PAK3 downregulation induces cognitive impairment following cranial irradiation.
Haksoo LeeHyunkoo KangChangjong MoonBuHyun YounPublished in: eLife (2023)
Cranial irradiation is used for prophylactic brain radiotherapy as well as the treatment of primary brain tumors. Despite its high efficiency, it often induces unexpected side effects, including cognitive dysfunction. Herein, we observed that mice exposed to cranial irradiation exhibited cognitive dysfunction, including altered spontaneous behavior, decreased spatial memory, and reduced novel object recognition. Analysis of the actin cytoskeleton revealed that ionizing radiation (IR) disrupted the filamentous/globular actin (F/G-actin) ratio and downregulated the actin turnover signaling pathway p21-activated kinase 3 (PAK3)-LIM kinase 1 (LIMK1)-cofilin. Furthermore, we found that IR could upregulate microRNA-206-3 p (miR-206-3 p) targeting PAK3. As the inhibition of miR-206-3 p through antagonist (antagomiR), IR-induced disruption of PAK3 signaling is restored. In addition, intranasal administration of antagomiR-206-3 p recovered IR-induced cognitive impairment in mice. Our results suggest that cranial irradiation-induced cognitive impairment could be ameliorated by regulating PAK3 through antagomiR-206-3 p, thereby affording a promising strategy for protecting cognitive function during cranial irradiation, and promoting quality of life in patients with radiation therapy.
Keyphrases
- cognitive impairment
- radiation therapy
- signaling pathway
- high glucose
- radiation induced
- diabetic rats
- high efficiency
- drug induced
- working memory
- cell migration
- high fat diet induced
- cell proliferation
- oxidative stress
- squamous cell carcinoma
- metabolic syndrome
- epithelial mesenchymal transition
- type diabetes
- adipose tissue
- endothelial cells
- white matter
- pi k akt
- locally advanced
- multiple sclerosis
- blood brain barrier
- smoking cessation
- body composition
- bone mineral density
- induced apoptosis