Intracisternal IGF-1 gene delivery attenuates early anxiety-like behavior but not dopaminergic neurodegeneration in a 6-OHDA rat model of parkinsonism.
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BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons, leading to a spectrum of motor and non-motor symptoms. In addition to the motor deficits serving as the primary criteria for diagnosis, mood and anxiety disorders also play a significant role in shaping the prognosis and overall disease progression in PD. OBJECTIVES: In this study, our aim was to characterize the progression of anxiety-like behavioral deficits in a rat model of neurotoxicity induced by 6-hydroxydopamine (6-OHDA) and to investigate insulin-like growth factor 1 (IGF-1) potential therapeutic effects on these pathological markers. METHODS: Behavioral changes were evaluated in male Wistar rats at 1, 2, and 3 weeks post-lesion using the elevated plus maze and dark-light box tests. Anxiety-like behaviors emerged as early as week 1 post-lesion and persisted through week 3. Following 6-OHDA infusion, immunohistochemical analysis revealed a decrease in tyrosine hydroxylase (TH) immunoreactivity within the ventral tegmental area (VTA) indicating a partial lesion of the nigrostriatal dopaminergic system. As a therapeutic approach we performed the intracisternal administration of a recombinant adenoviral vector encoding IGF-1 (RAd IGF-1) one week after 6-OHDA-induced neurotoxicity. RESULTS: At a behavioral level, IGF-1 treatment effectively prevented anxiety-like behavior by the third week of neurotoxicity. Nevertheless, IGF-1 overexpression was not able to modulate VTA dopaminergic neuron loss. These results reveal a dissociation between the behavioral effects of IGF-1 and its impact on dopaminergic neurodegeneration. DISCUSSION: These findings emphasize time-dependent alterations in anxiety-like behavior and dopaminergic neurodegeneration. In addition, these data support the potential use of IGF-1 as a therapeutic molecule and its novel administrations for future gene transfer interventions, which will shed light on the progressive nature of neurodegenerative mechanisms.