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Role of microRNA-665 in modulating PI3K/AKT/JNK signaling pathways: implications for radiation-induced neurobehavioral disorders
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J. Yang   , R. Luan , X. Zhao |
| Department of Psychiatry, The Affiliated Xi’an Central Hospital of Xi’an Jiaotong University, Xi’an, 710003, Shaanxi Province, China , 18791083860@163.com |
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Abstract: (10 Views) |
Background: Radiotherapy is an essential treatment for brain tumors but often causes radiation-induced brain injury (RIBI), leading to neurobehavioral deficits such as depression-like behaviors. MicroRNA-665 (miR-665) may regulate these injury pathways through its interaction with the PI3K/AKT (pro-survival) and JNK/p38 (pro-apoptotic) signaling cascades. Materials and Methods: Ninety-six male C57BL/6 mice received 10 Gy cranial irradiation and were assigned to four groups (n=24): control, radiation + pioglitazone (PIO), radiation + PIO + GW9662, and radiation + PIO + LY294002 or anisomycin. Depression-like behaviors were assessed by sucrose preference, open field, and forced swimming tests. miR-665 expression and signaling markers (p-AKT, p-JNK, p-p38) in the PFC were measured using qPCR and Western blot. Results: Cranial irradiation significantly reduced sucrose preference, exploratory activity, and increased immobility time (all P < 0.01). PIO pretreatment activated PI3K/AKT and suppressed JNK/p38 signaling, producing marked behavioral improvement (P < 0.01). These neuroprotective effects were fully abolished by GW9662 (PPAR-γ antagonist), LY294002 (PI3K inhibitor), and anisomycin (JNK/p38 activator). miR-665 expression increased 2.8-fold in the GW9662 group (P < 0.01), where PPAR-γ and PI3K/AKT protection were blocked, but was reduced (0.4–0.5-fold) when PI3K/AKT was inhibited or JNK/p38 was activated. Conclusion: These findings indicate that PIO protects against radiation-induced depression-like behaviors via PPAR-γ–dependent activation of PI3K/AKT and inhibition of JNK/p38. The bidirectional changes in miR-665 strongly suggest it acts as a negative regulator of the PI3K/AKT pathway or is suppressed by JNK/p38 activation. miR-665 may therefore represent a promising therapeutic target for mitigating neurobehavioral complications of cranial radiotherapy. |
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| Keywords: miR-665, Cranial irradiation, Depression-like behavior, PI3K/AKT pathway, JNK/p38 pathway. |
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Full-Text [PDF 1038 kb]
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Type of Study: Original Research |
Subject:
Radiation Biology
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