Luteolin Potentially Alleviates Methamphetamine Withdrawal-Induced Negative Emotions and Cognitive Deficits Through the AKT/FOXO1/HO-1 Signaling Pathway in the Prefrontal Cortex and Caudate Putamen

  • Int J Mol Sci. 2025 Jun 15;26(12):5739. doi: 10.3390/ijms26125739.
Baoyao Gao  1  2 ,  Ran An  1  2 ,  Min Liang  1  2 ,  Xinglin Wang  1  2 ,  Jianhang Peng  1  2 ,  Xingyao Chen  1  2 ,  Zijun Liu  1  2 ,  Tao Li  1  2 ,  Xinshe Liu  1  2 ,  Jianbo Zhang  1  2 ,  Wei Han  1  2
Affiliations
  • 1. College of Forensic Medicine, Xi'an Jiaotong University, Xi'an 710061, China.
  • 2. Key Laboratory of National Health Commission for Forensic Science, Xi'an Jiaotong University, Xi'an 710061, China.
PMID: 40565203 DOI: 10.3390/ijms26125739
Abstract

Methamphetamine (METH) misuse-induced affective and cognitive dysfunctions cause severe global health and economic burdens. However, the mechanisms underlying METH withdrawal-induced negative emotions and cognitive deficits, as well as the treatment strategies for them, remain elusive. Previous findings suggest that METH use triggers neuroinflammation and neuronal Apoptosis, and protein kinase B (Akt), forkhead box protein 1 (FOXO1), and heme-oxygenase-1 (HO-1) are implicated in these processes. In the present study, we aimed to reveal the role and potential mechanisms of luteolin, a flavonoid phytochemical with anti-inflammatory and antioxidative properties, in METH withdrawal-induced negative emotions and cognitive deficits. We found that prolonged METH withdrawal led to an increase in neuronal activity and a decrease in the protein expression of phosphorylated Akt (p-AKT) and HO-1 in the prefrontal cortex (PFC) and caudate putamen (CPu). Luteolin pretreatment partially mitigated these METH withdrawal-induced negative emotions and cognitive deficits, and prevented the abnormal activation of PFC and CPu as well as the downregulation of Akt/HO-1 expression. Notably, we further observed that luteolin inhibited the METH-induced nuclear translocation of FOXO1. Our findings suggest that luteolin may alleviate METH withdrawal-induced affective and cognitive dysfunctions by reducing oxidative injury in the brain through the Akt/FOXO1/HO-1 pathway, highlighting its potential for treating drug addiction-related health issues.

Keywords
cognitive deficits; forkhead box protein 1 (FOXO1); heme-oxygenase-1 (HO-1); luteolin; methamphetamine withdrawal; negative emotions; protein kinase B (AKT).
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