Scholarlink

<p>Tramadol withdrawal presents a significant clinical challenge, characterized by neurobehavioral impairments linked to neuroinflammation, oxidative stress and neurotransmitter dysregulation. The TNF-like weak inducer of apoptosis (TWEAK)/fibroblast growth factor-inducer 14 (Fn14) pathway and downstream effectors like cAMP response element binding protein (CREB) are implicated, but effective targeted therapies are lacking. Aurintricarboxylic acid (ATA), a TWEAK inhibitor, exhibits neuroprotective potential. This study aims to evaluate the therapeutic efficacy of ATA in mitigating the tramadol withdrawal-induced neurobehavioral alterations in mice model, focusing on the role of TWEAK/Fn14 pathway and CREB phosphorylation. Swiss albino mice were subjected to chronic tramadol administration (50&#xa0;mg/kg, s.c.) for 57 days, with withdrawal precipitated with naloxone (5&#xa0;mg/kg, i.p.) on day 57. Behavioural assessments included withdrawal severity score (WSS), jumping frequency, and hyperalgesia. Biochemical analyses measured the level of oxidative stress markers (TBARS, SOD, GSH and catalase), inflammatory biomarkers (TNF-α, IL-6, IL-1β), and neurotransmitters (glutamate, dopamine and serotonin). ATA (5&#xa0;mg/kg and 10&#xa0;mg/kg i.p.) dose-dependently reduced the WSS, jumping frequency and hyperalgesia. It also mitigated the oxidative stress, neuroinflammation, and glutamate level, while restoring the neurotransmitter level. Notably, pretreatment with CREB inhibitor (666 − 15) (10&#xa0;mg/kg i.p) significantly attenuated the protective effect of ATA, underscoring the pivotal role of CREB phosphorylation in its mechanism. Our findings demonstrate that ATA offers significant neuroprotection against tramadol withdrawal, primarily by inhibiting the TWEAK/Fn14 pathway and subsequently promoting the CREB phosphorylation. This study highlights ATA as a promising therapeutic candidate for managing tramadol withdrawal syndrome by targeting oxidative stress, neuroinflammation, and its downstream effectors.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Aurintricarboxylic Acid Attenuates Tramadol Withdrawal Syndrome Via TWEAK/FN14 Inhibition and CREB Modulation in Mice Model

  • 期刊论文

  • 发表日期：

    2025年10月29日

查看全文
  • Rajalaxmi,
  • Shahid Nazir Wani,
  • Amarjot Kaur Grewal,
  • Varinder Singh,
  • Amit Kumar,
  • Heena Khan,
  • Thakur Gurjeet Singh

摘要

Tramadol withdrawal presents a significant clinical challenge, characterized by neurobehavioral impairments linked to neuroinflammation, oxidative stress and neurotransmitter dysregulation. The TNF-like weak inducer of apoptosis (TWEAK)/fibroblast growth factor-inducer 14 (Fn14) pathway and downstream effectors like cAMP response element binding protein (CREB) are implicated, but effective targeted therapies are lacking. Aurintricarboxylic acid (ATA), a TWEAK inhibitor, exhibits neuroprotective potential. This study aims to evaluate the therapeutic efficacy of ATA in mitigating the tramadol withdrawal-induced neurobehavioral alterations in mice model, focusing on the role of TWEAK/Fn14 pathway and CREB phosphorylation. Swiss albino mice were subjected to chronic tramadol administration (50 mg/kg, s.c.) for 57 days, with withdrawal precipitated with naloxone (5 mg/kg, i.p.) on day 57. Behavioural assessments included withdrawal severity score (WSS), jumping frequency, and hyperalgesia. Biochemical analyses measured the level of oxidative stress markers (TBARS, SOD, GSH and catalase), inflammatory biomarkers (TNF-α, IL-6, IL-1β), and neurotransmitters (glutamate, dopamine and serotonin). ATA (5 mg/kg and 10 mg/kg i.p.) dose-dependently reduced the WSS, jumping frequency and hyperalgesia. It also mitigated the oxidative stress, neuroinflammation, and glutamate level, while restoring the neurotransmitter level. Notably, pretreatment with CREB inhibitor (666 − 15) (10 mg/kg i.p) significantly attenuated the protective effect of ATA, underscoring the pivotal role of CREB phosphorylation in its mechanism. Our findings demonstrate that ATA offers significant neuroprotection against tramadol withdrawal, primarily by inhibiting the TWEAK/Fn14 pathway and subsequently promoting the CREB phosphorylation. This study highlights ATA as a promising therapeutic candidate for managing tramadol withdrawal syndrome by targeting oxidative stress, neuroinflammation, and its downstream effectors.