Jones Matthew J, Uzuneser Taygun C, Laviolette Steven R
Department of Neuroscience, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada; Lawson Health Research Institute, St. Joseph's Health Care London, London, Ontario, Canada.
Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada; Department of Psychiatry, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada.
Neurobiol Dis. 2025 Aug;212:106952. doi: 10.1016/j.nbd.2025.106952. Epub 2025 May 11.
Anxiety and mood disorders represent the most prevalent neuropsychiatric conditions. Nevertheless, current pharmacotherapies often have a host of adverse side effects. Emerging evidence suggests modulation of lipid signaling pathways - particularly those involved in the endocannabinoid (eCB) system, may offer promising new targets for the treatment of anxiety and depression. Polyunsaturated fatty acids (PUFA) and their metabolic derivatives, including the eCB ligands, have garnered significant attention for their roles in neuropsychiatric disease mechanisms. Intracellular transportation of these lipids is facilitated by fatty acid binding proteins (FABP), which are increasingly recognized as key regulators of lipid signaling. Accumulating evidence indicates that FABPs may impact the development of neuropsychiatric disorders by mediating the signaling pathways of PUFAs and eCB ligands. In this review, we investigate the role of FABPs in two major categories of neuropsychiatric conditions - anxiety disorders and clinical depression. We begin by examining several neuropathophysiological mechanisms through which FABPs can impact these conditions, focusing on their role as lipid chaperones. These mechanisms include the trafficking of eCB ligands, as well as oleoylethanolamide and palmitoylethanolamide; modulation of inflammatory responses through PUFA transport and PPAR activation; regulation of PUFA availability to support neurogenesis; influence on stress-related pathways, including NMDA receptor activation and the hypothalamic-pituitary-adrenal axis; and the facilitation of dopamine receptor trafficking and localization. Next, we discuss preclinical evidence linking FABP function to anxiety- and depression-related behaviours. Finally, we propose that pharmacologically targeting FABP-mediated pathways holds considerable potential as a novel therapeutic strategy for addressing the symptoms associated with mood and anxiety disorders.
焦虑症和情绪障碍是最常见的神经精神疾病。然而，目前的药物治疗往往有许多不良副作用。新出现的证据表明，调节脂质信号通路——尤其是那些参与内源性大麻素（eCB）系统的通路，可能为焦虑症和抑郁症的治疗提供有前景的新靶点。多不饱和脂肪酸（PUFA）及其代谢衍生物，包括eCB配体，因其在神经精神疾病机制中的作用而受到广泛关注。这些脂质的细胞内运输由脂肪酸结合蛋白（FABP）促进，FABP越来越被认为是脂质信号的关键调节因子。越来越多的证据表明，FABP可能通过介导PUFA和eCB配体的信号通路影响神经精神疾病的发展。在这篇综述中，我们研究了FABP在两大类神经精神疾病——焦虑症和临床抑郁症中的作用。我们首先研究FABP影响这些疾病的几种神经病理生理机制，重点关注它们作为脂质伴侣的作用。这些机制包括eCB配体以及油酰乙醇胺和棕榈酰乙醇胺的运输；通过PUFA转运和PPAR激活调节炎症反应；调节PUFA的可用性以支持神经发生；影响与应激相关的通路，包括NMDA受体激活和下丘脑-垂体-肾上腺轴；以及促进多巴胺受体的运输和定位。接下来，我们讨论将FABP功能与焦虑和抑郁相关行为联系起来的临床前证据。最后，我们提出，以FABP介导的通路为药理靶点作为一种治疗与情绪和焦虑障碍相关症状的新型治疗策略具有相当大的潜力。
