Microglia depletion/repopulation does not affect light-induced retinal degeneration in mice

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 14

Published: Jan. 15, 2024

Reactive microglia are a hallmark of age-related retinal degenerative diseases including macular degeneration (AMD). These cells capable secreting neurotoxic substances that may aggravate inflammation leads to loss photoreceptors and impaired vision. Despite their role in driving detrimental inflammation, also play supporting roles the retina as they crucial cellular component regulatory innate immune system. In this study, we used colony stimulating factor 1 receptor (CSF1R)-antagonist PLX3397 investigate effects depletion repopulation mouse model acute mimics some aspects dry AMD. Our main goal was whether affects outcome light-induced degeneration. We found effectively decreased expression several key pro-inflammatory factors but unable influence extent determined by optical coherence tomography (OCT) histology. Interestingly, prominent cell debris accumulation outer under conditions depletion, presumably due lack efficient phagocytosis could not be compensated pigment epithelium. Moreover, our vivo experiments showed renewal did prevent rapid activation or preserve photoreceptor death light damage. conclude ablation strongly reduces cannot light-damage paradigm

Language: Английский

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“Neuroinflammation”: does it have a role in chronic pain? Evidence from human imaging

Pain, Journal Year: 2024, Volume and Issue: 165(11S), P. S58 - S67

Published: Oct. 14, 2024

Abstract Despite hundreds of studies demonstrating the involvement neuron-glia-immune interactions in establishment and/or maintenance persistent pain behaviors animals, role (or even occurrence) so-called “neuroinflammation” human has been an object contention for decades. Here, I present results multiple positron emission tomography (PET) measuring levels 18 kDa translocator protein (TSPO), a putative neuroimmune marker, individuals with various conditions. Overall, these suggest that brain TSPO PET signal: (1) is elevated, compared to healthy volunteers, chronic low back (with additional elevations spinal cord and neuroforamina), fibromyalgia, migraine other conditions characterized by pain; (2) spatial distribution exhibiting degree disorder specificity; (3) parametrically linked characteristics or comorbid symptoms (eg, nociplastic pain, fatigue, depression), as well measures function (ie, functional connectivity), regionally-specific manner. In this narrative, also discuss important caveats consider interpretation work regarding cellular source signal complexities inherent its acquisition analysis). While biological clinical significance findings awaits further work, emerging preclinical literature supports possible pathophysiological underpinnings pain. Gaining deeper understanding would likely have practical implications, possibly paving way novel interventions.

Language: Английский

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Enhanced structure/function of mTSPO translocator in lipid:surfactant mixed micelles

Biochimie, Journal Year: 2024, Volume and Issue: 224, P. 3 - 15

Published: April 23, 2024

TSPO is a ubiquitous transmembrane protein used as pharmacological marker in neuroimaging. The only known atomic structure of mammalian TSPOs comes from the solution NMR mouse (mTSPO) bound to PK11195 ligand and DPC surfactant environment. No available biomimetic environment without which strongly stiffens protein. We measured effect different amphiphilic environments on ligand-free mTSPO study its structure/function find optimal solubilization conditions. By replacing SDS surfactant, where recombinant purified, with mixed lipid:surfactant (DMPC:DPC) micelles at ratios (0:1, 1:2, 2:1, w:w), α-helix content interactions intrinsic tryptophan (Trp) fluorescence are gradually increased. Small-angle X-ray scattering (SAXS) shows more extended mTSPO/belt complex addition lipids: D

Language: Английский

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Glial overexpression of Tspo extends lifespan and protects against frataxin deficiency in Drosophila

Biochimie, Journal Year: 2024, Volume and Issue: 224, P. 71 - 79

Published: May 14, 2024

The translocator protein TSPO is an evolutionary conserved mitochondrial overexpressed in various contexts of neurodegeneration. Friedreich Ataxia (FA) a neurodegenerative disease due to GAA expansions the FXN gene leading decreased expression frataxin, involved biosynthesis iron-sulfur clusters. We previously reported that Tspo was Drosophila model this generated by CRISPR/Cas9 insertion approximately 200 intron fh, fly frataxin gene. Here, we describe new FA with 42 repeats, called fh-GAAs. smaller expansion size allowed obtain adults exhibiting hallmarks disease, including short lifespan, locomotory defects and hypersensitivity oxidative stress. reduced lifespan fully rescued ubiquitous human FXN, confirming both frataxins share functions. observed heads intestines these fh-GAAs flies. Then, further specifically glial cells improved survival. Finally, investigated effects overexpression healthy Increased longevity conferred glial-specific overexpression, opposite neurons. Overall, study highlights protective context.

Language: Английский

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Intrinsic factors behind long‐COVID: II. SARS‐CoV‐2, extracellular vesicles, and neurological disorders

Journal of Cellular Biochemistry, Journal Year: 2023, Volume and Issue: 124(10), P. 1466 - 1485

Published: Oct. 1, 2023

Abstract With the decline in number of new Severe Acute Respiratory Syndrome Coronavirus 2 (SARS‐CoV‐2) infections, World Health Organization announced end SARS‐CoV‐2 pandemic. However, repercussions this viral pandemic may remain with us for a longer period time, as it has remodeled lives humankind many ways, including social and economic. Of course, its most important on human health level. Long‐coronavirus disease (COVID) or post‐COVID is state which we do not have concrete definition, specific international classification diseases Code, clear diagnostic tools, well‐known effective cures yet. In second article from Intrinsic Factors behind long‐COVID Series, try to link symptoms their causes, starting nervous system. Extracellular vesicles (ECVs) play very complex ramified roles bodies both healthy not‐healthy individuals. ECVs facilitate entry bioactive molecules pathogens into tissues cells system across blood–brain barrier. Based size, quantity, quality cargo, are directly proportional pathological condition severity through intertwined mechanisms that evoke inflammatory immune responses typically accompanied by over variable time periods according type these symptoms.

Language: Английский

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Pregnenolone sulfate potentiates tetrodotoxin-resistant Na+ channels to increase the excitability of dural afferent neurons in rats

The Journal of Headache and Pain, Journal Year: 2025, Volume and Issue: 26(1)

Published: Feb. 25, 2025

Although peripheral administration of pregnenolone sulfate (PS) has been reported to produce pronociceptive effects, the mechanisms by which PS modulates excitability nociceptive neurons are poorly understood. Here, we report on excitatory role in neurons, focusing its effects tetrodotoxin-resistant (TTX-R) Na+ channels. TTX-R current (INa) mediated NaV1.8 was recorded from acutely isolated small-sized dural afferent rats, identified with retrograde fluorescent dye DiI, using a whole-cell patch-clamp technique. Transcripts for enzymes and transporters involved biosynthesis were detected ophthalmic branch trigeminal ganglia. In voltage-clamp mode, preferentially potentiated persistent INa, small non-inactivating during sustained depolarization. shifted voltage-inactivation relationship toward depolarizing range. also delayed onset inactivation accelerated recovery Additionally, decreased extent use-dependent inhibition current-clamp hyperpolarized increasing leak K+ conductance. Nevertheless, rheobase current—the minimum required generate action potentials—and increased number potentials elicited stimuli. We have shown that neurosteroid potentiates INa reduces channels, resulting neurons. The potential endogenous migraine pathology warrants further investigation.

Language: Английский

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Intranasal Delivery of Hydrophobic AC5216 Loaded Nanoemulsion into Brain To Alleviate Chronic Unpredictable Stress-Induced Depressive-like Behaviors

ACS Applied Materials & Interfaces, Journal Year: 2025, Volume and Issue: unknown

Published: March 10, 2025

Major depressive disorder (MDD) represents a widespread mental health condition. Efficiently moving therapeutic substances across the blood–brain barrier (BBB) remains critical obstacle in addressing disorders. AC5216, identified as translocator protein (TSPO) ligand and considered potential treatment for major (MDD), faces limitations due to its subpar druggability oral bioavailability. In this context, an amphiphilic polymer composed of polyethylene glycol, poly-l-lysine, poly(lactic-co-glycolic acid) (PEG-PLL-PLGA) has been utilized encapsulate hydrophobic compound AC5216. This results formation cell-penetrating peptide-modified nanoemulsions (termed CPP-PPP-AC5216), designed deliver AC5216 directly into central nervous system via intranasal administration MDD therapy. Research on animal models shown that CPP-PPP-AC5216 effectively transports brain, significantly mitigating chronic unpredictable stress (CUS)-induced behaviors with dosage low 0.03 mg/kg when administered intranasally. Furthermore, it was observed substantially reduces microglial activation, prevents BBB leakage, ameliorates astrocyte dysfunction caused by CUS. The findings suggest promising using nanoemulsion approach compounds through nasal route MDD.

Language: Английский

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Mitochondrial Translocator-Protein Ligand Etifoxine Reduces Pain Symptoms and Protects Against Motor Dysfunction Development Following Peripheral Nerve Injury in Rats

Neuropharmacology, Journal Year: 2025, Volume and Issue: unknown, P. 110456 - 110456

Published: April 1, 2025

Peripheral nerve injury enhances mitochondrial translocator protein (TSPO) expression in the spinal cord and dorsal root ganglia (DRG), which is associated with neuroinflammation dysfunction contributing to chronic pain development. Here, we investigate effect of TSPO ligand Etifoxine, on development motor following sciatic injury. Mechanical thermal sensitivity, as well function, were measured rats before after crush (SNC). Rats treated Etifoxine (50 mg/kg, twice daily) for one week. At end experiment, RT-PCR immunohistochemistry (IHC) performed assess stress neuroinflammation. Additionally, high-resolution respirometry (O2k) was used evaluate function permeability transition pore (mPTP) induction by Ca2+. treatment post-SNC alleviated mechanical hypersensitivity, rats. In addition, modulates stress. Specifically, found a significant reduction microglia presence transcription pro-inflammatory cytokines (TNFα, IL-6, IL-1β) DRG SNC/etifoxine-treated group. Furthermore, prevent decline respiration, including non-phosphorylation, ATP-linked maximal mPTP Our findings suggest that TSPO-ligand protects against reducing apoptosis cord. Importantly, beneficial effects TSPO-ligands are reflected restoration under challenging conditions.

Language: Английский

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GRT-X Stimulates Dorsal Root Ganglia Axonal Growth in Culture via TSPO and Kv7.2/3 Potassium Channel Activation

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(13), P. 7327 - 7327

Published: July 3, 2024

GRT-X, which targets both the mitochondrial translocator protein (TSPO) and Kv7.2/3 (KCNQ2/3) potassium channels, has been shown to efficiently promote recovery from cervical spine injury. In present work, we investigate role of GRT-X its two in axonal growth dorsal root ganglion (DRG) neurons. Neurite outgrowth was quantified DRG explant cultures prepared wild-type C57BL6/J TSPO-KO mice. TSPO pharmacologically targeted with agonist XBD173 Kv7 channels activator ICA-27243 inhibitor XE991. stimulated at 4 8 days after single administration. also promoted elongation, but only repeated contrast, ICA27243 XE991 tended decrease elongation. dissociated neuron/Schwann cell co-cultures, upregulated expression genes associated myelination. cultures, stimulatory effect on completely lost. However, activated neuronal Schwann gene knockout, indicating presence additional warranting further investigation. These findings uncover a key dual mode action elongation

Language: Английский

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Unraveling mitochondrial dysfunction: comprehensive perspectives on its impact on neurodegenerative diseases

Reviews in the Neurosciences, Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 20, 2024

Neurodegenerative diseases represent a significant challenge to modern medicine, with their complex etiology and progressive nature posing hurdles effective treatment strategies. Among the various contributing factors, mitochondrial dysfunction has emerged as pivotal player in pathogenesis of several neurodegenerative disorders. This review paper provides comprehensive overview how impairment contributes development including Alzheimer's disease, Parkinson's Huntington's amyotrophic lateral sclerosis, driven by bioenergetic defects, biogenesis impairment, alterations dynamics (such fusion or fission), disruptions calcium buffering, lipid metabolism dysregulation mitophagy dysfunction. It also covers current therapeutic interventions targeting these diseases.

Language: Английский

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