BUTYLPHTHALIDE CAN IMPROVE NEUROLOGICAL DYSFUNCTION IN MICE WITH CRANIOCEREBRAL INJURIES BY ACTIVATING THE NRF2-ARE PATHWAY

Xiaomin Fan¹, Jing Hu^{2, *}, Sheng Qiu³, Jianghua Yang⁴

¹Department of Electromyography Room, Huzhou Central Hospital, Huzhou 313000, Zhejiang Province, China - ²Department of Prevention and Protection, Anji people's Hospital, Huzhou 313300, Zhejiang Province, China - ³Department of Neurosurgery, Huzhou Central Hospital, Huzhou 313000, Zhejiang Province, China - ⁴Department of Radiology, Huzhou Central Hospital, Huzhou 313000, Zhejiang Province, China

Objective: To explore the mechanism of how butylphthalide can improve neurological dysfunction in mice with craniocerebral injuries. 

Methods: Ninety healthy male Kunming mice with clean grades were randomly selected to establish a craniocerebral injury mouse model. The mice were randomly divided into three equal groups: a control group, a model group and a butylphthalide group. In the control group, only the scalp was cut open to expose the skull. In the butylphthalide group, 100 mg/kg butylphthalide was diluted into normal saline containing 0.2% DMSO and an intraperitoneal injection was performed one hour after injury. The type of motor nerve function, brain water content, brain tissue pathology changes, malondialdehyde (MDA) levels, superoxide dismutase (SOD) levels, glutathione peroxidase (gsh-px) levels, neuron apoptosis and cortex in the cytoplasm and nucleus, the Nrf2 expression level and Nrf2 downstream factors, and changes in NQO HO-1-1 expression levels were all determined. 

Results: The neurological severity score (NSS) of the model group and butylphthalide group did not change significantly after one hour (P > 0.05). However, compared with the control group, the NSS, brain water content, MDA, apoptosis index, Nrf2 expression level in the nucleus, and the HO-1 and NQO-1 expression levels in the model group had increased significantly. By contrast, the expression of SOD, GSH-PX and Nrf2 in the cytoplasm decreased significantly (P < 0.05). Compared with the model group, the NSS, SOD, GSH-PX, Nrf2 expression levels in the nucleus, and the HO-1 and NQO-1 expression levels in the butylphthalide group increased significantly, while the brain water content, MDA level, apoptosis index and Nrf2 expression level in the cytoplasm significantly decreased (P < 0.05). In the control group, the brain cells were arranged neatly in a complete structure, the nucleoli were clear, the nuclear membrane was intact, and there was no bleeding and oedema. In the model group, the brain tissue arrangement was disordered, the tissue was loose, the damaged area contained punctate haemorrhagic oedema, the cell volume and the neuron space had significantly increased, cell vacuolation was obvious and was accompanied by inflammatory cell infiltration and glial cell proliferation. However, the cerebral haemorrhage oedema and glial cell proliferation in the brain tissue of the mice in the butylphthalide group were significantly reduced compared with the model group. 

Conclusion: Butylphthalide may reduce brain oedema through the NRF2-ARE pathway, improve oxidative stress injury, inhibit nerve cell apoptosis, and improve neurological dysfunction as a consequence.