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Inhibition of transforming growth factor beta-activated kinase 1 confers neuroprotection after traumatic brain injury
1Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, 305 East Zhongshan Road, Nanjing 210002, Jiangsu Province, PR China.
Abstract:
The transforming growth factor beta-activated kinase 1 (TAK1), a member of the Mitogen-activated protein kinase kinase kinase family, is characterized as a key regulator in inflammatory and apoptosis signaling pathways. The aim of the present study was to evaluate the role of the TAK1 pathway in experimental traumatic brain injury (TBI) in rats. Adult male Sprague-Dawley rats were subjected to TBI using a modified Feeney's weight-drop model. The time course showed that a significant increase of TAK1 and p-TAK1 expression in the cortex after TBI. Moreover, TBI induced TAK1 redistribution both in neurons and astrocytes of the lesion boundary zone. The effects of specific inhibition of the TAK1 pathway by 5Z-7-oxozeaenol (OZ, intracerebroventricular injection at 10min post-trauma) on histopathological and behavioral outcomes in rats were assessed at 24h post injury. The number of TUNEL-positive stained cells was diminished and neuronal survival and neurological function were improved with OZ treatment. Biochemically, the high dose of OZ significantly reduced the levels of TAK1 and p-TAK1, further decreased nuclear factor-κB and activator protein 1 activities and the release of inflammatory cytokines. In addition, we found that both 10min and 3h post-trauma OZ therapies could markedly improve neurological function and neuronal survival after long-term survival. These results revealed that the TAK1 pathway is activated after experimental TBI and the inhibitor OZ affords significant neuro- protection and amelioration of neurobehavioral deficits after experimental TBI, suggesting a potential rationale for manipulating this pathway in clinical practice.
Insights
Traumatic brain injury (TBI) activates the transforming growth factor beta-activated kinase 1 (TAK1) pathway. Inhibiting TAK1 with 5Z-7-oxozeaenol (OZ) significantly improves neurological function and neuronal survival after TBI in rats.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- The transforming growth factor beta-activated kinase 1 (TAK1) pathway is crucial in regulating inflammatory and apoptosis signaling.
- Understanding TAK1's role in traumatic brain injury (TBI) is essential for developing effective treatments.
Purpose of the Study:
- To investigate the role of the TAK1 pathway in an experimental rat model of TBI.
- To evaluate the neuroprotective effects of inhibiting TAK1 using 5Z-7-oxozeaenol (OZ).
Main Methods:
- Adult male Sprague-Dawley rats were subjected to TBI using a modified Feeney's weight-drop model.
- TAK1 and phosphorylated TAK1 (p-TAK1) expression and localization were analyzed post-TBI.
- The effects of intracerebroventricular injection of OZ (10 min post-trauma) on histopathological and behavioral outcomes were assessed at 24 hours and long-term survival.
Main Results:
- TBI significantly increased TAK1 and p-TAK1 expression and induced TAK1 redistribution in the cortex.
- OZ treatment diminished TUNEL-positive cells, improved neuronal survival, and enhanced neurological function.
- OZ significantly reduced TAK1/p-TAK1 levels, NF-κB and AP-1 activities, and inflammatory cytokine release.
- Both early (10 min) and delayed (3 h) OZ administration improved long-term neurological function and neuronal survival.
Conclusions:
- The TAK1 pathway is activated following experimental TBI.
- Inhibition of TAK1 with OZ provides significant neuroprotection and ameliorates neurobehavioral deficits in a TBI model.
- Targeting the TAK1 pathway represents a potential therapeutic strategy for clinical TBI management.
