BDNF augmentation reverses cranial radiation therapy-induced cognitive decline and neurodegenerative consequences.

Autor: El-Khatib SM; Department of Anatomy and Neurobiology, School of Medicine, University of California, Irvine, USA., Vagadia AR; Department of Anatomy and Neurobiology, School of Medicine, University of California, Irvine, USA., Le ACD; Department of Anatomy and Neurobiology, School of Medicine, University of California, Irvine, USA., Baulch JE; Department of Radiation Oncology, School of Medicine, University of California, Irvine, USA., Ng DQ; Department of Clinical Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, University of California, Irvine, USA., Du M; Center for Neural Circuit Mapping, School of Medicine, University of California, Irvine, USA., Johnston KG; Department of Anatomy and Neurobiology, School of Medicine, University of California, Irvine, USA.; Center for Neural Circuit Mapping, School of Medicine, University of California, Irvine, USA., Tan Z; Department of Anatomy and Neurobiology, School of Medicine, University of California, Irvine, USA.; Center for Neural Circuit Mapping, School of Medicine, University of California, Irvine, USA., Xu X; Department of Anatomy and Neurobiology, School of Medicine, University of California, Irvine, USA.; Center for Neural Circuit Mapping, School of Medicine, University of California, Irvine, USA., Chan A; Department of Clinical Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, University of California, Irvine, USA. a.chan@uci.edu.; Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University of California, Irvine, USA. a.chan@uci.edu., Acharya MM; Department of Anatomy and Neurobiology, School of Medicine, University of California, Irvine, USA. macharya@uci.edu.; Department of Radiation Oncology, School of Medicine, University of California, Irvine, USA. macharya@uci.edu.
Jazyk: angličtina
Zdroj: Acta neuropathologica communications [Acta Neuropathol Commun] 2024 Dec 18; Vol. 12 (1), pp. 190. Date of Electronic Publication: 2024 Dec 18.
DOI: 10.1186/s40478-024-01906-9
Abstrakt: Cranial radiation therapy (RT) for brain cancers is often associated with the development of radiation-induced cognitive dysfunction (RICD). RICD significantly impacts the quality of life for cancer survivors, highlighting an unmet medical need. Previous human studies revealed a marked reduction in plasma brain-derived neurotrophic factor (BDNF) post-chronic chemotherapy, linking this decline to a substantial cognitive dysfunction among cancer survivors. Moreover, riluzole (RZ)-mediated increased BDNF in vivo in the chemotherapy-exposed mice reversed cognitive decline. RZ is an FDA-approved medication for ALS known to increase BDNF in vivo. In an effort to mitigate the detrimental effects of RT-induced BDNF decline in RICD, we tested the efficacy of RZ in a cranially irradiated (9 Gy) adult mouse model. Notably, RT-exposed mice exhibited significantly reduced hippocampal BDNF, accompanied by increased neuroinflammation, loss of neuronal plasticity-related immediate early gene product, cFos, and synaptic density. Spatial transcriptomic profiling comparing the RT + Vehicle with the RT + RZ group showed gene expression signatures of neuroprotection of hippocampal excitatory neurons post-RZ. RT-exposed mice performed poorly on learning and memory, and memory consolidation tasks. However, irradiated mice receiving RZ (13 mg/kg, drinking water) for 6-7 weeks showed a significant improvement in cognitive function compared to RT-exposed mice receiving vehicle. Dual-immunofluorescence staining, spatial transcriptomics, and biochemical assessment of RZ-treated irradiated brains demonstrated preservation of synaptic integrity and mature neuronal plasticity but not neurogenesis and reduced neuroinflammation concurrent with elevated BDNF levels and transcripts compared to vehicle-treated irradiated brains. In summary, oral administration of RZ represents a viable and translationally feasible neuroprotective approach against RICD.
Competing Interests: Declarations. Ethics approval and consent to participate: All animal experiments were approved by the UCI Institutional Animal Care and Use Committee (IACUC) Consent to participate: Not applicable Consent for publication: Not applicable Competing interests: The authors declare no competing interests.
(© 2024. The Author(s).)
Databáze: MEDLINE
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