Subthalamic Nucleus Lesions Are Neuroprotective against Terminal 6-OHDA-Induced Striatal Lesions and Restore Postural Balancing Reactions

Carvalho, Gustavo A.; Nikkhah, Guido

doi:10.1006/exnr.2001.7742

Cited by 56 publications

(50 citation statements)

References 40 publications

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“…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. Although the exact physiological mechanisms of DBS are still debated, in particular whether high‐frequency stimulation drives or inhibits axons,34, 35 the behavioral effects of DBS are lesioning‐like and similar observations have been made in settings using experimental DBS to study neuroprotection: Improved motor function and less SN neurodegeneration was observed in 6‐OHDA rats that received STN‐DBS for 2 weeks starting 2 days before 6‐OHDA administration 15.…”

Section: Discussionmentioning

confidence: 96%

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: 96%

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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“…Some investigators have reported that STN lesion prevented the loss of dopaminergic neurons in the SNpc after intrastriatal injection of 6-OHDA in rats (13,32). However, the protection obtained following STN lesion was more effective when the lesion was performed before 6-OHDA administration rather than after it.…”

Section: Discussionmentioning

confidence: 99%

“…In experimental models of PD induced by parkinsonian neurotoxins such as 6-hydroxydopamine (6-OHDA) or 1-methyl-2-phenyl-1,2,3,6-tetrahydropyridine (MPTP), inhibition of STN function by ablation (12)(13)(14)(15), HFS (16,17) or pharmacological antagonism (18,19) has been reported to ameliorate some of the parkinsonian motor deficits and even to protect nigrostriatal dopaminergic neurons against the injury induced by these neurotoxins. On the other hand, some investigators were unable to find any neuroprotective effects of STN inactivation on SNpc neuron survival (20)(21)(22).…”

Section: Introductionmentioning

confidence: 99%

Lesion of the subthalamic nucleus reverses motor deficits but not death of nigrostriatal dopaminergic neurons in a rat 6-hydroxydopamine-lesion model of Parkinson's disease

Rizelio¹,

Szawka²,

Xavier³

et al. 2010

Braz J Med Biol Res

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“…36 It has been proposed that by reducing the excitotoxic drive to the SN, STN modulation could even halt disease progression. 14,15 In the current work, STN-HFS boosted grafted cell survival by 180%, fiber outgrowth by 140%, and the overall graft volume by 230%. This suggests that by reducing striatal neuronal firing and excitotoxicity, subthalamic neuromodulation provides a better environment for dopaminergic precursor cells, which, once transplanted, develop and integrate into the host striatum.…”

Section: Neuronal Circuitry and Neuromodulation In Pdmentioning

confidence: 99%

“…Studies involving STN lesion and STN-HFS following nigrostriatal 6-OHDA-induced lesions revealed increased nigral dopamine expression and reduced neuronal loss compared to controls, documenting a neuroprotective effect of STN modulation in this model. 14,15 Nevertheless, the electrophysiological and behavioral aspects of this technique have yet to be explored.…”

Section: Introductionmentioning

confidence: 99%

Continuous High-Frequency Stimulation of the Subthalamic Nucleus Improves Cell Survival and Functional Recovery Following Dopaminergic Cell Transplantation in Rodents

Furlanetti

Cordeiro

et al. 2015

Neurorehabil Neural Repair

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Subthalamic nucleus (STN) high-frequency stimulation (HFS) is a routine treatment in Parkinson's disease (PD), with confirmed long-term benefits. An alternative, but still experimental, treatment is cell replacement and restorative therapy based on transplanted dopaminergic neurons. The current experiment evaluated the potential synergy between neuromodulation and grafting by studying the effect of continuous STN-HFS on the survival, integration, and functional efficacy of ventral mesencephalic dopaminergic precursors transplanted into a unilateral 6-hydroxydopamine medial forebrain bundle lesioned rodent PD model. One group received continuous HFS of the ipsilateral STN starting a week prior to intrastriatal dopaminergic neuron transplantation, whereas the sham-stimulated group did not receive STN-HFS but only dopaminergic grafts. A control group was neither lesioned nor transplanted. Over the following 7 weeks, the animals were probed on a series of behavioral tasks to evaluate possible graft and/or stimulation-induced functional effects. Behavioral and histological data suggest that STN-HFS significantly increased graft cell survival, graft-host integration, and functional recovery. These findings might open an unexplored road toward combining neuromodulative and neuroregenerative strategies to treat severe neurologic conditions.

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Subthalamic Nucleus Lesions Are Neuroprotective against Terminal 6-OHDA-Induced Striatal Lesions and Restore Postural Balancing Reactions

Cited by 56 publications

References 40 publications

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

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

Lesion of the subthalamic nucleus reverses motor deficits but not death of nigrostriatal dopaminergic neurons in a rat 6-hydroxydopamine-lesion model of Parkinson's disease

Continuous High-Frequency Stimulation of the Subthalamic Nucleus Improves Cell Survival and Functional Recovery Following Dopaminergic Cell Transplantation in Rodents

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