Department of Biochemistry and Molecular Biology, Faculty of Medicine, Institute on Neurochemistry Research, Complutense University, 28040 Madrid, Spain.
Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), 28031 Madrid, Spain.
Molecules. 2021 May 28;26(11):3245. doi: 10.3390/molecules26113245.
The 3-hydroxyquinone derivative of the non-psychotrophic phytocannabinoid cannabigerol, so-called VCE-003.2, and some other derivatives have been recently investigated for neuroprotective properties in experimental models of Parkinson's disease (PD) in mice. The pharmacological effects in those models were related to the activity on the peroxisome proliferator-activated receptor-γ (PPAR-γ) and possibly other pathways. In the present study, we investigated VCE-004.8 (formulated as EHP-101 for oral administration), the 3-hydroxyquinone derivative of cannabidiol (CBD), with agonist activity at the cannabinoid receptor type-2 (CB) receptor in addition to its activity at the PPAR-γ receptor. Studies were conducted in both in vivo (lesioned-mice) and in vitro (SH-SY5Y cells) models using the classic parkinsonian neurotoxin 6-hydroxydopamine (6-OHDA). Our data confirmed that the treatment with VCE-004.8 partially reduced the loss of tyrosine hydroxylase (TH)-positive neurons measured in the substantia nigra of 6-OHDA-lesioned mice, in parallel with an almost complete reversal of the astroglial (GFAP) and microglial (CD68) reactivity occurring in this structure. Such neuroprotective effects attenuated the motor deficiencies shown by 6-OHDA-lesioned mice in the cylinder rearing test, but not in the pole test. Next, we explored the mechanism involved in the beneficial effect of VCE-004.8 in vivo, by analyzing cell survival in cultured SH-SY5Y cells exposed to 6-OHDA. We found an important cytoprotective effect of VCE-004.8 at a concentration of 10 µM, which was completely reversed by the addition of antagonists, T0070907 and SR144528, aimed at blocking PPAR-γ and CB receptors, respectively. The treatment with T0070907 alone only caused a partial reversal, whereas SR144528 alone had no effect, indicating a major contribution of PPAR-γ receptors in the cytoprotective effect of VCE-004.8 at 10 µM. In summary, our data confirmed the neuroprotective potential of VCE-004.8 in 6-OHDA-lesioned mice, and in vitro studies confirmed a greater relevance for PPAR-γ receptors rather than CB receptors in these effects.
非精神类大麻素大麻萜酚的 3-羟基醌衍生物，所谓的 VCE-003.2，以及其他一些衍生物最近在帕金森病（PD）的实验模型中被研究用于神经保护特性。在这些模型中的药理作用与过氧化物酶体增殖物激活受体-γ（PPAR-γ）和可能的其他途径的活性有关。在本研究中，我们研究了 VCE-004.8（作为 EHP-101 进行口服给药），即大麻二酚（CBD）的 3-羟基醌衍生物，除了其在 PPAR-γ受体上的活性外，还具有大麻素受体 2 型（CB）受体的激动剂活性。这些研究是在体内（损伤小鼠）和体外（SH-SY5Y 细胞）模型中进行的，使用经典的帕金森神经毒素 6-羟多巴胺（6-OHDA）。我们的数据证实，VCE-004.8 的治疗部分减轻了在 6-OHDA 损伤的小鼠黑质中测量的酪氨酸羟化酶（TH）阳性神经元的损失，同时几乎完全逆转了该结构中发生的星形胶质（GFAP）和小胶质（CD68）反应性。这种神经保护作用减轻了 6-OHDA 损伤的小鼠在圆柱饲养试验中表现出的运动缺陷，但在杆试验中没有减轻。接下来，我们通过分析暴露于 6-OHDA 的培养的 SH-SY5Y 细胞中的细胞存活，来探索 VCE-004.8 在体内的有益作用所涉及的机制。我们发现 VCE-004.8 在 10 µM 浓度下具有重要的细胞保护作用，该作用被分别针对阻断 PPAR-γ 和 CB 受体的拮抗剂 T0070907 和 SR144528 完全逆转。单独使用 T0070907 仅导致部分逆转，而单独使用 SR144528 则没有作用，表明在 10 µM 时 VCE-004.8 的细胞保护作用主要与 PPAR-γ 受体有关。总之，我们的数据证实了 VCE-004.8 在 6-OHDA 损伤的小鼠中的神经保护潜力，并且体外研究证实了在这些作用中，PPAR-γ 受体而不是 CB 受体具有更大的相关性。
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