Tabernanthalog, a Non-Hallucinogenic Psychedelic, Alleviates Cancer-Induced Cognitive Deficits via Serotonergic Pathways
Abstract
1. Introduction
2. Results
2.1. Lung Cancer Induces Anxiety-like Behavior and Contextual Memory Impairment in Mice
2.2. Reduced Hippocampal Tryptophan Availability and Serotonin Synthesis Gene Expression in 3LL Mice
2.3. Downregulation of Serotonergic Receptors and Heightened Neuroinflammation in the Hippocampus of 3LL Mice
2.4. Reduced Serotonergic Terminals and Enhanced Microglial Activation in the Hippocampus of 3LL Mice
2.5. TBG Alleviates Anxiety-like Behavior and Cognitive Impairment in 3LL Mice
2.6. Upregulation of Serotonergic Receptors and Suppression of Neuroinflammation in the Hippocampus of TBG Mice
2.7. TBG Inhibits Alterations in Microglial Morphology and Gene Expression in the Hippocampus of 3LL Mice
2.8. TBG Suppresses Neuroinflammatory Gene Expression in BV-2 Microglia Exposed to 3LL Cell-Conditioned Medium
3. Discussion
4. Materials and Methods
4.1. Animals
4.2. Cell Line
4.3. Cancer Transplantation
4.4. Drug Administration and Animal Groups
4.5. Behavioral Test Battery
4.6. Perfusion Fixation and Sectioning
4.7. Measurement of Tryptophan and Kynurenine Concentrations
4.8. Voxel Counting Analysis of 5-HT+ Terminals
4.9. Optical Disector Analysis
4.10. Morphometric Analysis
- (1)
- Number of primary processes: The total number of primary processes.
- (2)
- Number of nodes: The total number of process nodes.
- (3)
- Number of ends: The total number of process ends.
- (4)
- Total process length: The sum of the lengths of all process branches.
- (5)
- Mean process length: The average length of all process branches.
- (6)
- Process volume: The total volume of all process branches.
- (7)
- Convex hull: The area of the convex polygon formed by connecting the tips of the most distal processes.
- (8)
- Cell body: the area of the cell body.
- (9)
- Length of 1st/2nd/3rd processes: The total length of the 1st, 2nd, and 3rd process branches, respectively.
- (10)
- Number of nodes in 1st/2nd/3rd processes: The total number of nodes in the 1st, 2nd, and 3rd processes, respectively.
- (11)
- Number of intersections (Sholl analysis): The number of intersections between processes and concentric circles at increasing distances from the cell body [22].
- (12)
- Process length (Sholl analysis): The cumulative length of processes intersecting concentric circles at increasing distances from the cell body.
4.11. Culture of BV-2 Microglia
4.12. RT–qPCR
- (1)
- Tph2.
- (2)
- Ido1.
- (3)
- Ido2.
- (4)
- Tdo2.
- (5)
- Htr2a.
- (6)
- Htr3.
- (7)
- Htr4.
- (8)
- Il1b.
- (9)
- Tnf.
- (10)
- Il6.
- (11)
- Aif1.
- (12)
- Tmem119.
- (13)
- P2ry12.
- (14)
- P2ry13.
- (15)
- Cd68.
- (16)
- Cd33.
- (17)
- Cx3cr1.
- (18)
- C1q.
- (19)
- Gapdh.
4.13. Statistical Analysis and Illustration Preparations
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Gene | Forward | Reverse |
Tph2 | CCACCATTGTGACCCTGAATCC | ATGAGGACTCGGTGAGAGCATC |
Ido1 | GCAGACTGTGTCCTGGCAAACT | AGAGACGAGGAAGAAGCCCTTG |
Ido2 | GACAGTCTTGGTGGAGAAGGCA | ATCCTGGATGGAGAGTCTCAGC |
Tdo2 | CATGCTCAAGGTGATAGCTCGG | GGAAGCCTGATGCTGGAGACAG |
Htr2a | CCTGATGTCACTTGCCATAGCTG | CAGGTAAATCCAGACGGCACAG |
Htr3 | CACACTCCTTCTGGGATACTCAG | GATGGTCTCAGCGAGGCTTATC |
Htr4 | TGCTCACGTTCCTTGCAGTGGT | GTCAGCAAAGGCGAGAGACACA |
Il1b | TGGACCTTCCAGGATGAGGACA | GTTCATCTCGGAGCCTGTAGTG |
Tnf | GGTGCCTATGTCTCAGCCTCTT | GCCATAGAACTGATGAGAGGGAG |
Il6 | TACCACTTCACAAGTCGGAGGC | CTGCAAGTGCATCATCGTTGTTC |
Aif1 | TCTGCCGTCCAAACTTGAAGCC | CTCTTCAGCTCTAGGTGGGTCT |
Tmem119 | ACTACCCATCCTCGTTCCCTGA | TAGCAGCCAGAATGTCAGCCTG |
P2ry12 | CATTGACCGCTACCTGAAGACC | GCCTCCTGTTGGTGAGAATCATG |
P2ry13 | TGGCATCAGGTGGTCAGTCACA | TTGTGCCTGCTGTCCTTACTCC |
Cd68 | GGCGGTGGAATACAATGTGTCC | AGCAGGTCAAGGTGAACAGCTG |
Cd33 | TGCAGAACATCACAATGAGAAAC | GAAAGGACCATCCAGCTCAA |
Cx3cr1 | TCTGGACTCACTACCTCATCAG | TCCGGTTGTTCATGGAGTTGG |
C1q | ATGGAGACCTCTCAGGGATG | ATACCAGTCCGGATGCCAGC |
Gapdh | CATCACTGCCACCCAGAAGACTG | ATGCCAGTGAGCTTCCCGTTCAG |
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Arinaga, M.; Yamada, J.; Maeda, S.; Okamura, A.; Oshima, Y.; Zhang, L.; Han, Y.; Iinuma, K.M.; Jinno, S. Tabernanthalog, a Non-Hallucinogenic Psychedelic, Alleviates Cancer-Induced Cognitive Deficits via Serotonergic Pathways. Int. J. Mol. Sci. 2025, 26, 7519. https://doi.org/10.3390/ijms26157519
Arinaga M, Yamada J, Maeda S, Okamura A, Oshima Y, Zhang L, Han Y, Iinuma KM, Jinno S. Tabernanthalog, a Non-Hallucinogenic Psychedelic, Alleviates Cancer-Induced Cognitive Deficits via Serotonergic Pathways. International Journal of Molecular Sciences. 2025; 26(15):7519. https://doi.org/10.3390/ijms26157519
Chicago/Turabian StyleArinaga, Masahide, Jun Yamada, Shoichiro Maeda, Ayumi Okamura, Yuto Oshima, Liye Zhang, Yiying Han, Kyoko M. Iinuma, and Shozo Jinno. 2025. "Tabernanthalog, a Non-Hallucinogenic Psychedelic, Alleviates Cancer-Induced Cognitive Deficits via Serotonergic Pathways" International Journal of Molecular Sciences 26, no. 15: 7519. https://doi.org/10.3390/ijms26157519
APA StyleArinaga, M., Yamada, J., Maeda, S., Okamura, A., Oshima, Y., Zhang, L., Han, Y., Iinuma, K. M., & Jinno, S. (2025). Tabernanthalog, a Non-Hallucinogenic Psychedelic, Alleviates Cancer-Induced Cognitive Deficits via Serotonergic Pathways. International Journal of Molecular Sciences, 26(15), 7519. https://doi.org/10.3390/ijms26157519