Arecoline alleviates autism spectrum disorder-like behaviors and cognition disorders in a valproic acid mouse model by activating the AMPK/CREB/BDNF signaling pathway
Studies in humans have revealed that the pathogenesis of autism spectrum disorder (ASD) is linked to white matter abnormalities involving hypomyelination and oligodendroglia dysfunction; however, effective treatments remain limited. Similarly, the valproic acid (VPA) model mice, which are widely use...
Saved in:
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-09-01
|
| Series: | Brain Research Bulletin |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0361923025002436 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849687017243279360 |
|---|---|
| author | Chunyan Wen Zhizhong Xu Fengling Cao Qianfa Yuan Weichao Su Zhiyuan Huang |
| author_facet | Chunyan Wen Zhizhong Xu Fengling Cao Qianfa Yuan Weichao Su Zhiyuan Huang |
| author_sort | Chunyan Wen |
| collection | DOAJ |
| description | Studies in humans have revealed that the pathogenesis of autism spectrum disorder (ASD) is linked to white matter abnormalities involving hypomyelination and oligodendroglia dysfunction; however, effective treatments remain limited. Similarly, the valproic acid (VPA) model mice, which are widely used to study ASD, also exhibit white matter abnormalities with hypomyelination. Arecoline has been reported to enhance memory and cognition, facilitate myelination and improve neurological function. This study investigated the therapeutic potential of arecoline in a mouse model of prenatal VPA-induced ASD. We established an ASD mouse model through prenatal exposure to VPA and treated the mice with arecoline for 4 weeks. Behavioral analyses, including the elevated-plus maze, open field, self-grooming, marble-burying, three-chamber, Y-maze, and Morris water maze tests, were conducted to assess the effects of arecoline on behavior. Western blotting was used to detect changes in protein expression in the frontal cortex after arecoline treatment. The results revealed that offspring prenatally exposed to VPA presented characteristic behavioral abnormalities, including increased repetitive and stereotyped behaviors, deficits in social interaction, and impairments in learning and memory, accompanied by reduced expression of the myelin marker MBP and the mature oligodendrocyte marker GST-pi in the frontal cortex. Four-week arecoline treatment (1 and 2 mg/kg/day) significantly ameliorated these behavioral and cognitive abnormalities and restored myelination markers. Further mechanistic investigations demonstrated that arecoline enhanced the phosphorylation levels of AMPKα and CREB in the frontal cortex. This activation upregulated the expression of downstream BDNF, an essential neurotrophic factor for oligodendrocyte maturation and remyelination. These findings suggest that the AMPK/CREB/BDNF pathway may contribute to the therapeutic effects of arecoline, potentially through increased oligodendrocyte maturation and remyelination. This study provides preclinical evidence supporting arecoline as a potential myelination-targeting intervention, with implications for ASD and other neurological disorders involving myelination deficits. |
| format | Article |
| id | doaj-art-bdf5278920dc49139ecf61273d3f2fa1 |
| institution | DOAJ |
| issn | 1873-2747 |
| language | English |
| publishDate | 2025-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Brain Research Bulletin |
| spelling | doaj-art-bdf5278920dc49139ecf61273d3f2fa12025-08-20T03:22:29ZengElsevierBrain Research Bulletin1873-27472025-09-0122911143110.1016/j.brainresbull.2025.111431Arecoline alleviates autism spectrum disorder-like behaviors and cognition disorders in a valproic acid mouse model by activating the AMPK/CREB/BDNF signaling pathwayChunyan Wen0Zhizhong Xu1Fengling Cao2Qianfa Yuan3Weichao Su4Zhiyuan Huang5Fujian Psychiatric Center, Fujian Clinical Research Center for Mental Disorders, Xiamen Xianyue Hospital, Xianyue Hospital Affiliated with Xiamen Medical College, Xiamen, Fujian 361012, ChinaFujian Psychiatric Center, Fujian Clinical Research Center for Mental Disorders, Xiamen Xianyue Hospital, Xianyue Hospital Affiliated with Xiamen Medical College, Xiamen, Fujian 361012, ChinaFujian Psychiatric Center, Fujian Clinical Research Center for Mental Disorders, Xiamen Xianyue Hospital, Xianyue Hospital Affiliated with Xiamen Medical College, Xiamen, Fujian 361012, ChinaFujian Psychiatric Center, Fujian Clinical Research Center for Mental Disorders, Xiamen Xianyue Hospital, Xianyue Hospital Affiliated with Xiamen Medical College, Xiamen, Fujian 361012, ChinaFujian Psychiatric Center, Fujian Clinical Research Center for Mental Disorders, Xiamen Xianyue Hospital, Xianyue Hospital Affiliated with Xiamen Medical College, Xiamen, Fujian 361012, ChinaCorrespondence to: Xiamen Xianyue Hospital, 387-399 Xianyue Road, Xiamen, Fujian 361012, China.; Fujian Psychiatric Center, Fujian Clinical Research Center for Mental Disorders, Xiamen Xianyue Hospital, Xianyue Hospital Affiliated with Xiamen Medical College, Xiamen, Fujian 361012, ChinaStudies in humans have revealed that the pathogenesis of autism spectrum disorder (ASD) is linked to white matter abnormalities involving hypomyelination and oligodendroglia dysfunction; however, effective treatments remain limited. Similarly, the valproic acid (VPA) model mice, which are widely used to study ASD, also exhibit white matter abnormalities with hypomyelination. Arecoline has been reported to enhance memory and cognition, facilitate myelination and improve neurological function. This study investigated the therapeutic potential of arecoline in a mouse model of prenatal VPA-induced ASD. We established an ASD mouse model through prenatal exposure to VPA and treated the mice with arecoline for 4 weeks. Behavioral analyses, including the elevated-plus maze, open field, self-grooming, marble-burying, three-chamber, Y-maze, and Morris water maze tests, were conducted to assess the effects of arecoline on behavior. Western blotting was used to detect changes in protein expression in the frontal cortex after arecoline treatment. The results revealed that offspring prenatally exposed to VPA presented characteristic behavioral abnormalities, including increased repetitive and stereotyped behaviors, deficits in social interaction, and impairments in learning and memory, accompanied by reduced expression of the myelin marker MBP and the mature oligodendrocyte marker GST-pi in the frontal cortex. Four-week arecoline treatment (1 and 2 mg/kg/day) significantly ameliorated these behavioral and cognitive abnormalities and restored myelination markers. Further mechanistic investigations demonstrated that arecoline enhanced the phosphorylation levels of AMPKα and CREB in the frontal cortex. This activation upregulated the expression of downstream BDNF, an essential neurotrophic factor for oligodendrocyte maturation and remyelination. These findings suggest that the AMPK/CREB/BDNF pathway may contribute to the therapeutic effects of arecoline, potentially through increased oligodendrocyte maturation and remyelination. This study provides preclinical evidence supporting arecoline as a potential myelination-targeting intervention, with implications for ASD and other neurological disorders involving myelination deficits.http://www.sciencedirect.com/science/article/pii/S0361923025002436Autism spectrum disorderCognitionMyelinationArecolineAMPK signaling pathway |
| spellingShingle | Chunyan Wen Zhizhong Xu Fengling Cao Qianfa Yuan Weichao Su Zhiyuan Huang Arecoline alleviates autism spectrum disorder-like behaviors and cognition disorders in a valproic acid mouse model by activating the AMPK/CREB/BDNF signaling pathway Brain Research Bulletin Autism spectrum disorder Cognition Myelination Arecoline AMPK signaling pathway |
| title | Arecoline alleviates autism spectrum disorder-like behaviors and cognition disorders in a valproic acid mouse model by activating the AMPK/CREB/BDNF signaling pathway |
| title_full | Arecoline alleviates autism spectrum disorder-like behaviors and cognition disorders in a valproic acid mouse model by activating the AMPK/CREB/BDNF signaling pathway |
| title_fullStr | Arecoline alleviates autism spectrum disorder-like behaviors and cognition disorders in a valproic acid mouse model by activating the AMPK/CREB/BDNF signaling pathway |
| title_full_unstemmed | Arecoline alleviates autism spectrum disorder-like behaviors and cognition disorders in a valproic acid mouse model by activating the AMPK/CREB/BDNF signaling pathway |
| title_short | Arecoline alleviates autism spectrum disorder-like behaviors and cognition disorders in a valproic acid mouse model by activating the AMPK/CREB/BDNF signaling pathway |
| title_sort | arecoline alleviates autism spectrum disorder like behaviors and cognition disorders in a valproic acid mouse model by activating the ampk creb bdnf signaling pathway |
| topic | Autism spectrum disorder Cognition Myelination Arecoline AMPK signaling pathway |
| url | http://www.sciencedirect.com/science/article/pii/S0361923025002436 |
| work_keys_str_mv | AT chunyanwen arecolinealleviatesautismspectrumdisorderlikebehaviorsandcognitiondisordersinavalproicacidmousemodelbyactivatingtheampkcrebbdnfsignalingpathway AT zhizhongxu arecolinealleviatesautismspectrumdisorderlikebehaviorsandcognitiondisordersinavalproicacidmousemodelbyactivatingtheampkcrebbdnfsignalingpathway AT fenglingcao arecolinealleviatesautismspectrumdisorderlikebehaviorsandcognitiondisordersinavalproicacidmousemodelbyactivatingtheampkcrebbdnfsignalingpathway AT qianfayuan arecolinealleviatesautismspectrumdisorderlikebehaviorsandcognitiondisordersinavalproicacidmousemodelbyactivatingtheampkcrebbdnfsignalingpathway AT weichaosu arecolinealleviatesautismspectrumdisorderlikebehaviorsandcognitiondisordersinavalproicacidmousemodelbyactivatingtheampkcrebbdnfsignalingpathway AT zhiyuanhuang arecolinealleviatesautismspectrumdisorderlikebehaviorsandcognitiondisordersinavalproicacidmousemodelbyactivatingtheampkcrebbdnfsignalingpathway |