Abstract
Background/Objectives: Glial cell line-derived neurotrophic factor (GDNF) has demonstrated potent neuroprotective and neurorestorative effects in preclinical models of Parkinson’s disease (PD). However, clinical trials using direct intracranial GDNF infusion or adeno-associated virus-mediated GDNF gene delivery have shown limited efficacy, in part because of challenges associated with invasive delivery. We previously identified prokineticin-2 (PK2) signaling as a compensatory protective pathway against dopaminergic neurodegeneration. This study investigated whether PK2 signaling regulates astrocytic GDNF expression and whether pharmacological activation of this pathway provides neuroprotection in PD models. Methods: Cultured astrocytes were treated with recombinant PK2 or the prokineticin receptor 1 (PKR1) agonist IS20, followed by assessment of GDNF gene expression and protein secretion. The neuroprotective effects of PK2/PKR1-mediated astrocytic signaling were evaluated in dopaminergic cell culture models. In male C57BL/6 mice and MitoPark transgenic mice, IS20 was administered systemically through intraperitoneal or intranasal routes, and brain GDNF levels and neuroprotective efficacy were evaluated in the MPTP-induced and chronically progressive MitoPark transgenic models of PD. Results: PK2 and IS20 significantly increased GDNF expression and secretion in cultured astrocytes and enhanced dopaminergic cell survival. Systemic administration of IS20 elevated GDNF levels in the mouse brain, including the nigrostriatal system. Moreover, IS20 treatment produced significant neuroprotective effects in both MPTP-treated mice and MitoPark transgenic mice. Conclusions: These findings identify PK2/PKR1 signaling as a novel regulator of astrocytic GDNF expression and support pharmacological activation of this pathway as a non-invasive strategy for enhancing endogenous GDNF signaling and protecting dopaminergic neurons in PD.