Rava Alessandro, Buzzelli Valeria, Feo Alessandro, Ascone Fabrizio, Di Trapano Melania, Schiavi Sara, Carbone Emilia, Pasquadibisceglie Andrea, Polticelli Fabio, Manduca Antonia, Trezza Viviana
Dept. Science, Roma Tre University, Rome, Italy.
Dept. Science, Roma Tre University, Rome, Italy; Dept. Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy; Neuroendocrinology, Metabolism and Neuropharmacology Unit, IRCCS Fondazione Santa Lucia, Rome, Italy.
Prog Neuropsychopharmacol Biol Psychiatry. 2025 Jan 10;136:111234. doi: 10.1016/j.pnpbp.2024.111234. Epub 2024 Dec 24.
β-Caryophyllene (BCP) is a naturally occurring sesquiterpene found in numerous plant species, including Cannabis sativa. BCP has shown a high safety profile and a wide range of biological functions, including beneficial effects in neurodegenerative and inflammatory diseases. Here, we used behavioral, pharmacological, and in-silico docking analyses to investigate the effects and mechanism of action of BCP in Fragile X Syndrome (FXS), the most common inherited cause of Autism Spectrum Disorder (ASD) and intellectual disability. To this aim, we used the recently validated Fmr1-exon 8 rat model of FXS, that is also a genetic rat model of ASD. Acute and repeated oral administration of BCP rescued the cognitive deficits displayed by Fmr1-exon 8 rats, without inducing tolerance after repeated administration. These beneficial effects were mediated by activation of hippocampal peroxisome proliferator-activated receptors (PPARs) α and γ, and were mimicked by the PPARα agonist Fenofibrate and the PPARγ agonist Pioglitazone. Conversely, CB2 cannabinoid receptors were not involved. Docking analyses further confirmed the ability of BCP to bind rat PPARs. Together, our findings demonstrate that hippocampal PPARs α and γ play a role in the cognitive deficits observed in a rat model of FXS, and provide first preclinical evidence about the efficacy and mechanism of action of BCP in neurodevelopmental disorders.
β-石竹烯（BCP）是一种天然存在的倍半萜烯，存在于包括大麻在内的多种植物物种中。BCP已显示出较高的安全性和广泛的生物学功能，包括对神经退行性疾病和炎症性疾病的有益作用。在此，我们使用行为学、药理学和计算机对接分析来研究BCP在脆性X综合征（FXS）中的作用效果和作用机制，FXS是自闭症谱系障碍（ASD）和智力残疾最常见的遗传病因。为此，我们使用了最近验证的FXS的Fmr1外显子8大鼠模型，该模型也是ASD的遗传大鼠模型。急性和重复口服BCP可挽救Fmr1外显子8大鼠表现出的认知缺陷，重复给药后不会产生耐受性。这些有益作用是由海马体过氧化物酶体增殖物激活受体（PPARs）α和γ的激活介导的，并且被PPARα激动剂非诺贝特和PPARγ激动剂吡格列酮所模拟。相反，CB2大麻素受体未参与其中。对接分析进一步证实了BCP与大鼠PPARs结合的能力。总之，我们的研究结果表明海马体PPARsα和γ在FXS大鼠模型中观察到的认知缺陷中起作用，并提供了关于BCP在神经发育障碍中的疗效和作用机制的首个临床前证据。
