Heat stroke-induced structural and functional impairments of cognition-relevant brain areas in mice is associated with alpha-7 nicotinic acetylcholine receptors downregulation

  • Eur J Pharmacol. 2026 Mar 28:1019:178723. doi: 10.1016/j.ejphar.2026.178723.
Kangli Zhang  1 ,  Lin-Yu Wang  2 ,  Liyong Yan  3 ,  Zhujun Ye  4 ,  Kai Liu  5 ,  Xiaohong Liu  6 ,  Xiaojing Lin  7 ,  Yunfei Shi  8 ,  Tao Ma  9 ,  Ruoxu Liu  10 ,  Xiaowen Wang  11 ,  Xueqing Yi  12 ,  Zixuan Qu  13 ,  Chenyi Li  14 ,  Cheng-Hsien Lin  15 ,  Gang Sun  16
Affiliations
  • 1. The Guidance Center for Military Psychology of PLA, Jinan, Shandong Province, PR China; Key Laboratory of Military Medical Psychology and Stress Biology of PLA, Jinan, Shandong Province, PR China; Department of Psychology, The 960th Hospital of Joint Logistics Support Force of PLA, Jinan, Shandong Province, PR China. Electronic address: [email protected].
  • 2. Department of Pediatrics, Chi Mei Medical Center, Tainan City, 71004, Taiwan; Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, 701, Taiwan; Center for General Education, Southern Taiwan University of Science and Technology, Tainan City, 71005, Taiwan; School of Medicine, Kaohsiung Medical University, Kaohsiung, 81201, Taiwan. Electronic address: [email protected].
  • 3. Center for Health Care Management, Affiliated Taian City Central Hospital of Qingdao University, Taian, Shandong Province, PR China. Electronic address: [email protected].
  • 4. Department of Orthopedics, PLA General Hospital of Southern Theater Command, Guangzhou, Guangdong Province, PR China. Electronic address: [email protected].
  • 5. Department of Medical Imaging, The 960th Hospital of Joint Logistics Support Force of PLA, Jinan, Shandong Province, PR China. Electronic address: [email protected].
  • 6. Shandong Huayi Biotechnology Co., Jinan, Shandong Province, PR China. Electronic address: [email protected].
  • 7. The Guidance Center for Military Psychology of PLA, Jinan, Shandong Province, PR China; Key Laboratory of Military Medical Psychology and Stress Biology of PLA, Jinan, Shandong Province, PR China; Department of Psychology, The 960th Hospital of Joint Logistics Support Force of PLA, Jinan, Shandong Province, PR China. Electronic address: [email protected].
  • 8. Center for Health Care Management, Affiliated Taian City Central Hospital of Qingdao University, Taian, Shandong Province, PR China. Electronic address: [email protected].
  • 9. Shandong Huayi Biotechnology Co., Jinan, Shandong Province, PR China. Electronic address: [email protected].
  • 10. State Key Laboratory of Proteomics and Department of Neurobiology, Beijing Institute of Basic Medical Sciences, Beijing, PR China. Electronic address: [email protected].
  • 11. Frankston ED, Peninsula Health, Frankston Hospital, Victoria, Australia. Electronic address: [email protected].
  • 12. Department of Orthopedics, PLA General Hospital of Southern Theater Command, Guangzhou, Guangdong Province, PR China. Electronic address: [email protected].
  • 13. Shandong Huayi Biotechnology Co., Jinan, Shandong Province, PR China. Electronic address: [email protected].
  • 14. Shandong Huayi Biotechnology Co., Jinan, Shandong Province, PR China. Electronic address: [email protected].
  • 15. Department of Medicine, Mackay Medical University, New Taipei City, Taiwan. Electronic address: [email protected].
  • 16. The Guidance Center for Military Psychology of PLA, Jinan, Shandong Province, PR China; Key Laboratory of Military Medical Psychology and Stress Biology of PLA, Jinan, Shandong Province, PR China; Department of Psychology, The 960th Hospital of Joint Logistics Support Force of PLA, Jinan, Shandong Province, PR China. Electronic address: [email protected].
PMID: 41786068 DOI: 10.1016/j.ejphar.2026.178723
Abstract

Objective: Classic heat stroke (CHS) results from prolonged exposure to high environmental temperatures without physical exertion. However, the involvement of α7 nicotinic acetylcholine receptors (α7nAChR) in CHS-associated neurobehavioral abnormalities remains unclear.

Methods: Immediately after CHS onset, mice received intraperitoneal lonafarnib (LNF-40; 40 mg/kg) or vehicle twice daily for 14 days. Animals were assigned to four groups: non-CHS + Veh, non-CHS + LNF-40, CHS + Veh, and CHS + LNF-40. After the final dose, neurobehavioral performance was evaluated using novel object recognition, forced swim, rotarod, and Morris water maze tests. Dendritic morphology of prefrontal cortical neurons was assessed by Golgi staining, whereas hippocampal neurogenesis was evaluated by doublecortin (DCX) immunofluorescence. Finally, α7nAChR levels and pro-inflammatory cytokines in the prefrontal cortex and hippocampus were quantified by ELISA.

Results: Compared with non-CHS controls, CHS + Veh mice exhibited impaired recognition and spatial memory, increased depressive-like behavior, and reduced motor coordination. Relative to CHS + Veh, CHS + LNF-40 mice showed attenuated neurobehavioral deficits. Structurally, Golgi analyses indicated that LNF-40 reduced CHS-associated dendritic/spine pathology in prefrontal cortical neurons, and DCX immunofluorescence showed higher hippocampal neurogenesis in LNF-40-treated CHS mice. Biochemically, LNF-40 was associated with higher α7 nAChR levels and lower pro-inflammatory cytokines in both the prefrontal cortex and hippocampus. LNF-40 did not significantly alter these measures in non-CHS mice.

Conclusion: CHS is associated with structural and functional impairments in cognition-relevant brain regions, accompanied by reduced α7nAChR expression. Lonafarnib mitigated CHS-related neurobehavioral abnormalities in parallel with restoration of α7nAChR expression in mice.

Keywords
Classic heat stroke; Cognition; Lonafarnib; Neurobehavioral disorders; α-7 nicotinic acetyl choline receptors.
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