Cannabinoids as Multitarget Drugs for the Treatment of Autoimmunity in Glaucoma

ACS Pharmacology & Translational Science, Journal Year: 2025, Volume and Issue: unknown

Published: March 26, 2025

Diseases of multifactorial origin like neurodegenerative and autoimmune diseases require a multitargeted approach. The discovery the role autoimmunity in glaucoma retinal ganglionic cell (RGC) death has led to paradigm shift our understanding etiopathology glaucoma. Glaucoma can cause irreversible vision loss that affects up an estimated 3% population over 40 years age. current pharmacotherapy primarily aims manage only intraocular pressure (IOP), modifiable risk factor glaucomatous neurodegeneration RGCs. However, continues happen normotensive patients (where IOP is below reference value), silent nature disease significant visual impairment take massive toll on healthcare system. Cannabinoids, although known reduce since 1970s, have received renewed interest due their neuroprotective, anti-inflammatory, immunosuppressive effects autoimmunity. Additionally, gut-retina axis abnormal Wnt signaling makes cannabinoids even more relevant because action multiple targets, all converging pathogenesis neurodegeneration. Cannabinoids also epigenetic changes immune cells associated with In this Review, we are proposing use as approach for treating neurodegeneration, especially patients.

Language: Английский

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The role of transcytosis in the blood-retina barrier: from pathophysiological functions to drug delivery

Frontiers in Pharmacology, Journal Year: 2025, Volume and Issue: 16

Published: April 16, 2025

The blood-retina barrier (BRB) serves as a critical interface that separates the retina from circulatory system, playing an essential role in preserving homeostasis of microenvironment within retina. Specialized tight junctions and limited vesicle trafficking restrict paracellular transcellular transport, respectively, thereby maintaining BRB properties. Additionally, transcytosis macromolecules through retinal vascular endothelial cells constitutes primary mechanism for transporting substances compartment into surrounding tissue. This review summarizes fundamental aspects including its function healthy retina, biochemical properties transcytosis, methodologies used to study this process. Furthermore, we discuss current understanding context pathological breakdown present recent findings highlight significant advances drug delivery based on transcytosis.

Language: Английский

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Single-cell profiling of trabecular meshwork identifies mitochondrial dysfunction in a glaucoma model that is protected by vitamin B3 treatment

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

Published: Nov. 1, 2024

Since the trabecular meshwork (TM) is central to intraocular pressure (IOP) regulation and glaucoma, a deeper understanding of its genomic landscape needed. We present multimodal, single-cell resolution analysis mouse limbal cells (includes TM). In total, we sequenced 9,394 wild-type TM cell transcriptomes. discovered three subtypes with characteristic signature genes validated by immunofluorescence on tissue sections whole-mounts. The are robust, being detected in datasets for two diverse strains independent data from institutions. Results show compartmentalized enrichment critical pathways specific subtypes. Distinctive signatures include increased expression responsible 1) extracellular matrix structure metabolism (TM1 subtype), 2) secreted ligand signaling support Schlemm's canal (TM2), 3) contractile mitochondrial/metabolic activity (TM3). ATAC-sequencing identified active transcription factors cells, including LMX1B. Mutations LMX1B cause high IOP glaucoma. emerging as key factor normal mitochondrial function much higher TM3 than other cells. To understand role Lmx1b V265D/+ mutant mice. mice, were uniquely affected pronounced pathway changes. This supports primary dysfunction within initiating elevation that causes glaucoma these Importantly, treatment vitamin B 3 (nicotinamide), enhance metabolic resilience, significantly protected mice elevation.

Language: Английский

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Stress-induced mitochondrial fragmentation in endothelial cells disrupts blood-retinal barrier integrity causing neurodegeneration.

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

Published: Dec. 22, 2024

Increased vascular leakage and endothelial cell (EC) dysfunction are major features of neurodegenerative diseases. Here, we investigated the mechanisms leading to EC dysregulation asked whether altered mitochondrial dynamics in ECs impinge on barrier integrity neurodegeneration. We show that ocular hypertension, a risk factor develop glaucoma, induced fragmentation retinal capillary accompanied by increased oxidative stress ultrastructural defects. Analysis components revealed overactivation dynamin-related protein 1 (DRP1), central regulator fission, during glaucomatous damage. Pharmacological inhibition or EC-specific vivo gene delivery dominant negative DRP1 mutant was sufficient rescue volume, reduce leakage, increase expression tight junction claudin-5 (CLDN5). further demonstrate EC-targeted CLDN5 augmentation restored blood-retinal-barrier integrity, promoted neuronal survival, improved light-evoked visual behaviors mice. Our findings reveal preserving homeostasis function valuable strategies enhance neuroprotection improve vision glaucoma.

Language: Английский

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