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Retinal pharmacodynamic and pharmacokinetic profile of cannabidiol in an in vivo model of retinal excitotoxicity

F. Conti, F. Lazzara, K. Thermos, E. Zingale, D. Spyridakos, GL. Romano, S. Di Martino, V. Micale, M. Kuchar, A. Spadaro, R. Pignatello, S. Rossi, M. D'Amico, CB. Maria Platania, F. Drago, C. Bucolo

. 2025 ; 991 (-) : 177323. [pub] 20250130

Language English Country Netherlands

Document type Journal Article

Persistent link   https://www.medvik.cz/link/bmc25009487

Cannabidiol (CBD) is one of the principal constituents of Cannabis Sativa with no psychoactive properties. CBD is a promising neuroprotective compound bearing anti-inflammatory and antioxidant properties. However, considering its low solubility, CBD delivery to the retina represents an unresolved issue. The first aim was to investigate the potential neuroprotective effects of CBD in an in vivo model of retinal excitotoxicity induced by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA). Rats underwent intravitreal co-injection of AMPA (42 nmol) and CBD (10-4 M). The neuroprotective effect of CBD was investigated with histology and immunohistochemical evaluation of inflammatory and oxidative stress biomarkers. CBD reversed the AMPA-induced total retinal, inner nuclear layer and inner plexiform layer shrinkage and loss of amacrine cells. Moreover, CBD decreased the AMPA induced number of cleaved caspase-3, Iba-1 and nitrotyrosine (NT) positive cells. Based on this evidence, we developed a nanotechnological formulation of CBD to overcome critical issues related to its eye delivery. Particularly, nanostructured lipid carriers (NLC) loaded with CBD were prepared, optimized and characterized. Due to the optimal physicochemical characteristics, CBD-NLC3 has been selected and the in vitro release profile has been investigated. Additionally, CBD-NLC3 was topically administered to rats, and retinal CBD levels were determined. CBD-NLC3 formulation, after a single topical administration, efficiently delivered CBD in the retina (Cmax = 98 ± 25.9 ng/mg; Tmax = 60 min), showing a high translational value. In conclusion, these findings showed a good PD/PK profile of CBD warranting further pre-clinical and clinical evaluation of the new formulation for the treatment of retinal degenerative diseases.

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$a Conti, Federica $u Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania, Italy
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$a Retinal pharmacodynamic and pharmacokinetic profile of cannabidiol in an in vivo model of retinal excitotoxicity / $c F. Conti, F. Lazzara, K. Thermos, E. Zingale, D. Spyridakos, GL. Romano, S. Di Martino, V. Micale, M. Kuchar, A. Spadaro, R. Pignatello, S. Rossi, M. D'Amico, CB. Maria Platania, F. Drago, C. Bucolo
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$a Cannabidiol (CBD) is one of the principal constituents of Cannabis Sativa with no psychoactive properties. CBD is a promising neuroprotective compound bearing anti-inflammatory and antioxidant properties. However, considering its low solubility, CBD delivery to the retina represents an unresolved issue. The first aim was to investigate the potential neuroprotective effects of CBD in an in vivo model of retinal excitotoxicity induced by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA). Rats underwent intravitreal co-injection of AMPA (42 nmol) and CBD (10-4 M). The neuroprotective effect of CBD was investigated with histology and immunohistochemical evaluation of inflammatory and oxidative stress biomarkers. CBD reversed the AMPA-induced total retinal, inner nuclear layer and inner plexiform layer shrinkage and loss of amacrine cells. Moreover, CBD decreased the AMPA induced number of cleaved caspase-3, Iba-1 and nitrotyrosine (NT) positive cells. Based on this evidence, we developed a nanotechnological formulation of CBD to overcome critical issues related to its eye delivery. Particularly, nanostructured lipid carriers (NLC) loaded with CBD were prepared, optimized and characterized. Due to the optimal physicochemical characteristics, CBD-NLC3 has been selected and the in vitro release profile has been investigated. Additionally, CBD-NLC3 was topically administered to rats, and retinal CBD levels were determined. CBD-NLC3 formulation, after a single topical administration, efficiently delivered CBD in the retina (Cmax = 98 ± 25.9 ng/mg; Tmax = 60 min), showing a high translational value. In conclusion, these findings showed a good PD/PK profile of CBD warranting further pre-clinical and clinical evaluation of the new formulation for the treatment of retinal degenerative diseases.
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$a Lazzara, Francesca $u Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania, Italy
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$a Thermos, Kyriaki $u Department of Pharmacology, School of Medicine, University of Crete, Heraklion, Crete, Greece. Electronic address: thermos@uoc.gr
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$a Zingale, Elide $u Laboratory of Drug Delivery Technology, Department of Drug and Health Sciences, University of Catania, Catania, Italy; NANOMED-Research Centre for Nanomedicine and Pharmaceutical Nanotechnology, University of Catania, Catania, Italy
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$a Spyridakos, Dimitris $u Department of Pharmacology, School of Medicine, University of Crete, Heraklion, Crete, Greece
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$a Romano, Giovanni Luca $u Faculty of Medicine and Surgery, University of Enna "Kore", Enna, Italy
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$a Di Martino, Serena $u Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania, Italy
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$a Micale, Vincenzo $u Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania, Italy
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$a Kuchar, Martin $u Forensic Laboratory of Biologically Active Substances, Dept. Chemistry of Natural Compounds, University of Chemistry and Technologies, Prague, Czech Republic; Psychedelic Research Center, National Institute of Mental Health, Klecany, Czech Republic
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$a Spadaro, Angelo $u Department of Drug Sciences, University of Catania, Catania, Italy
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$a Pignatello, Rosario $u Laboratory of Drug Delivery Technology, Department of Drug and Health Sciences, University of Catania, Catania, Italy; NANOMED-Research Centre for Nanomedicine and Pharmaceutical Nanotechnology, University of Catania, Catania, Italy
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$a Rossi, Settimio $u Eye Clinic, Multidisciplinary Department of Medical, Surgical and Dental Sciences, University of Campania "Luigi Vanvitelli", Napoli, Italy
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$a D'Amico, Michele $u Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
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$a Maria Platania, Chiara Bianca $u Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania, Italy; Center for Research in Ocular Pharmacology-CERFO, University of Catania, Catania, Italy
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$a Drago, Filippo $u Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania, Italy; Center for Research in Ocular Pharmacology-CERFO, University of Catania, Catania, Italy
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$a Bucolo, Claudio $u Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania, Italy; Center for Research in Ocular Pharmacology-CERFO, University of Catania, Catania, Italy. Electronic address: claudio.bucolo@unict.it
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