Telmisartan Reduces LPS-Mediated Inflammation and Induces Autophagy of Microglia DOI Creative Commons
Kwame Ofori Affram, Zachary C. Janatpour, Nagesh C. Shanbhag

et al.

Neuroglia, Journal Year: 2024, Volume and Issue: 5(2), P. 182 - 201

Published: June 20, 2024

Background: Chronic neuroinflammation mediated by persistent microglial activation is strongly linked to neurodegeneration. Therefore, targeting could be beneficial in treating neurodegenerative disorders. Angiotensin receptor blockers (ARBs), commonly prescribed for high blood pressure, exhibit prominent anti-inflammatory effects the brain and are considered potential therapies diseases neurotrauma. Although all ARBs angiotensin II type I antagonists, some act through other signaling pathways, allowing multiple mechanisms of action. The not well understood. Methods: In this study, we compared eight different FDA-approved their ability reduce LPS stimulation primary microglia or BV2 cells analyses nitric oxide production, reactive oxygen species generation, mRNA proinflammatory cytokines. Finding specific unique telmisartan, interrogated pathways downstream effectors telmisartan activity on microglia. Results: Our findings indicate that showed greatest efficacy reducing induction (ROS) production Uniquely amongst ARBs, activated AMPK phosphorylation inhibited mTOR phosphorylation. Telmisartan’s was partially inhibitor compound C. Furthermore, uniquely induced markers autophagy an AMPK–mTOR–autophagy pathway. Telmisartan also reduced viability. cytotoxicity ameliorated a pan-caspase inhibitor, indicating link between apoptosis. Conclusions: We conclude has properties relative including potent actions autophagy, which may enable therapeutic uses.

Language: Английский

Microglia, Trem2, and Neurodegeneration DOI Creative Commons
Qian Shi,

Raul A. Gutierrez,

Manzoor A. Bhat

et al.

The Neuroscientist, Journal Year: 2024, Volume and Issue: unknown

Published: May 20, 2024

Microglia are a specialized type of neuroimmune cells that undergo morphological and molecular changes through multiple signaling pathways in response to pathological protein aggregates, neuronal death, tissue injury, or infections. express Trem2, which serves as receptor for multitude ligands enhancing their phagocytic activity. Trem2 has emerged critical modulator microglial activity, especially many neurodegenerative disorders. Human TREM2 mutations associated with an increased risk developing Alzheimer disease (AD) other diseases. plays dual roles neuroinflammation more specifically disease-associated microglia. Most recent developments on the mechanisms emphasizing its role uptake clearance amyloid β (Aβ) aggregates debris help protect preserve brain, encouraging. Although normally stimulates defense mechanisms, dysregulation can intensify inflammation, poses major therapeutic challenges. Recent approaches targeting via agonistic antibodies gene therapy methodologies present possible avenues reducing burden This review highlights promise target, Aβ-associated AD, calls mechanistic investigations understand context-specific effective therapies against

Language: Английский

Citations

10
Primary microglia cell cultures in translational research: Strengths and limitations DOI Creative Commons

István Pesti,

Ádám Légrádi, Eszter Farkas

et al.

Journal of Biotechnology, Journal Year: 2024, Volume and Issue: 386, P. 10 - 18

Published: March 20, 2024

Microglia are the resident macrophages in central nervous system, accounting for 10-15% of cell mass brain. Next to their physiological role development, monitoring neuronal function and maintenance homeostasis, microglia crucial brain's immune defense. Brain injury chronic neurological disorders associated with neuroinflammation, which activation is a element. acquire wide spectrum states diseased or injured brain, some neurotoxic. The investigation (patho)physiology therapeutic interventions targeting neuroinflammation substantial challenge. In addition vivo approaches, application vitro model systems has gained significant ground essential complement work. Primary cultures have proved be useful tool. offered opportunity explore mechanistic, molecular elements activation, secretome, efficacy treatments against neuroinflammation. As all systems, primary distinct strengths limitations weighed when experiments designed data interpreted. Here, we set out provide succinct overview advantages pitfalls use cultures, instructs refinement further development this technique remain toolbox researchers. Since there no conclusive therapy combat neurotoxicity linked acute brain neurodegenerative disorders, these research tools opportunities.

Language: Английский

Citations

7
CD300LF+ microglia impede the neuroinflammation following traumatic brain injury by inhibiting STING pathway DOI Creative Commons
Zhichao Lu,

Zongheng Liu,

Chenxing Wang

et al.

CNS Neuroscience & Therapeutics, Journal Year: 2024, Volume and Issue: 30(7)

Published: July 1, 2024

The diversity in microglial phenotypes and functions following traumatic brain injury (TBI) is poorly characterized. aim of this study was to explore precise targets for improving the prognosis TBI patients from a perspective.

Language: Английский

Citations

6
Recognition of Traumatic Brain Injury as a Chronic Condition: A Commentary DOI
John D. Corrigan, Flora M. Hammond, Angelle M. Sander

et al.

Journal of Neurotrauma, Journal Year: 2024, Volume and Issue: 41(23-24), P. 2602 - 2605

Published: Sept. 14, 2024

Many clinicians believe that residual impairments due to traumatic brain injury (TBI) are static once initial recovery has plateaued. That is, the effects of not expected change significantly over remainder a person's life. This assumption been called into question by several independent longitudinal studies showing long-term course TBI may be better characterized as

Language: Английский

Citations

5
Context is key: glucocorticoid receptor and corticosteroid therapeutics in outcomes after traumatic brain injury DOI Creative Commons

Morgan Taylor,

Olga N. Kokiko‐Cochran

Frontiers in Cellular Neuroscience, Journal Year: 2024, Volume and Issue: 18

Published: March 11, 2024

Traumatic brain injury (TBI) is a global health burden, and survivors suffer functional psychiatric consequences that can persist long after injury. TBI induces physiological stress response by activating the hypothalamic-pituitary-adrenal (HPA) axis, but effects of on become more complex in term. Clinical experimental evidence suggests lasting dysfunction TBI. Additionally, pre- post-injury both have negative impacts outcome following This bidirectional relationship between impedes recovery exacerbates TBI-induced cognitive dysfunction. Previous clinical studies explored use synthetic glucocorticoids as therapeutic for stress-related outcomes, these yielded mixed results. Furthermore, long-term steroid treatment associated with multiple side effects. There pressing need alternative approaches improve functionality Glucocorticoid receptor (GR) has been identified fundamental link immune responses, preclinical GR plays an important role microglia-mediated outcomes other neuroinflammatory conditions. In this review, we will summarize GR-mediated TBI, highlighting microglia. We discuss recent which target microglial context injury, suggest cell-specific interventions may be promising strategy pathophysiology.

Language: Английский

Citations

4
Traumatic injury causes selective degeneration and TDP-43 mislocalization in human iPSC-derivedC9orf72-associated ALS/FTD motor neurons DOI Creative Commons
Éric Martin,

Citlally Santacruz,

Angela Mitevska

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: March 26, 2024

ABSTRACT A hexanucleotide repeat expansion (HRE) in C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, patients with HRE exhibit a wide disparity clinical presentation age symptom onset suggesting an interplay between background environmental stressors. Neurotrauma as result traumatic brain or spinal cord injury has been shown to increase risk ALS/FTD epidemiological studies. Here, we combine patient-specific induced pluripotent stem cells (iPSCs) custom-built device deliver biofidelic stretch trauma patient isogenic control motor neurons (MNs) vitro . We find that mutant but not MNs selective degeneration after single incident severe trauma, which can be partially rescued by pretreatment antisense oligonucleotide. mild does leads cytoplasmic accumulation TDP-43 MNs. This mislocalization, only occurs briefly controls, eventually restored 6 days. Lastly, repeated ablates ability recover. These findings highlight alterations dynamics following demonstrate neurotrauma compounds neuropathology ALS/FTD. More broadly, our work establishes platform used interrogate mechanistic interactions neurotrauma.

Language: Английский

Citations

4
Diffuse Traumatic Brain Injury Induced Stimulator of Interferons (STING) Signaling in Microglia Drives Cortical Neuroinflammation, Neuronal Dysfunction, and Impaired Cognition DOI Creative Commons
Jonathan M. Packer,

Samantha G. Giammo,

Lynde M. Wangler

et al.

Research Square (Research Square), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 17, 2025

Abstract Neuropsychiatric complications including depression and cognitive impairment develop, persist, worsen in the years after traumatic brain injury (TBI), negatively affecting life lifespan. Inflammatory responses mediated by microglia are associated with transition from acute to chronic neuroinflammation TBI. Moreover, type I interferon (IFN-I) signaling is a key mediator of inflammation during this transition. Thus, purpose study was determine degree which microglia-specific knockout stimulator interferons (STING) influenced TBI-induced neuroinflammation, neuronal dysfunction, impairment. Here, microglial inducible STING (CX₃CR1Cre/ERT2 x STINGfl/fl) mice were created validated (mSTING-/-). Diffuse (midline fluid percussion) male female increased expression microglia, promoted morphological restructuring, induced robust cortical pathology 7 days post (dpi). These TBI-associated attenuated mSTING-/- mice. Increased astrogliosis rod-shaped TBI independent mSTING-/-. dpi, 237 differentially expressed genes (DEG) cortex functionally wildtype (STING+/+) associated STING, NF- κB, Interferon Alpha 85% Components reduced NeuN expression, lipofuscin, neurofilament light chain plasma dependent on mSTING. tasks (novel object recognition/location, NOR/NOL) at dpi Notably, deficits NOR/NOL unaffected global interferon-α/β receptor 1 (IFNAR1) In final study, RNA profile neurons STING+/+ assessed single nucleus RNA-sequencing. There TBI-dependent suppression homeostasis reductions CREB signaling, synaptogenesis, oxytocin increases cilium assembly PTEN signaling. Overall, prevented 50% DEGs neurons. Collectively, ablation attenuates IFN-dependent responses, inflammation, pathology,

Language: Английский

Citations

0
IDO1 modulates pain sensitivity and comorbid anxiety in chronic migraine through microglial activation and synaptic pruning DOI Creative Commons

Jiao Hu,

Wen-Juan Ji,

Gui-Yu Liu

et al.

Journal of Neuroinflammation, Journal Year: 2025, Volume and Issue: 22(1)

Published: Feb. 18, 2025

Language: Английский

Citations

0
Repetitive concussions promote microglia-mediated engulfment of presynaptic excitatory input associated with cognitive dysfunction DOI Creative Commons

Maryam Chahin,

Jochen Mutschler,

Stephanie P. Dzhuleva

et al.

Communications Biology, Journal Year: 2025, Volume and Issue: 8(1)

Published: Feb. 28, 2025

Abstract Concussions are a current health concern and account for the vast majority of head trauma. While symptoms after single impact usually transient, repetitive concussions, as often occur in sports, responsible persistent acute chronic deficits. Here, we used model bilateral midline-centered concussions mice to show that selectively induce impairments learning ability compared single-impact injuries. Since microglial cells their activation considered key factors degenerative pathology brain trauma, examined structure function cortex underlying hippocampus. We found only led significant long-lasting structural microglia an increase microglia-mediated engulfment presynaptic excitatory synapses, while elimination inhibitory synapses was not altered. density input did change during 6-week study period, hypothesize there is turnover following concussion can be compensated for, anatomically but behaviorally.

Language: Английский

Citations

0
Immunity in neuromodulation: probing neural and immune pathways in brain disorders DOI Creative Commons

Camille M. Hours,

Pia Vayssière,

Pierre Gressèns

et al.

Journal of Neuroinflammation, Journal Year: 2025, Volume and Issue: 22(1)

Published: April 28, 2025

Immunity finely regulates brain function. It is directly involved in the pathological processes of neurodegenerative diseases such as Parkinson's and Alzheimer's disease, post-stroke conditions, multiple sclerosis, traumatic injury, psychiatric disorders (mood disorders, major depressive disorder (MDD), anxiety psychosis schizophrenia, neurodevelopmental (NDD)). Neuromodulation currently a leading therapeutic strategy for treatment these but little yet known about its immune impact on neuronal function precise beneficial or harmful consequences. We review relevant clinical preclinical studies identify several specific modifications. These data not only provide insights into how neuromodulation acts to optimize immune-brain interactions, also pave way better understanding interactions processes.

Language: Английский

Citations

0