Intracerebral Infusion of Glial Cell Line-Derived Neurotrophic Factor Promotes Striatal Neurogenesis After Stroke in Adult Rats

Abstract

Stroke triggers increased progenitor proliferation in the subventricular zone (SVZ) and the generation of medium spiny neurons in the damaged striatum of rodents. We explored whether intrastriatal infusion of glial cell line-derived neurotrophic factor (GDNF) promotes neurogenesis after stroke. Adult rats were subjected to 2-hour middle cerebral artery occlusion (MCAO). GDNF was infused into the ischemic striatum either during the first week after MCAO, with the animals being killed directly thereafter, or during the third and fourth weeks, with the rats being killed 1 week later. New cells were labeled with 5'-bromo-2'deoxyuridine (BrdU) on day 7 or during the second week, respectively. Neurogenesis was assessed immunocytochemically with antibodies against BrdU and neuronal, glial, or progenitor markers. GDNF receptor expression was analyzed in SVZ tissue and neurospheres by reverse transcription-polymerase chain reaction and immunocytochemistry. GDNF infusion increased cell proliferation in the ipsilateral SVZ and the recruitment of new neuroblasts into the striatum after MCAO and improved survival of new mature neurons. The GDNF receptor GFRalpha1 was upregulated in the SVZ 1 week after MCAO and was coexpressed with markers of dividing progenitor cells. Intrastriatal infusion of GDNF in the postischemic period promotes several steps of striatal neurogenesis after stroke, partly through direct action on SVZ progenitors. Because delivery of GDNF has biological effects in the human brain, our data suggest that administration of this factor may promote neuroregenerative responses in stroke patients.