Modulation of 6-OHDA-induced Behavioral Impairments by Gene Therapy with TGF-β3

Congreso; 34to Congreso Anual IBNS; 2025

Parkinson ́s disease is a complex pathology marked by motor impairments due to neurodegeneration in dopaminergic neurons of the nigrostriatal system. The early prodromal phase has been recognized for the presence of non-motor symptoms that could be predictive of later motor disease. By inducing dopaminergic neuron death with 6-hydroxydopamine (6-OHDA) in male Wistar rats we have observed alterations in cognitive functions within 3 weeks of the surgery. This phase therefore has potential to be a suitable window for the administration of disease-modifying therapies. We aimed to test the potential of TGF-β3, a trophic and anti-inflammatory factor, to mitigate these early changes. We hypothesized that the administration of the TGF-β3 gene in an early phase of the pathology could reduce the cognitive alterations observed and the dopaminergic degeneration. We administered an adenoviral vector containing the TGF-β3 gene (RAd-TGF-β3), or its control, 14 days after 6-OHDA (or vehicle) surgery. On day 21 we performed the Barnes Maze test, where we measured the latency of the animal to find an escape box in consecutive trials. We found that RAd-TGF-β3 in animals with 6-OHDA induced a better performance in the test compared to animals administered with the control vector which suggests improved learning and memory (n=12-15/group). At this time we demonstrated an anti-inflammatory effect measuring pro-inflammatory factors? expression (IL-6, TNF-α) in the hippocampus, observing a reduction with RAd-TGF-β3 in comparison to 6-OHDA animals (n=3-4/group). On day 28 we measured the time spent by the rats in an upright position in the Open Field test as motor vertical activity and the relative time spent in the peripheric area as anxiety-like behavior. We observed impairments in 6-OHDA animals, both of which were reduced with the RAd-TGF-β3, showing better motor and cognitive performance (n=3-5/group). We propose that the overexpression of TGF-β3 can overcome the damaging processes induced by 6-OHDA and therefore has potential to treat parkinsonism?s motor and non-motor behavioral impairments. Funding was supported by grants from CONICET, ANPCyT and UNC.