Early deep brain stimulation attenuates parkinsonism progression in a neurotoxin-induced Parkinson's disease mouse model.

Abstract

Deep brain stimulation (DBS) is an effective symptomatic therapy for Parkinson's disease (PD). Although unproven in humans, animal studies suggest that DBS, when applied beyond the acute phase of parkinsonism induction, may be neuroprotective. This study investigated motor responses and neuroprotection resulting from DBS initiated 24 h after induction of dopaminergic terminal loss via intrastriatal injection of 6-hydroxydopamine (6-OHDA) in mice. For that, three groups were analyzed: 6-OHDA/DBS-ON (n = 6) and 6-OHDA/DBS-OFF (n = 8), which received ipsilateral-to-lesion subthalamic nucleus (STN) DBS, implanted immediately after neurotoxin infusion, and Naive (n = 5), without interventions. 6-OHDA/DBS-ON received DBS for 4 days, 3  hours per day. The protocol began on day zero (D0). From D1 to D3, the Cylinder test was conducted. On D4, the Rotarod test was performed immediately before stimulation. Body mass was recorded daily until D4 and again on D7, before euthanasia. Tyrosine Hydroxylase (TH) immunohistochemistry was used to assess nigral neuronal loss and dopaminergic axon density in the striatum. The 6-OHDA/DBS-ON group showed less pronounced body mass loss from D0 to D4: -5.92 % (p = 0.22) vs. -18.04 % in 6-OHDA/DBS-OFF (p = 0.03). Additionally, during the 4 days of the protocol, the 6-OHDA/DBS-ON group exhibited a 3.88-fold superior impaired-limb use (p = 0.006) and a 17.14-fold improvement in Rotarod performance (p = 0.02). At the time of euthanasia (D7), the 6-OHDA/DBS-ON group had 82 % more nigral neurons (p = 0.03) and an 18.8 % higher lesioned/healthy striatal TH+ optical density ratio (p = 0.02). Altogether, the results indicate that early DBS attenuates disease progression and may contribute to neuroprotection in potential future premotor PD diagnosis scenarios.