The neuroprotective effect of 10-hydroxy-2-decenoic acid in traumatic brain injury by inhibiting copper-mediated neuronal pyroptosis.

BACKGROUND: 10‑hydroxy-2-decenoic acid (10-HDA), the major fatty acid in royal jelly, exhibits antibacterial, anti-inflammatory, and antioxidant properties, suggesting its potential therapeutic benefits for traumatic brain injury (TBI). TBI induces significant neurological deficits through cell death, including pyroptosis. Although the role of copper in cell death and TBI has been recognized, the specific mechanisms by which 10-HDA facilitates brain injury recovery remain poorly understood, highlighting a critical need for further investigation.

METHODS: All animals were randomly assigned to undergo controlled cortical impact (CCI) to establish a TBI mouse model. 10-HDA was administered intragastric immediately after TBI. The positive control was a copper ion chelator, Tetrathiomolybdate (TTM). The water content of brain tissue, the level of copper ion in serum and the cortex were measured. Brain histological changes were detected with Evans blue staining, FJB staining, and Nissl staining. The wire-grip test, bean balance test, open field test, novel object recognition test, and Morris water maze were used to assess motor function, learning and memory, anxiety-like behavior, and cognitive ability in TBI mice treated with 10-HDA. Western blot and immunohistochemical analysis were used to detect the expression of pyroptosis related proteins and copper homeostasis related proteins in the brain tissues of each group.

RESULTS: 10-HDA reduces the expression level of pyroptosis related proteins in cortical tissues, and improves the motor dysfunction, cognitive and emotional dysfunction in post-traumatic mice. The copper accumulation in the brain after TBI does not induce cuproptosis; instead, it results from an imbalance in copper homeostasis. Moreover, it has been proved that 10-HDA can regulate the expression of copper transport-related proteins, maintain copper homeostasis in brain, and thus reduce neuronal pyroptosis after TBI. At the same time, we explored the specific mechanism of its neuroprotective function by mediating the expression of ATP7A to maintain copper homeostasis, and then inhibit the pyroptosis of neurons.

CONCLUSION: This study demonstrated the neuroprotective effect of 10-HDA in TBI and uncovered a novel molecular mechanism, showing that 10-HDA reduces copper-mediated neuronal pyroptosis by regulating ATP7A expression rather than cuproptosis.