Treatment with
levodopa enhances functional recovery after experimental
stroke but its mechanisms of action are elusive. Reactive astrocytes in the ischemic hemisphere are involved in mechanisms promoting recovery and also express
dopamine 1 (D1) and
dopamine 2 (D2) receptors. Here we investigated if the activation of astrocytic
dopamine receptors (D1 and D2) regulates the expression of
glial cell line-derived neurotrophic factor (
GDNF) after combined in vitro
hypoxia/aglycemia (H/A) and studied the expression of
GDNF in the ischemic brain
after treatment with
levodopa/
benserazide following transient occlusion of the middle cerebral artery (tMCAO) in the rat. Twenty-four hours after H/A,
GDNF levels were upregulated in exposed astrocytes compared to normoxic control cultures and further elevated by the addition of the selective D1 receptor agonist (R)-(+)-
SKF-38393 hydrochloride while D1 receptor antagonism by R(+)-
SCH-23390 hydrochloride significantly reduced
GDNF. No effect on
GDNF levels was observed by the application of the D2 receptor agonist R(-)-2,10,11-trihydroxy-N-propyl-noraporphine hydrobromide hydrate or S-(-)-
eticlopride hydrochloride (D2 receptor antagonist). After tMCAO,
GDNF was upregulated in D1 expressing reactive astrocytes in the peri-
infarct area. In addition, treatment with
levodopa/
benserazide significantly increased
GDNF levels in the
infarct core and peri-
infarct area after tMCAO without affecting the expression of glial fibrillar acidic
protein (GFAP), an intermediate filament and marker of reactive
gliosis. After
stroke,
GDNF levels increase in the ischemic hemisphere in rats treated with
levodopa, implicating
GDNF in the mechanisms of tissue reorganization and plasticity and in
l-DOPA enhanced recovery of lost brain function. Our results support
levodopa treatment as a potential recovery enhancing
therapy in
stroke patients.