Parkinson's disease (PD) is a neurodegenerative disorder characterized by a progressive loss of substantia nigra dopaminergic neurons, leading to dopaminergic deafferentation of the striatum and invalidating motor symptoms. Several studies suggest that doxycycline (DOX), an old antibiotic from the tetracycline family, could be a neuroprotective drug candidate for PD (Bortolanza et al, J Neural Transm, 2018). Its antibiotic activity may, however, preclude chronic use in patients. Therefore, we have developed a non-antibiotic derivative of DOX referred to as DDOX (12a-deoxy-dedimethylamino-DOX), which has shown promising properties in ex vitro and in vitro PD model systems (Tourville et al, Antioxidants, 2023). Here, we tested its neuroprotective potential and functional effects in a unilaterally-lesioned 6-OHDA rat model of PD. Precisely, partially lesioned animals receiving, or not, daily subcutaneous injections of 20 mg/kg of DDOX were assessed histologically and behaviorally to evaluate treatment efficacy. We established that DDOX substantially decreased the intensity of rotations ipsilateral to the lesion side under amphetamine treatment, suggesting significant preservation of striatal dopaminergic nerve terminals. Consistent with this observation, tyrosine hydroxylase immunodetection revealed that DDOX reduced the lesion surface area in the striatum. In addition, DDOX restored normal latency to fall in the Rotarod test and reinstated horizontal exploration behaviour in the actimeter test. The mechanisms underlying DDOX neurorestorative effects are currently under investigation. Overall, present results suggest that DDOX might be of therapeutic utility for PD treatment.Keywords: 6-hydroxydopamine; motor activity; tetracyclines; Parkinson’s diseaseFinancial support: CAPES-COFECUB Me928; FAPESP, CNPq