The quinone derivative of the non-psychotropic cannabinoid cannabigerol (CBG), so-called VCE-003.2, has been recently investigated for its neuroprotective properties in inflammatory models of Parkinson's disease (PD) in mice. Such potential derives from its activity at the peroxisome proliferator-activated receptor-γ (PPAR-γ). In the present study, we investigated the neuroprotective properties of VCE-003.2 against the parkinsonian neurotoxin 6-hydroxydopamine (6-OHDA), in comparison with two new CBG-related derivatives, the cannabigerolic acid quinone (CBGA-Q) and its sodium salt CBGA-Q-Salt, which, similarly to VCE-003.2, were found to be active at the PPAR-γ receptor, but not at the cannabinoid CB₁ and CB₂ receptors. First, we investigated their cytoprotective properties in vitro by analyzing cell survival in cultured SH-SY5Y cells exposed to 6-OHDA. We found an important cytoprotective effect of VCE-003.2 at a concentration of 20 μM, which was not reversed by the blockade of PPAR-γ receptors with GW9662, supporting its activity at an alternative site (non-sensitive to classic antagonists) in this receptor. We also found CBGA-Q and CBGA-Q-Salt being cytoprotective in this cell assay, but their effects were completely eliminated by GW9662, thus indicating that they are active at the canonical site in the PPAR-γ receptor. Then, we moved to in vivo testing using mice unilaterally lesioned with 6-OHDA. Our data confirmed that VCE-003.2 administered orally (20 mg/kg) preserved tyrosine hydroxylase (TH)-positive nigral neurons against 6-OHDA-induced damage, whereas it completely attenuated the astroglial (GFAP) and microglial (CD68) reactivity found in the substantia nigra of lesioned mice. Such neuroprotective effects caused an important recovery in the motor deficiencies displayed by 6-OHDA-lesioned mice in the pole test and the cylinder rearing test. We also investigated CBGA-Q, given orally (20 mg/kg) or intraperitoneally (10 mg/kg, i.p.), having similar benefits compared to VCE-003.2 against the loss of TH-positive nigral neurons, glial reactivity and motor defects caused by 6-OHDA. Lastly, the sodium salt of CBGA-Q, given orally (40 mg/kg) to 6-OHDA-lesioned mice, also showed benefits at behavioral and histopathological levels, but to a lower extent compared to the other two compounds. In contrast, when given i.p., CBGA-Q-Salt (10 mg/kg) was poorly active. We also analyzed the concentrations of dopamine and its metabolite DOPAC in the striatum of 6-OHDA-lesioned mice after the treatment with the different compounds, but recovery in the contents of both dopamine and DOPAC was only found after the treatment with VCE-003.2. In summary, our data confirmed the neuroprotective potential of VCE-003.2 in 6-OHDA-lesioned mice, which adds to its previous activity found in an inflammatory model of PD (LPS-lesioned mice). Additional phytocannabinoid derivatives, CBGA-Q and CBGA-Q-Salt, also afforded neuroprotection in 6-OHDA-lesioned mice, but their effects were lower compared to VCE-003.2, in particular in the case of CBGA-Q-Salt. In vitro studies confirmed the relevance of PPAR-γ receptors for these effects.

非精神性大麻素大麻酚 (CBG) 的醌衍生物，即所谓的 VCE-003.2，最近因其在小鼠帕金森病 (PD) 炎症模型中的神经保护特性而受到研究。这种潜力源自其对过氧化物酶体增殖物激活受体-γ (PPAR-γ) 的活性。在本研究中，我们研究了 VCE-003.2 对帕金森神经毒素 6-羟基多巴胺 (6-OHDA) 的神经保护特性，并与两种新的 CBG 相关衍生物大麻二酚酸醌 (CBGA-Q) 及其钠盐进行了比较CBGA-Q-Salt 与 VCE-003.2 类似，被发现对 PPAR-γ 受体有活性，但对大麻素 CB ₁和 CB ₂受体没有活性。首先，我们研究了它们的细胞保护特性通过分析暴露于 6-OHDA 的培养的 SH-SY5Y 细胞中的细胞存活率进行体外分析。我们发现浓度为 20 μM 的 VCE-003.2 具有重要的细胞保护作用，这不会被 GW9662 阻断 PPAR-γ 受体所逆转，支持其在该受体的替代位点（对经典拮抗剂不敏感）的活性. 我们还发现 CBGA-Q 和 CBGA-Q-Salt 在该细胞试验中具有细胞保护作用，但它们的作用被 GW9662 完全消除，因此表明它们在 PPAR-γ 受体的规范位点具有活性。然后，我们转移到体内使用单侧受 6-OHDA 损伤的小鼠进行测试。我们的数据证实，VCE-003.2 口服 (20 mg/kg) 保留了酪氨酸羟化酶 (TH) 阳性黑质神经元对抗 ​​6-OHDA 诱导的损伤，而它完全减弱了星形胶质细胞 (GFAP) 和小胶质细胞 (CD68) 反应性受损小鼠的黑质。这种神经保护作用导致了 6-OHDA 损伤小鼠在极杆试验和圆柱体饲养试验中表现出的运动缺陷的重要恢复。我们还研究了口服 (20 mg/kg) 或腹腔注射 (10 mg/kg, ip) 的 CBGA-Q，与 VCE-003.2 相比，在减少 TH 阳性黑质神经元丢失、胶质反应性和运动缺陷方面具有相似的益处由 6-OHDA。最后，CBGA-Q 的钠盐，口服 (40 mg/kg) 给 6-OHDA 损伤的小鼠，在行为和组织病理学水平上也显示出益处，但与其他两种化合物相比程度较低。相比之下，当 ip 给药时，CBGA-Q-Salt (10 mg/kg) 活性较差。我们还分析了用不同化合物处理后 6-OHDA 损伤小鼠纹状体中多巴胺及其代谢物 DOPAC 的浓度，但仅在用 VCE-003.2 处理后才发现多巴胺和 DOPAC 的含量恢复。总之，我们的数据证实了 VCE-003.2 在 6-OHDA 损伤小鼠中的神经保护潜力，这增加了其先前在 PD（LPS 损伤小鼠）炎症模型中发现的活性。其他植物大麻素衍生物 CBGA-Q 和 CBGA-Q-Salt 也为 6-OHDA 损伤的小鼠提供神经保护，但与 VCE-003.2 相比，它们的作用较低，体外研究证实了 PPAR-γ 受体与这些效应的相关性。