IGF-1 gene therapy prevents spatial memory deficits and modulates dopaminergic neurodegeneration and inflammation in a parkinsonism model

Abstract

Cognitive impairment in Parkinson’s disease is considered an indicator of the prodromal stages of this condition,occurring prior to the onset of classic and pathognomonic motor symptoms. Among other factors, neuroinflammation is increasingly recognized as a potential mediator of this neurodegenerative process, and glial cellsare directly involved. However, the use of neurotrophic factors is associated with neuroprotection and cognitiveimprovements. Among all those factors, insulin-like growth factor 1 (IGF-1) has attracted considerable attention.In this study, we aimed to investigate the effect of IGF-1 gene therapy in an early animal model of 6-hydroxidopamine (6-OHDA)- induced parkinsonism.For this purpose, we employed male Wistar rats. The animals were first divided into two groups according tothe bilateral injection into de Caudate Putamen unit (CPu):(a) VEH group (vehicle solution) and (b) 6-OHDAgroup (neurotoxic solution). After that, the animals in each group were divided, according to the bilateral injection into the dorsal hippocampus, in a control group (who received a control virus RAd-DSRed) and anexperimental group (who received a therapeutic virus (RAd-IGF1). After three weeks of exposure to 6-OHDA, ourstudy showed that IGF-1 gene therapy improved cognitive deficits related to short-term and spatial workingmemory, it also increased expression levels of tyrosine hydroxylase in the CPu. In addition, the therapy resultedin significant changes in several parameters (area, perimeter, roundness, ramification, and skeleton ́s analyses)related to microglia and astrocyte phenotypes, particularly in the CPu and dorsal hippocampal areas.Our data support the use of IGF-1 as a therapeutic molecule for future gene transfer interventions, that willcontribute to a better understanding of the mechanisms correlating cognitive function and inflammatory process.