Objective To investigate the role and mechanism of action of pertussis toxin (PTx) in the mouse model of experimental autoimmune encephalomyelitis (EAE).Methods C57BL/6 mice were randomly divided into normal control group, EAE group, and PTx treatment group, with 12 mice in each group. In the EAE group and PTx treatment group, EAE model was established using MOG 35-55, and the mice in the PTx treatment group were given 1000 ng intraperitoneally injected PTx at 7 days after modeling. The clinical symptoms were observed in these two groups. Histological staining was used to evaluate inflammatory response and changes in demyelination and observe vascular endothelial growth factor (VEGF) and angiogenesis. Western blot was used to measure the levels of VEGF and collagen IV. PTx was used to stimulate primary cultured neurons in vitro to assess the in vitro effect of PTx on VEGF expression in neurons.Results PTx alleviated the inflammatory response and demyelination in EAE model, and in the brain, PTx treatment reduced the inflammation score from 3.4±0.55 to 1.2±0.45 (P<0.01) and the demyelination score from 3.6±0.55 to 1.4±0.55 (P<0.01). In the spinal cord, PTx treatment reduced the inflammation score from 3.6±0.55 to 1.0±0.71 (P<0.01) and the demyelination score from 4.2±0.84 to 1.4±0.55 (P<0.01). The results of Western blot showed that compared with the normal control group, the EAE group showed a 49.0% reduction in VEGF (P<0.01) and a 36.0% reduction in Collagen IV (P<0.01); compared with the EAE group, the PTx treatment group showed a 59.5% increase in VEGF (P<0.01) and a 45.0% increase in collagen IV (P<0.01). The in vitro experiment showed that at 24 hours after PTx treatment, the expression of VEGF in neurons was upregulated; compared with the normal control group, the 100 ng/ml group showed a 34.6% increase in the expression of VEGF, and the 400 ng/ml group showed a 76.9% increase.Conclusions PTx can upregulate endogenous VEGF in neurons and angiogenesis, and thus exerts a protective effect in EAE model.