventing early neurodegeneration sustaining trophic factor release during neuroinflammation, thereby maintaining CNS integrity mice.

Language: Английский

Deferoxamine ameliorates neurological dysfunction by inhibiting ferroptosis and neuroinflammation after traumatic brain injury DOI
Hao‐Ran Jia,

Xilei Liu,

Yiyao Cao

et al.

Brain Research, Journal Year: 2023, Volume and Issue: 1812, P. 148383 - 148383

Published: May 4, 2023

Language: Английский

Citations

27
Dysregulated brain-gut axis in the setting of traumatic brain injury: review of mechanisms and anti-inflammatory pharmacotherapies DOI Creative Commons

Mahmoud G. El Baassiri,

Zachariah Raouf,

Sarah Badin

et al.

Journal of Neuroinflammation, Journal Year: 2024, Volume and Issue: 21(1)

Published: May 10, 2024

Abstract Traumatic brain injury (TBI) is a chronic and debilitating disease, associated with high risk of psychiatric neurodegenerative diseases. Despite significant advancements in improving outcomes, the lack effective treatments underscore urgent need for innovative therapeutic strategies. The brain-gut axis has emerged as crucial bidirectional pathway connecting gastrointestinal (GI) system through an intricate network neuronal, hormonal, immunological pathways. Four main pathways are primarily implicated this crosstalk, including systemic immune system, autonomic enteric nervous systems, neuroendocrine microbiome. TBI induces profound changes gut, initiating unrestrained vicious cycle that exacerbates axis. Alterations gut include mucosal damage malabsorption nutrients/electrolytes, disintegration intestinal barrier, increased infiltration cells, dysmotility, dysbiosis, enteroendocrine cell (EEC) dysfunction disruption (ENS) (ANS). Collectively, these further contribute to neuroinflammation neurodegeneration via gut-brain In review article, we elucidate roles various anti-inflammatory pharmacotherapies capable attenuating dysregulated inflammatory response along TBI. These agents hormones such serotonin, ghrelin, progesterone, ANS regulators beta-blockers, lipid-lowering drugs like statins, flora modulators probiotics antibiotics. They attenuate by targeting distinct both post-TBI. exhibit promising potential mitigating inflammation enhancing neurocognitive outcomes patients.

Language: Английский

Citations

12
Preclinical characterization of macrophage-adhering gadolinium micropatches for MRI contrast after traumatic brain injury in pigs DOI
Liwen Wang, Yongsheng Gao, Vineeth Chandran Suja

et al.

Science Translational Medicine, Journal Year: 2024, Volume and Issue: 16(728)

Published: Jan. 3, 2024

The choroid plexus (ChP) of the brain plays a central role in orchestrating recruitment peripheral leukocytes into nervous system (CNS) through blood-cerebrospinal fluid (BCSF) barrier pathological conditions, thus offering unique niche to diagnose CNS disorders. We explored whether magnetic resonance imaging ChP could be optimized for mild traumatic injury (mTBI). mTBI induces subtle, yet influential, changes and is currently severely underdiagnosed. hypothesized that sufficient alterations cause infiltration circulating BCSF developed macrophage-adhering gadolinium [Gd(III)]-loaded anisotropic micropatches (GLAMs), specifically designed image infiltrating immune cells. GLAMs are hydrogel-based discoidal microparticles adhere macrophages without phagocytosis. present fabrication process prepare at scale demonstrate their loading with Gd(III) high relaxivities, key indicator effectiveness enhancing contrast clarity medical imaging. In vitro experiments primary murine porcine demonstrated also under shear stress did not affect macrophage viability or functions. Studies model confirmed intravenously administered provide differential signal lateral ventricles doses 500- 1000-fold lower than those used current clinical standard Gadavist. Under same Gadavist offer clinically doses. Our results suggest facilitate diagnosis.

Language: Английский

Citations

9
Past, present, and future of cell replacement therapy for parkinson’s disease: a novel emphasis on host immune responses DOI Creative Commons
Tae Yoon Park, Jeha Jeon, Young Cha

et al.

Cell Research, Journal Year: 2024, Volume and Issue: 34(7), P. 479 - 492

Published: May 22, 2024

Abstract Parkinson’s disease (PD) stands as the second most common neurodegenerative disorder after Alzheimer’s disease, and its prevalence continues to rise with aging global population. Central pathophysiology of PD is specific degeneration midbrain dopamine neurons (mDANs) in substantia nigra. Consequently, cell replacement therapy (CRT) has emerged a promising treatment approach, initially supported by various open-label clinical studies employing fetal ventral mesencephalic (fVM) cells. Despite initial favorable results, fVM intrinsic logistical limitations that hinder transition standard for PD. Recent efforts field have shifted focus towards utilization human pluripotent stem cells, including embryonic cells induced surmount existing challenges. However, regardless transplantable sources (e.g., xenogeneic, allogeneic, or autologous), poor variable survival implanted remains major obstacle. Emerging evidence highlights pivotal role host immune responses following transplantation influencing mDANs, underscoring an important area further research. In this comprehensive review, building upon insights derived from previous studies, we delve into functional ramifications on efficacy grafted Furthermore, explore potential strategic approaches modulate response, ultimately aiming optimal outcomes future applications CRT

Language: Английский

Citations

9
Mechanistic and therapeutic relationships of traumatic brain injury and γ-amino-butyric acid (GABA) DOI
Jeffrey M. Witkin, Hana Shafique, Rok Cerne

et al.

Pharmacology & Therapeutics, Journal Year: 2024, Volume and Issue: 256, P. 108609 - 108609

Published: Feb. 16, 2024

Language: Английский

Citations

8
Targeting Cytokine-Mediated Inflammation in Brain Disorders: Developing New Treatment Strategies DOI Creative Commons
Rahul Mallick, Sanjay Basak, Parimal Chowdhury

et al.

Pharmaceuticals, Journal Year: 2025, Volume and Issue: 18(1), P. 104 - 104

Published: Jan. 15, 2025

Cytokine-mediated inflammation is increasingly recognized for playing a vital role in the pathophysiology of wide range brain disorders, including neurodegenerative, psychiatric, and neurodevelopmental problems. Pro-inflammatory cytokines such as interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) cause neuroinflammation, alter function, accelerate disease development. Despite progress understanding these pathways, effective medicines targeting are still limited. Traditional anti-inflammatory immunomodulatory drugs peripheral inflammatory illnesses. Still, they face substantial hurdles when applied to central nervous system (CNS), blood-brain barrier (BBB) unwanted systemic effects. This review highlights developing treatment techniques modifying cytokine-driven focusing on advances that selectively target critical involved pathology. Novel approaches, cytokine-specific inhibitors, antibody-based therapeutics, gene- RNA-based interventions, sophisticated drug delivery systems like nanoparticles, show promise with respect lowering neuroinflammation greater specificity safety. Furthermore, developments biomarker discoveries neuroimaging improving our ability monitor responses, allowing more accurate personalized regimens. Preclinical clinical trial data demonstrate therapeutic potential tailored techniques. However, significant challenges remain, across BBB reducing off-target As research advances, creation personalized, cytokine-centered therapeutics has therapy landscape illnesses, giving patients hope better results higher quality life.

Language: Английский

Citations

1
Effects of Tasimelteon Treatment on Traumatic Brain Injury Through NRF-2/HO-1 and RIPK1/RIPK3/MLKL Pathways in Rats DOI Creative Commons
Eyyüp Sabri Özden, Mustafa Soner Özcan, Mehtap Savran

et al.

Molecular Neurobiology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 29, 2025

Abstract Secondary brain damageafter traumatic injury (TBI) involves oxidative stress, neuroinflammation, apoptosis, and necroptosis can be reversed by understanding these molecular pathways. The objective of this study was to examine the impact tasimelteon (Tasi) administration on through nuclear factor erythroid 2-related 2 (NRF-2)/heme oxygenase-1 (HO-1) receptor-interacting protein kinase 1 (RIPK1)/receptor-interacting 3 (RIPK3)/mixed lineage domain-like (MLKL) pathways in rats with TBI. Thirty-two male Wistar albino weighing 300–350 g were randomly divided into four groups: control group, trauma Tasi-1 group (trauma + mg/kg Tasi intraperitoneally), Tasi-10 10 intraperitoneally). At end experimental phase, after sacrifice, blood samples tissue collected for biochemical, histopathological, immunohistochemical, genetic analyses. increased total antioxidant status decreased oxidant stress index. In addition, caused histopathological changes characterized a markedly reduced hemorrhage area group. Normal meningeal structure observed Immunohistochemical analysis indicated that also expression interferon-gamma, caspase-3, tumor necrosis factor-alpha tissue. Although NRF-2 HO-1 decreased, RIPK1/RIPK3/MLKL gene due trauma. However, treatment all findings. protected against NRF-2/HO-1

Language: Английский

Citations

1
NINJ1-mediated plasma membrane rupture of pyroptotic endothelial cells exacerbates blood-brain barrier destruction caused by neutrophil extracellular traps in traumatic brain injury DOI Creative Commons

Xiaobo Zheng,

Xue Wang, Sheng-Qing Gao

et al.

Cell Death Discovery, Journal Year: 2025, Volume and Issue: 11(1)

Published: Feb. 20, 2025

Abstract Brain endothelial cell (bEC) dysfunction is the main factor of blood-brain barrier (BBB) breakdown, which triggers a vicious cycle aggravating traumatic brain injury (TBI) pathogenesis. Previous studies have revealed that neutrophil extracellular traps (NETs) released by neutrophils can lead to BBB disruption, but there lack research on underlying mechanisms after TBI. Here, excessive NETs were found in both contused tissue and circulation following We could activate TLR4/NF-κB pathway induce bEC pyroptosis, led disruption During this process, ninjurin-1 (NINJ1) was activated pyroptotic bECs, it mediated release high mobility group box 1 protein (HMGB1) via plasma membrane rupture (PMR) promote NET formation. NINJ1-mediated HMGB1 aggravated accumulation forming circle Knockdown NINJ1 rescued formation, attenuated leakage, improved neurological outcomes may represent promising target for alleviating NET-induced destruction other related injuries

Language: Английский

Citations

1
Role of Inflammation in Traumatic Brain Injury–Associated Risk for Neuropsychiatric Disorders: State of the Evidence and Where Do We Go From Here DOI Creative Commons
Victoria B. Risbrough, Melonie N. Vaughn, Samantha F. Friend

et al.

Biological Psychiatry, Journal Year: 2021, Volume and Issue: 91(5), P. 438 - 448

Published: Nov. 24, 2021

Language: Английский

Citations

42
The contribution of altered neuronal autophagy to neurodegeneration DOI Creative Commons
Alessia Filippone, Emanuela Esposito,

Deborah Mannino

et al.

Pharmacology & Therapeutics, Journal Year: 2022, Volume and Issue: 238, P. 108178 - 108178

Published: March 26, 2022

Defects in cellular functions related to altered protein homeostasis and associated progressive accumulation of pathological intracellular material is a critical process involved the pathogenesis many neurodegenerative disorders, including Alzheimer's disease Parkinson's disease. Autophagy an essential mechanism that ensures neuronal health by removing long-lived proteins or defective organelles doing so prevents cell toxicity death within central nervous system. Abundant evidence has shown autophagy pathways are disease, traumas system Spinal Cord Injury Traumatic Brain Injury. In this review, we aimed summarize latest studies on role plays brain these conditions, how knowledge can be leveraged for development novel therapeutics against them.

Language: Английский

Citations

37