Patricio Felipe, Morales-Andrade Alan Axel, Patricio-Martínez Aleidy, Limón Ilhuicamina Daniel
Laboratorio De Neurofarmacología, Facultad De Ciencias Químicas, Benemérita Universidad Autónoma de Puebla, Puebla, Mexico.
Facultad De Ciencias Biológicas, Benemérita Universidad Autónoma de Puebla, Puebla, Mexico.
Front Pharmacol. 2020 Dec 15;11:595635. doi: 10.3389/fphar.2020.595635. eCollection 2020.
The phytocannabinoids of L. have, since ancient times, been proposed as a pharmacological alternative for treating various central nervous system (CNS) disorders. Interestingly, cannabinoid receptors (CBRs) are highly expressed in the basal ganglia (BG) circuit of both animals and humans. The BG are subcortical structures that regulate the initiation, execution, and orientation of movement. CBRs regulate dopaminergic transmission in the pathway and, thus, the BG circuit also. The functioning of the BG is affected in pathologies related to movement disorders, especially those occurring in Parkinson's disease (PD), which produces motor and non-motor symptoms that involving GABAergic, glutamatergic, and dopaminergic neural networks. To date, the most effective medication for PD is levodopa (l-DOPA); however, long-term levodopa treatment causes a type of long-term dyskinesias, l-DOPA-induced dyskinesias (LIDs). With neuromodulation offering a novel treatment strategy for PD patients, research has focused on the endocannabinoid system (ECS), as it participates in the physiological neuromodulation of the BG in order to control movement. CBRs have been shown to inhibit neurotransmitter release, while endocannabinoids (eCBs) play a key role in the synaptic regulation of the BG. In the past decade, cannabidiol (CBD), a non-psychotropic phytocannabinoid, has been shown to have compensatory effects both on the ECS and as a neuromodulator and neuroprotector in models such as 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and reserpine, as well as other PD models. Although the CBD-induced neuroprotection observed in animal models of PD has been attributed to the activation of the CB1 receptor, recent research conducted at a molecular level has proposed that CBD is capable of activating other receptors, such as CB2 and the TRPV-1 receptor, both of which are expressed in the dopaminergic neurons of the pathway. These findings open new lines of scientific inquiry into the effects of CBD at the level of neural communication. Cannabidiol activates the PPARγ, GPR55, GPR3, GPR6, GPR12, and GPR18 receptors, causing a variety of biochemical, molecular, and behavioral effects due to the broad range of receptors it activates in the CNS. Given the low number of pharmacological treatment alternatives for PD currently available, the search for molecules with the therapeutic potential to improve neuronal communication is crucial. Therefore, the investigation of CBD and the mechanisms involved in its function is required in order to ascertain whether receptor activation could be a treatment alternative for both PD and LID.
自古以来，L.的植物大麻素就被提议作为治疗各种中枢神经系统（CNS）疾病的药理学替代物。有趣的是，大麻素受体（CBRs）在动物和人类的基底神经节（BG）回路中高度表达。BG是调节运动的起始、执行和方向的皮质下结构。CBRs调节该通路中的多巴胺能传递，因此也调节BG回路。BG的功能在与运动障碍相关的疾病中受到影响，尤其是在帕金森病（PD）中出现的那些疾病，PD会产生涉及GABA能、谷氨酸能和多巴胺能神经网络的运动和非运动症状。迄今为止，治疗PD最有效的药物是左旋多巴（l-DOPA）；然而，长期左旋多巴治疗会导致一种长期运动障碍，即l-DOPA诱导的运动障碍（LIDs）。随着神经调节为PD患者提供了一种新的治疗策略，研究集中在内源性大麻素系统（ECS），因为它参与BG的生理神经调节以控制运动。已证明CBRs可抑制神经递质释放，而内源性大麻素（eCBs）在BG的突触调节中起关键作用。在过去十年中，大麻二酚（CBD），一种非精神活性植物大麻素，已被证明在6-羟基多巴胺（6-OHDA）、1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）和利血平以及其他PD模型等模型中对ECS以及作为神经调节剂和神经保护剂具有补偿作用。尽管在PD动物模型中观察到的CBD诱导的神经保护作用归因于CB1受体的激活，但最近在分子水平上进行的研究提出，CBD能够激活其他受体，如CB2和TRPV-1受体，这两种受体都在该通路的多巴胺能神经元中表达。这些发现为CBD在神经通讯水平上的作用开辟了新的科学探究途径。大麻二酚激活PPARγ、GPR55、GPR3、GPR6、GPR12和GPR18受体，由于它在中枢神经系统中激活的受体范围广泛，会引起各种生化、分子和行为效应。鉴于目前可用于PD的药物治疗选择数量较少，寻找具有改善神经元通讯治疗潜力的分子至关重要。因此，需要对CBD及其功能所涉及的机制进行研究，以确定受体激活是否可能成为治疗PD和LID的替代方法。
