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    题名: 甜菜鹼與左旋茶胺酸改善利血平所誘發的小鼠疼痛和類憂鬱行為
    Betaine and L-theanine alleviate pain and depression-like behaviors induced by reserpine in mice
    作者: 田心如
    Tien, Hsin-Ju
    贡献者: 詹銘煥
    陳慧諴
    Chan, Ming-Huan
    Chen, Hwei-Hsien
    田心如
    Tien, Hsin-Ju
    关键词: 纖維肌痛症
    憂鬱症
    利血平
    甜菜鹼
    左旋茶胺酸
    fibromyalgia
    depression
    reserpine
    betaine
    L-theanine
    日期: 2025
    上传时间: 2025-02-04 16:15:42 (UTC+8)
    摘要: 纖維肌痛經常共病憂鬱，導致治療難度提高，本研究旨在評估甜菜鹼與左旋茶胺酸作為輔助療法的潛力，探討其在利血平 (reserpine) 誘導的纖維肌痛及憂鬱小鼠模型中的鎮痛與抗憂鬱作用及其可能的作用機制。利血平(1 mg/kg, 腹腔注射) 連續給藥三天，成功誘導相關症狀，包括疼痛、憂鬱、焦慮及認知功能障礙。所誘導之疼痛行為可維持長達2個月，而類憂鬱行為則可維持1個月。同時臨床纖維肌痛治療藥物Duloxetine和pregabalin在此模型中均顯示鎮痛與抗憂鬱效果。成功建立模型後，透過腹腔注射給予甜菜鹼與左旋茶胺酸進行行為測試，評估疼痛敏感度、類憂鬱行為及認知功能。結果顯示，甜菜鹼與左旋茶胺酸均顯著減輕疼痛、改善類憂鬱行為及增強認知功能。透過腦室注射以及脊髓鞘內注射評估甜菜鹼與左旋茶胺酸之鎮痛效果，顯示腦和脊髓均參與兩者之鎮痛效果。腦室內及脊髓鞘內注射AMPA受體正向變構調節劑CX614不影響甜菜鹼的鎮痛效果；但完全阻斷左旋茶胺酸的鎮痛作用。腦室注射NMDA受體拮抗劑7-Chlorokynurenic acid (7-CK)可完全阻斷甜菜鹼的鎮痛效果，但不影響左旋茶胺酸的作用；脊髓鞘內注射7-CK則不影響甜菜鹼和左旋茶胺酸的鎮痛作用。使用GABAA受體拮抗劑Picrotoxin進行脊髓鞘內注射時，無法抑制甜菜鹼的鎮痛效果，但能完全阻斷左旋茶胺酸的鎮痛作用。此外，CSF1R抑制劑 (Pexidartinib, PLX3397)誘導的小膠質細胞耗竭抑制了兩種化合物的抗憂鬱作用，但對鎮痛及認知增強效果無影響，顯示兩種化合物的鎮痛機轉可能獨立於小膠質細胞調控。研究結果顯示，甜菜鹼與左旋茶胺酸透過不同的分子機轉發揮鎮痛作用，甜菜鹼的鎮痛效果可能依賴於腦內NMDAR的活化，特別可能透過其glycine結合位點發揮作用。左旋茶胺酸可能透過 AMPAR調節影響大腦與脊髓的疼痛傳導，並調節脊髓中GABA的神經傳導，進而抑制疼痛，且兩者均透過小膠質細胞產生抗憂鬱作用。這些發現支持甜菜鹼與左旋茶胺酸具有改善纖維肌痛症病人疼痛與憂鬱症狀的潛力。
    Fibromyalgia (FM) often coexists with depression, which complicates treatment strategies. This study evaluated the potential of betaine and L-theanine as adjunct therapies by investigating their analgesic and antidepressant effects, along with their possible mechanisms, using the FM model. Reserpine (1 mg/kg, administered via i.p.) was given for three consecutive days and successfully induced FM syndromes (FMS), such as pain, depression, anxiety, and cognitive dysfunction. The pain-related behaviors lasted for up to two months, while depression-like behaviors persisted for one month. Duloxetine and pregabalin, the current clinical drugs for the treatment of FM, demonstrated both analgesic and antidepressant effects in this model. After establishing the model, betaine and L-theanine were administered via i.p. to evaluate FMS. Results indicated that both betaine and L-theanine significantly reduced pain, improved depression-like behaviors, and enhanced cognitive performance. Further investigations using intracerebroventricular (i.c.v.) and intrathecal (i.t.) injections confirmed that both brain and spinal cord mechanisms contributed to their analgesic effects. Mechanistic studies revealed that the analgesic effects of betaine were not influenced by i.c.v. or i.t. administration of the AMPAR-positive allosteric modulator CX614 but were entirely blocked by the NMDAR inhibitor 7-Chlorokynurenic acid (7-CK) via i.c.v. injection. However, i.t. injection of 7-CK did not affect betaine's analgesic action. In contrast, the analgesic effects of L-theanine were entirely abolished by CX614 administration through both i.c.v. and i.t. routes but were unaffected by 7-CK. Additionally, i.t. administration of the GABAA receptor antagonist picrotoxin completely blocked L-theanine's analgesic effects but did not impact betaine. Furthermore, the antidepressant effects of both compounds were diminished by microglial depletion induced by the CSF1R inhibitor Pexidartinib (PLX3397) without affecting their analgesic or cognitive-enhancing properties. This indicates that betaine and L-theanine analgesic mechanisms are likely independent of microglial regulation. In summary, betaine and L-theanine exert analgesic effects through distinct molecular pathways: betaine likely acts via NMDAR activation, particularly through the glycine-binding site in the brain. At the same time, L-theanine modulates AMPAR and spinal GABAergic transmission. Additionally, both compounds demonstrate antidepressant effects that involve microglial pathways. These findings highlight the potential of betaine and L-theanine as therapeutic agents for managing pain and depression in FM patients.
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