〔Abstract〕 Objective To investigate the effect of dexmedetomidine(Dex) on the release of glial cell line-derived neurotrophic factor(GDNF) during the anti-ischemic stroke. Methods SD rats were randomly divided into sham group(Sham group), sham + dexmedetomidine group(Sham+Dex group), ischemic stroke group(IS group), ischemic stroke + dexmedetomidine group(IS+Dex group), ischemic stroke + dexmedetomidine group +anti-GDNF(IS+Dex+anti-GDNF group), with 15 rats in each group. IS model was established by Longa′s methods. 24 hours later, the neurological scores were evaluated. Then, the rats were sacrificed and the cerebral spinal fluid, as well as the peripheral blood, were collected to detect the content of GDNF. In addition, TTC staining was used to evaluate the area of cerebral ischemic infarction, and immunofluorescence was applied to detect the activation of astrocytes. Furthermore, the activation phenotype of astrocytes was detected by qRT-PCR. Results Compared with Sham group, there were no significant changes in all indexes of rats in Sham+Dex group. In IS group, the neurological score increased(P<0.05), the local infarction area appeared, the release of GDNF in peripheral and central system increased(P<0.05), and the microglia activation was induced by IS, and the expression of neurotoxic and neuroprotective phenotype genes increased significantly(P<0.05). Compared with the IS group, the neurological function score of the rats in the IS + Dex group significantly decreased(P<0.05), the local infarct area was significantly reduced(P<0.05), and the release of GDNF further increased(P<0.05). The expression of neurotoxic astrocyte phenotype genes significantly decreased(P<0.05), while the expression of neuroprotective astrocyte phenotype genes further increased(P<0.05). However, intervention with anti-GDNF antibody obviously reversed the therapeutic effect of Dex compared with the IS + Dex group.Conclusion Dex can inhibit the phenotype of neurotoxic astrocytes, increase the proportion of neuroprotective astrocytes, further promote the release of GDNF, and play an anti-ischemic stroke role.