Survival of midbrain dopaminergic cells after lesion or deep brain stimulation of the subthalamic nucleus in MPTP-treated monkeys

Abstract

We have examined dopaminergic cell survival after alteration of the subthalamic nucleus (STN) in methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys. The STN was lesioned with kainic acid (B series) or underwent deep brain stimulation (DBS) at high frequency (C series). In another series, MPTP-treated and non-MPTP-treated monkeys had no STN alteration (intact animals; A series). Animals were treated with MPTP either after (B1, C1) or before (B2, C2) STN alteration. We also explored the long-term ( approximately 7 months) effect of DBS in non-MPTP-treated monkeys (D series). Brains were aldehyde-fixed and processed for routine Nissl staining and tyrosine hydroxylase immunocytochemistry. Our results showed that there were significantly more (20-24%) dopaminergic cells in the substantia nigra pars compacta (SNc) of the MPTP-treated monkeys that had STN alteration, either with kainic acid lesion or DBS, compared to the non-MPTP-treated monkeys (intact animals). We suggest that this saving or neuroprotection was due to a reduction in glutamate excitotoxicity, as a result of the loss or reduction of the STN input to the SNc. Our results also showed that SNc cell number in the B1 and C1 series were very similar to those in the B2 and C2 series. In the cases that had long-term DBS of the STN (D series), there was no adverse impact on SNc cell number. In summary, these results indicated that STN alteration offered neuroprotection to dopaminergic cells that would normally die as part of the disease process.

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

“…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%).…”

“…Only a few preclinical studies in toxin‐based models with a more clinically relevant design have been conducted. 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.…”

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

“…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].…”

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. 125 The authors of these studies speculated that the neuroprotective effects resulted from a reduction in glutamate excitotoxicity by limiting STN input into SNc. Although this hypothesis is not congruent with evidence of increased output activity during DBS, other mechanisms may explain their results, including the release of neurotrophic factors or stimulation of GABAergic fibers of passage that innervate the SNc.…”