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Glial cell line-derived neurotrophic factor (GDNF), a disease-modifying drug for Parkinson’s disease (PD) is in Phase 2 clinical trials (EudraCT number: 2011-003866-34), however it is administered by direct intrastriatal delivery via stereotaxy, which is accompanied with intracranial infection, brain tissue damage, and other complications. In addition, because of complex administration routes, clinical trials of GDNF have yielded contrary results, largely due to differences in dose and concentration brought by intracranial device. Herein, a small molecular agonist SC79 was screened to open blood-brain barrier (BBB) and promote GDNF liposomes to get into brain. SC79 reversibly reduces the expression of claudin-5, one of dominant tight junctions of BBB. Animal study showed SC79 promoted liposomes to enter into brain parenchyma 2.43 times more than that of the control. Motor deficits of PD mice receiving SC79 and brain-targeted GDNF liposomes were recovered by 36.70% and tyrosine hydroxylase positive neurons in striatum were restored by 39.90%. Our combination therapy effectively avoids the side effects such as secondary infection and uneven delivery caused by intracranial injection, improving patients’ compliance and providing valuable research ideas for the clinic.
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