Oxidative stress induced by sustained supraphysiological intrastriatal GDNF delivery is prevented by dose regulation

Marcelo Duarte Azevedo; Naika Prince; Marie Humbert-Claude; Virginia Mesa-Infante; Cheryl Jeanneret; Valentine Golzne; Kevin De Matos; Benjamin Boury Jamot; Fulvio Magara; Tomas Gonzalez-Hernandez; Liliane Tenenbaum

doi:10.1016/j.omtm.2023.09.002

Oxidative stress induced by sustained supraphysiological intrastriatal GDNF delivery is prevented by dose regulation

Mol Ther Methods Clin Dev. 2023 Sep 9:31:101106. doi: 10.1016/j.omtm.2023.09.002. eCollection 2023 Dec 14.

Affiliations

¹ Laboratory of Cellular and Molecular Neurotherapies, Center for Neuroscience Research, Clinical Neurosciences Department, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), 1011 Lausanne, Switzerland.
² Departamento de Ciencias Médicas Básicas, Facultad de Ciencias de la Salud, Instituto de Tecnologías Biomédicas (ITB), Universidad de La Laguna, La Laguna, 38200 Tenerife, Spain.
³ Center for the Study of Behaviour, Department of Psychiatry, Lausanne University Hospital and University of Lausanne (CHUV-UNIL), 1008 Lausanne, Switzerland.

Abstract

Despite its established neuroprotective effect on dopaminergic neurons and encouraging phase I results, intraputaminal GDNF administration failed to demonstrate significant clinical benefits in Parkinson's disease patients. Different human GDNF doses were delivered in the striatum of rats with a progressive 6-hydroxydopamine lesion using a sensitive doxycycline-regulated AAV vector. GDNF treatment was applied either continuously or intermittently (2 weeks on/2 weeks off) during 17 weeks. Stable reduction of motor impairments as well as increased number of dopaminergic neurons and striatal innervation were obtained with a GDNF dose equivalent to 3- and 10-fold the rat endogenous level. In contrast, a 20-fold increased GDNF level only temporarily provided motor benefits and neurons were not spared. Strikingly, oxidized DNA in the substantia nigra increased by 50% with 20-fold, but not 3-fold GDNF treatment. In addition, only low-dose GDNF allowed to preserve dopaminergic neuron cell size. Finally, aberrant dopaminergic fiber sprouting was observed with 20-fold GDNF but not at lower doses. Intermittent 20-fold GDNF treatment allowed to avoid toxicity and spare dopaminergic neurons but did not restore their cell size. Our data suggest that maintaining GDNF concentration under a threshold generating oxidative stress is a pre-requisite to obtain significant symptomatic relief and neuroprotection.

Keywords: 6-hydroxydopamine; AAV; GDNF; Parkinson’s disease; dopaminergic neurons; doxycycline; inducible; motor test; neuroprotection; oxidative stress.