A p75 neurotrophin receptor-sparing nerve growth factor protects retinal ganglion cells from neurodegeneration by targeting microglia.

Autor: Latini L; European Brain Research Institute-Fondazione Rita Levi-Montalcini, Rome, Italy., De Araujo DSM; Department of Health Sciences, Clinical Pharmacology and Oncology Section, University of Florence, Florence, Italy., Amato R; Department of Biology, University of Pisa, Pisa, Italy., Canovai A; Department of Biology, University of Pisa, Pisa, Italy., Buccarello L; European Brain Research Institute-Fondazione Rita Levi-Montalcini, Rome, Italy., De Logu F; Department of Health Sciences, Clinical Pharmacology and Oncology Section, University of Florence, Florence, Italy., Novelli E; Institute of Neuroscience, Italian National Research Council-CNR, Pisa, Italy., Vlasiuk A; Faculty of Biosciences, Collaboration for Joint PhD Degree Between EMBL and Heidelberg University, Heidelberg, Germany.; Epigenetics and Neurobiology Unit, EMBL Rome, European Molecular Biology Laboratory, Rome, Italy., Malerba F; European Brain Research Institute-Fondazione Rita Levi-Montalcini, Rome, Italy., Arisi I; European Brain Research Institute-Fondazione Rita Levi-Montalcini, Rome, Italy., Florio R; European Brain Research Institute-Fondazione Rita Levi-Montalcini, Rome, Italy., Asari H; Faculty of Biosciences, Collaboration for Joint PhD Degree Between EMBL and Heidelberg University, Heidelberg, Germany., Capsoni S; BIO@SNS Laboratory, Scuola Normale Superiore, Pisa, Italy.; Section of Human Physiology, Department of Neuroscience and Rehabilitation, University of Ferrara, Ferrara, Italy., Strettoi E; Institute of Neuroscience, Italian National Research Council-CNR, Pisa, Italy., Villetti G; Department of Research & Development, Chiesi Farmaceutici, Parma, Italy., Imbimbo BP; Department of Research & Development, Chiesi Farmaceutici, Parma, Italy., Dal Monte M; Department of Biology, University of Pisa, Pisa, Italy., Nassini R; Department of Health Sciences, Clinical Pharmacology and Oncology Section, University of Florence, Florence, Italy., Geppetti P; Department of Health Sciences, Clinical Pharmacology and Oncology Section, University of Florence, Florence, Italy., Marinelli S; European Brain Research Institute-Fondazione Rita Levi-Montalcini, Rome, Italy., Cattaneo A; European Brain Research Institute-Fondazione Rita Levi-Montalcini, Rome, Italy.; BIO@SNS Laboratory, Scuola Normale Superiore, Pisa, Italy.
Jazyk: angličtina
Zdroj: British journal of pharmacology [Br J Pharmacol] 2024 Dec; Vol. 181 (23), pp. 4890-4919. Date of Electronic Publication: 2024 Sep 09.
DOI: 10.1111/bph.17316
Abstrakt: Background and Purpose: Retinal ganglion cells (RGCs) are the output stage of retinal information processing, via their axons forming the optic nerve (ON). ON damage leads to axonal degeneration and death of RGCs, and results in vision impairment. Nerve growth factor (NGF) signalling is crucial for RGC operations and visual functions. Here, we investigate a new neuroprotective mechanism of a novel therapeutic candidate, a p75-less, TrkA-biased NGF agonist (hNGFp) in rat RGC degeneration, in comparison with wild type human NGF (hNGFwt).
Experimental Approach: Both neonate and adult rats, whether subjected or not to ON lesion, were treated with intravitreal injections or eye drops containing either hNGFp or hNGFwt. Different doses of the drugs were administered at days 1, 4 or 7 after injury for a maximum of 10 days, when immunofluorescence, electrophysiology, cellular morphology, cytokine array and behaviour studies were carried out. Pharmacokinetic evaluation was performed on rabbits treated with hNGFp ocular drops.
Results: hNGFp exerted a potent RGC neuroprotection by acting on microglia cells, and outperformed hNGFwt in rescuing RGC degeneration and reducing inflammatory molecules. Delayed use of hNGFp after ON lesion resulted in better outcomes compared with treatment with hNGFwt. Moreover, hNGFp-based ocular drops were less algogenic than hNGFwt. Pharmacokinetic measurements revealed that biologically relevant quantities of hNGFp were found in the rabbit retina.
Conclusions and Implications: Our data point to microglia as a new cell target through which NGF-induced TrkA signalling exerts neuroprotection of the RGC, emphasizing hNGFp as a powerful treatment to tackle retinal degeneration.
(© 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)
Databáze: MEDLINE
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