Department of Experimental Physiology and Pathophysiology, Medical University of Białystok, Mickiewicz str. 2A, 15-222 Białystok, Poland.
Department of Experimental Physiology and Pathophysiology, Medical University of Białystok, Mickiewicz str. 2A, 15-222 Białystok, Poland.
Life Sci. 2018 Jul 1;204:20-45. doi: 10.1016/j.lfs.2018.04.054. Epub 2018 May 2.
The endocannabinoid system is up-regulated in numerous pathophysiological states such as inflammatory, neurodegenerative, gastrointestinal, metabolic and cardiovascular diseases, pain, and cancer. It has been suggested that this phenomenon primarily serves an autoprotective role in inhibiting disease progression and/or diminishing signs and symptoms. Accordingly, enhancement of endogenous endocannabinoid tone by inhibition of endocannabinoid degradation represents a promising therapeutic approach for the treatment of many diseases. Importantly, this allows for the avoidance of unwanted psychotropic side effects that accompany exogenously administered cannabinoids. The effects of endocannabinoid metabolic pathway modulation are complex, as endocannabinoids can exert their actions directly or via numerous metabolites. The two main strategies for blocking endocannabinoid degradation are inhibition of endocannabinoid-degrading enzymes and inhibition of endocannabinoid cellular uptake. To date, the most investigated compounds are inhibitors of fatty acid amide hydrolase (FAAH), an enzyme that degrades the endocannabinoid anandamide. However, application of FAAH inhibitors (and consequently other endocannabinoid degradation inhibitors) in medicine became questionable due to a lack of therapeutic efficacy in clinical trials and serious adverse effects evoked by one specific compound. In this paper, we discuss multiple pathways of endocannabinoid metabolism, changes in endocannabinoid levels across numerous human diseases and corresponding experimental models, pharmacological strategies for enhancing endocannabinoid tone and potential therapeutic applications including multi-target drugs with additional targets outside of the endocannabinoid system (cyclooxygenase-2, cholinesterase, TRPV1, and PGF-EA receptors), and currently used medicines or medicinal herbs that additionally enhance endocannabinoid levels. Ultimately, further clinical and preclinical studies are warranted to develop medicines for enhancing endocannabinoid tone.
内源性大麻素系统在许多生理病理状态下上调，如炎症、神经退行性、胃肠道、代谢和心血管疾病、疼痛和癌症。有人认为，这种现象主要起到自保护作用，抑制疾病进展和/或减轻症状。因此，通过抑制内源性大麻素的降解来增强内源性大麻素的张力代表了治疗许多疾病的一种有前途的治疗方法。重要的是，这可以避免外源性给予大麻素伴随的不必要的精神副作用。内源性大麻素代谢途径调节的影响是复杂的，因为内源性大麻素可以直接或通过许多代谢物发挥作用。阻断内源性大麻素降解的两种主要策略是抑制内源性大麻素降解酶和抑制内源性大麻素细胞摄取。迄今为止，研究最多的化合物是脂肪酸酰胺水解酶 (FAAH) 的抑制剂，该酶降解内源性大麻素大麻素。然而，由于在临床试验中缺乏治疗效果和一种特定化合物引起的严重不良反应，FAAH 抑制剂（以及其他内源性大麻素降解抑制剂）在医学中的应用受到质疑。在本文中，我们讨论了内源性大麻素代谢的多种途径，在许多人类疾病和相应的实验模型中内源性大麻素水平的变化，增强内源性大麻素张力的药理学策略以及包括除内源性大麻素系统（环加氧酶-2、胆碱酯酶、TRPV1 和 PGF-EA 受体）以外的其他靶点的多靶点药物在内的潜在治疗应用，以及目前使用的可增强内源性大麻素水平的药物或草药。最终，需要进一步的临床和临床前研究来开发增强内源性大麻素张力的药物。
