Protection of nigral cell death by bilateral subthalamic nucleus stimulation

Temel, Yasin; Visser‐Vandewalle, Veerle; Kaplan, Süleyman; Kozan, Ramazan; Daemen, M.A.R.C.; Blokland, Arjan; Schmitz, Christoph; Steinbusch, Harry W.M.

doi:10.1016/j.brainres.2006.08.082

Cited by 143 publications

(93 citation statements)

References 28 publications

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“…A similar dissociation between TH + dopaminergic and total SN neurons is very common in toxic PD rodent models induced by MPTP30 or 6‐OHDA,12 because damage to the dopaminergic neurons might lead to functional loss of TH phenotype before cell death occurs. Both a rescue of TH expression only31 and in addition total SN neuron number8, 13, 14 have been described in PD models after STN lesioning/DBS. However, more studies reported the number of TH + neurons without determining total SN neuron counts 12, 15, 16, 17, 25, 32.…”

Section: Discussionmentioning

confidence: 97%

“…We present results of chronic high‐frequency STN neurostimulation in a PD rat model that provides chronic stress on SN neurons by AAV1/2‐A53T‐aSyn expression, progressive neurodegeneration, and the presence of insoluble aSyn aggregates as opposed to the more acute MPTP‐ or 6‐OHDA‐mediated toxicity without aSyn pathology that have been used in previous reports investigating the effects of DBS in PD animal models 9, 12, 13, 14, 15, 16, 20. We could demonstrate that unilateral injection of AAV1/2‐A53T‐aSyn into the SN, followed by ipsilateral STN‐DBS electrode implantation 3 weeks later, can be accomplished with low dropout rates attributed to mistargeting the SN (6%) or STN (5%).…”

Section: Discussionmentioning

confidence: 99%

“…STN‐DBS commencing 6 days after MPTP administration in monkeys led to survival of dopaminergic neurons in the SN 14. A beneficial effect on SN dopaminergic neuron survival was observed by bilateral striatal 6‐OHDA injections in rats and at the same time bilateral STN electrode implantations that were activated 1 week later, and stimulated for 1 hour per day, over a period of 3 months, although this stimulation protocol does not reflect the chronic stimulation in PD patients 13. Another group demonstrated that unilateral 6‐OHDA administration and STN‐DBS electrode implantation at the same time, followed by chronic stimulation for 2 weeks that commenced 2 weeks after surgery, also reduced dopaminergic SN cell loss 12.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

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confidence: 99%

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

Musacchio

Rebenstorff

Brotchie

et al. 2017

Annals of Neurology

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ObjectiveDeep brain stimulation (DBS) of the subthalamic nucleus (STN) is a highly effective symptomatic therapy for motor deficits in Parkinson's disease (PD). An additional, disease‐modifying effect has been suspected from studies in toxin‐based PD animal models, but these models do not reflect the molecular pathology and progressive nature of PD that would be required to evaluate a disease‐modifying action. Defining a disease‐modifying effect could radically change the way in which DBS is used in PD.MethodsWe applied STN‐DBS in an adeno‐associated virus (AAV) 1/2‐driven human mutated A53T α‐synuclein (aSyn)‐overexpressing PD rat model (AAV1/2‐A53T‐aSyn). Rats were injected unilaterally, in the substantia nigra (SN), with AAV1/2‐A53T‐aSyn or control vector. Three weeks later, after behavioral and nigrostriatal dopaminergic deficits had developed, rats underwent STN‐DBS electrode implantation ipsilateral to the vector‐injected SN. Stimulation lasted for 3 weeks. Control groups remained OFF stimulation. Animals were sacrificed at 6 weeks.ResultsMotor performance in the single pellet reaching task was impaired in the AAV1/2‐A53T‐aSyn–injected stim‐OFF group, 6 weeks after AAV1/2‐A53T‐aSyn injection, compared to preoperative levels (–82%; p < 0.01). Deficits were reversed in AAV1/2‐A53T‐aSyn, stim‐ON rats after 3 weeks of active stimulation, compared to the AAV1/2‐A53T‐aSyn stim‐OFF rats (an increase of ∼400%; p < 0.05), demonstrating a beneficial effect of DBS. This motor improvement was maintained when the stimulation was turned off and was accompanied by a higher number of tyrosine hydroxylase+ SN neurons (increase of ∼29%), compared to AAV1/2‐A53T‐aSyn stim‐OFF rats (p < 0.05).InterpretationOur data support the putative neuroprotective and disease‐modifying effect of STN‐DBS in a mechanistically relevant model of PD. Ann Neurol 2017;81:825–836

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

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

Musacchio

Rebenstorff

Brotchie

et al. 2017

Annals of Neurology

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“…Based on animal studies, DBS may have effects on the release of growth factors (e.g., brain-derived neurotrophic factor), which may, in turn, promote neuroplasticity, neurogenesis, or neuroprotection [312][313][314][315][316]. At the present time there is no strong evidence from the human literature for a disease-modifying effect of DBS, although a recent study suggests that such effects may occur [317].…”

Section: Dbs Mechanism Of Actionmentioning

confidence: 99%

Deep Brain Stimulation for Movement Disorders of Basal Ganglia Origin: Restoring Function or Functionality?

2016

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Deep brain stimulation (DBS) is highly effective for both hypo-and hyperkinetic movement disorders of basal ganglia origin. The clinical use of DBS is, in part, empiric, based on the experience with prior surgical ablative therapies for these disorders, and, in part, driven by scientific discoveries made decades ago. In this review, we consider anatomical and functional concepts of the basal ganglia relevant to our understanding of DBS mechanisms, as well as our current understanding of the pathophysiology of two of the most commonly DBS-treated conditions, Parkinson's disease and dystonia. Finally, we discuss the proposed mechanism(s) of action of DBS in restoring function in patients with movement disorders. The signs and symptoms of the various disorders appear to result from signature disordered activity in the basal ganglia output, which disrupts the activity in thalamocortical and brainstem networks. The available evidence suggests that the effects of DBS are strongly dependent on targeting sensorimotor portions of specific nodes of the basal gangliathalamocortical motor circuit, that is, the subthalamic nucleus and the internal segment of the globus pallidus. There is little evidence to suggest that DBS in patients with movement disorders restores normal basal ganglia functions (e.g., their role in movement or reinforcement learning). Instead, it appears that high-frequency DBS replaces the abnormal basal ganglia output with a more tolerable pattern, which helps to restore the functionality of downstream networks.

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