A regulatable AAV vector mediating GDNF biological effects at clinically-approved sub-antimicrobial doxycycline doses.

Preclinical and clinical data stress the importance of pharmacologically-controlling glial cell line-derived neurotrophic factor (GDNF) intracerebral administration to treat PD. The main challenge is finding a combination of a genetic switch and a drug which, when administered at a clinically-approved dose, reaches the brain in sufficient amounts to induce a therapeutic effect. We describe a highly-sensitive doxycycline-inducible adeno-associated virus (AAV) vector. This vector allowed for the first time a longitudinal analysis of inducible transgene expression in the brain using bioluminescence imaging. To evaluate the dose range of GDNF biological activity, the inducible AAV vector (8.0 × 10(9) viral genomes) was injected in the rat striatum at four delivery sites and increasing doxycycline doses administered orally. ERK/Akt signaling activation as well as tyrosine hydroxylase downregulation, a consequence of long-term GDNF treatment, were induced at plasmatic doxycycline concentrations of 140 and 320 ng/ml respectively, which are known not to increase antibiotic-resistant microorganisms in patients. In these conditions, GDNF covered the majority of the striatum. No behavioral abnormalities or weight loss were observed. Motor asymmetry resulting from unilateral GDNF treatment only appeared with a 2.5-fold higher vector and a 13-fold higher inducer doses. Our data suggest that using the herein-described inducible AAV vector, biological effects of GDNF can be obtained in response to sub-antimicrobial doxycycline doses.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Preclinical models of levodopa-induced dyskinesia

L -DOPA-induced dyskinesia (LID) represents one of the major limitations in the current pharmacotherapy of Parkinson's disease (PD) and affects the majority of PD patients. Animal models are the most important preclinical tool for molecular investigations of LID mechanisms and therapeutic targets. Over the last two decades, models of LID have been developed in both nonhuman primate and rodent species, recapitulating several aspects of the human dyskinesia. This chapter will review and compare the main features of the rodent and nonprimate models of LID currently available and summarize some of the main neurobiological fi ndings obtained from these models