Subthalamic Nucleus Lesion in Rats Prevents Dopaminergic Nigral Neuron Degeneration After Striatal 6‐OHDA Injection: Behavioural and Immunohistochemical Studies

Abstract

Several studies have shown that antagonists of N-methyl-D-aspartate receptors provide protection of the dopaminergic nigrostriatal pathway in animal models of Parkinson's disease. Since the substantia nigra compacta receives a moderate glutamatergic innervation from the subthalamic nucleus, we tried to determine whether subthalamic nucleus lesion could prevent the toxicity of the selective dopaminergic neurotoxin 6-hydroxydopamine (6-OHDA). Experiments were carried out on four groups of rats. Group 1 (n = 10) received a unilateral injection of 6-hydroxydopamine in the striatum and group 2 (n = 10) received kainic acid in the subthalamic nucleus. Group 3 (n = 10) received an injection of kainic acid in the subthalamic nucleus and 1 week later an injection of 6-OHDA in the striatum. Group 4 (n = 5) received the same treatment but kainic acid was replaced by saline. Apomorphine induced an ipsilateral rotation in rats of groups 2 and 3 and a contralateral rotation in rats of groups 1 and 4. The number of tyrosine hydroxylase-immunoreactive cells in the pars compacta of the substantia nigra was not significantly decreased on the side ipsilateral to 6-OHDA striatal injection in rats of groups 1 and 4. These results show that subthalamic nucleus lesion provides neuroprotection of the dopaminergic nigrostriatal pathway against 6-OHDA toxicity and opens a new way for slowing or stopping the progression of Parkinson's disease.

Subthalamic nucleus deep brain stimulation is neuroprotective in the A53T α‐synuclein Parkinson's disease rat model

“…After nigrostriatal lesion by 3‐nitropropionic acid (3‐NP) injection, a preventive ablation of the STN, by quinolinic acid 2 weeks before 3‐NP administration, led to an attenuation of dopaminergic SN neuron loss 8. In a comparable approach using the 6‐OHDA model, prevention of dopaminergic SN neuronal degeneration by 1 week before STN lesioning, using kainic acid injections, was demonstrated 17. Additionally, ibotenic acid lesioning of STN neurons (loss of 50–60%), 1 week before 6‐OHDA delivery, rescued 23% of dopaminergic SN neurons 32.…”

“…In contrast, numerous preclinical studies, conducted in rodent and nonhuman primate (NHP) models of PD have demonstrated a beneficial effect of STN lesion or STN‐DBS on SN neuronal survival 8, 12, 13, 14, 15, 16, 17. However, the common drawback of these preclinical studies was the use of toxin‐mediated PD models, either by 1 methyl‐4 phenyl 1,2,3,6‐tetrahydropyridine (MPTP) in NHP14 or 6‐hydroxydopamine (6‐OHDA) in rodents 12, 15, 18, 19.…”

Mechanisms and Targets of Deep Brain Stimulation in Movement Disorders

“…[124][125][126] In monkeys, several weeks of continuous STN HFS, preceding or following systemic injection of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), resulted in 20% more tyrosine hydroxylase-positive (TH ϩ ) cells in the ipsilateral SNc. Similarly, kainic acid lesions of the STN appeared to have a protective effect on dopaminergic SNc neurons during subsequent injections of the neurotoxins 6-OHDA in rats 127 and MPTP in monkeys. 124 STN ablation after injection of these neurotoxins could also recover damaged dopaminergic neurons in the SNc; however, when the DBS implant or injection volume extended into fibers of passage surrounding the STN, a notable reduction in TH ϩ SNc cells occurred, which may reflect nigrostriatal axotomy.…”

Subthalamotomy in the treatment of Parkinson's disease: clinical aspects and mechanisms of action

“…115,131,140 It was, however, shown that the phenotype, measured by tyrosine hydroxylase immunohistochemistry, the rate-limiting enzyme in the production of dopamine synthesis, was preserved in the surviving cells in the first weeks after exposure to 6-OHDA. 36,131,187 On the contrary, some authors observed neuroprotection in rats with small dopamine depletion, 133 but its effectiveness decreased in a time-dependent manner and was no longer detected after 1 week.…”