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Steroidal alkaloid H89712 ameliorates neuroinflammation and memory deficits: Enhancing cerebral oxidative phosphorylation in APP/PS1 mice.

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Τίτλος: Steroidal alkaloid H89712 ameliorates neuroinflammation and memory deficits: Enhancing cerebral oxidative phosphorylation in APP/PS1 mice.
Συγγραφείς: Jiang L; Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China; Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, 410008, Hunan, China; Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, 410008, Hunan, China; National Clinical Research Center for Geriatric Disorders, Changsha, 410008, Hunan, China., Zhang Z; Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China; Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, 410008, Hunan, China; Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, 410008, Hunan, China; National Clinical Research Center for Geriatric Disorders, Changsha, 410008, Hunan, China., Luo X; Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China; Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, 410008, Hunan, China; Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, 410008, Hunan, China; National Clinical Research Center for Geriatric Disorders, Changsha, 410008, Hunan, China., Wu H; Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China; Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, 410008, Hunan, China; Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, 410008, Hunan, China; National Clinical Research Center for Geriatric Disorders, Changsha, 410008, Hunan, China., Huang Z; Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China; Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, 410008, Hunan, China; Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, 410008, Hunan, China; National Clinical Research Center for Geriatric Disorders, Changsha, 410008, Hunan, China., Wu W; Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China; Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, 410008, Hunan, China; Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, 410008, Hunan, China; National Clinical Research Center for Geriatric Disorders, Changsha, 410008, Hunan, China., Xu S; Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China; Phase I Clinical Trial Center, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China., Pan J; Clinical Research Laboratory, the Second Affiliated Hospital of University of South China, Hengyang, 421001, Hunan, China. Electronic address: 13787702128@139.com., Tan Z; Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China; Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, 410008, Hunan, China; Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, 410008, Hunan, China; National Clinical Research Center for Geriatric Disorders, Changsha, 410008, Hunan, China. Electronic address: 803119@csu.edu.cn.
Πηγή: Life sciences [Life Sci] 2026 Oct 01; Vol. 402, pp. 124583. Date of Electronic Publication: 2026 Jul 08.
Τύπος έκδοσης: Journal Article
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Elsevier Country of Publication: Netherlands NLM ID: 0375521 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1879-0631 (Electronic) Linking ISSN: 00243205 NLM ISO Abbreviation: Life Sci Subsets: MEDLINE
Imprint Name(s): Publication: <2008->: Amsterdam : Elsevier
Original Publication: Oxford; Elmsford, N. Y. [etc.] Pergamon Press.
Ιατρικοί όροι (MeSH): Memory Disorders*/drug therapy , Memory Disorders*/metabolism , Oxidative Phosphorylation*/drug effects , Neuroinflammatory Diseases*/drug therapy , Neuroinflammatory Diseases*/metabolism , Alkaloids*/pharmacology , Alzheimer Disease*/drug therapy , Alzheimer Disease*/metabolism , Steroids*/pharmacology, Amyloid beta-Protein Precursor/genetics ; Hippocampus/drug effects ; Hippocampus/metabolism ; Neuroprotective Agents/pharmacology ; Maze Learning/drug effects ; Presenilin-1/genetics ; Apoptosis/drug effects ; Animals ; Mice ; Male ; Mice, Transgenic ; Disease Models, Animal
Περίληψη: Aims: Alzheimer's disease (AD) poses a major health challenge with limited therapeutic options. This study aimed to investigate the anti-AD potential and underlying mechanism of a novel steroidal alkaloid, H89.
Materials and Methods: In vitro, Aβ25-35-exposed HT-22 hippocampal neurons and LPS-stimulated BV2 microglia were used to assess H89 neuroprotection and anti-inflammatory activity. In vivo, 6-month-old APP/PS1 mice were orally administered H89 for 2 months. Spatial memory was assessed by Y-maze (YM) and Morris water maze (MWM). Hippocampal morphology, neuronal apoptosis (TUNEL/NeuN), Aβ deposition (IHC), microglial activation (Iba1), inflammatory cytokines (ELISA), and oxidative phosphorylation (RNA-seq, qRT-PCR, Western blot) were examined. Brain malondialdehyde (MDA), ATP, and cellular ROS were quantified.
Key Findings: H89 (10 and 50 nM) significantly protected HT-22 cells against Aβ25-35-induced injury and attenuated LPS-induced TNF-α, IL-1β, and IL-6 secretion while elevating IL-10 in BV2 cells. In APP/PS1 mice, H89 increased novel arm exploration in the YM and target quadrant residence in the MWM, indicating improved spatial learning and memory. H89 ameliorated hippocampal neuronal morphology, reduced apoptosis, attenuated Aβ plaques and microglial activation (Iba1), decreased TNF-α, IL-6 and MDA, and elevated IL-10 and cerebral ATP. Transcriptomic and molecular analyses confirmed that H89 upregulated oxidative phosphorylation-related genes and proteins (ATP5E, ATP5J2, NDUFA13, NDUFB3, COX7C, COX11). Cerebral ATP positively correlated with spatial memory but negatively correlated with neuroinflammation and oxidative stress.
Significance: H89 exerts neuroprotective effects by enhancing mitochondrial oxidative phosphorylation and brain energy supply, concurrently suppressing neuroinflammation, oxidative stress, and neuronal apoptosis, suggesting its potential as a therapeutic candidate for AD.
(Copyright © 2026 Elsevier Inc. All rights reserved.)
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Contributed Indexing: Keywords: Alzheimer's disease; H89712; Mitochondrial dysfunction; Neuroinflammation; Oxidative phosphorylation; Steroidal alkaloid
Substance Nomenclature: 0 (Alkaloids)
0 (Amyloid beta-Protein Precursor)
0 (Neuroprotective Agents)
0 (Steroids)
0 (Presenilin-1)
Entry Date(s): Date Created: 20260707 Date Completed: 20260811 Latest Revision: 20260811
Update Code: 20260812
DOI: 10.1016/j.lfs.2026.124583
PMID: 42413720
Βάση Δεδομένων: MEDLINE
Περιγραφή
ISSN:1879-0631
DOI:10.1016/j.lfs.2026.124583