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High-Frequency Stimulation of the Rat Entopeduncular Nucleus Does Not Provide Functional or Morphological Neuroprotection from 6-Hydroxydopamine.

Fischer DL, Collier TJ, Cole-Strauss A, Wohlgenant SL, Lipton JW, Steece-Collier K, Manfredsson FP, Kemp CJ, Sortwell CE - PLoS ONE (2015)

Bottom Line: Outcome measures included quantification of contralateral forelimb use, stereological assessment of SNpc neurons and BDNF levels.EP DBS 1) did not ameliorate forelimb impairments induced by 6-OHDA, 2) did not provide neuroprotection for SNpc neurons and 3) did not significantly increase BDNF levels in any of the structures examined.These results are in sharp contrast to the functional improvement, neuroprotection and BDNF-enhancing effects of STN DBS under identical experimental parameters in the rat.

View Article: PubMed Central - PubMed

Affiliation: Department of Translational Science and Molecular Medicine, College of Human Medicine, Michigan State University, Grand Rapids, MI, United States of America; MD/PhD and Neuroscience Graduate Programs, College of Human Medicine, Michigan State University, Grand Rapids, MI, United States of America.

ABSTRACT
Deep brain stimulation (DBS) is the most common neurosurgical treatment for Parkinson's disease (PD). Whereas the globus pallidus interna (GPi) has been less commonly targeted than the subthalamic nucleus (STN), a recent clinical trial suggests that GPi DBS may provide better outcomes for patients with psychiatric comorbidities. Several laboratories have demonstrated that DBS of the STN provides neuroprotection of substantia nigra pars compacta (SNpc) dopamine neurons in preclinical neurotoxin models of PD and increases brain-derived neurotrophic factor (BDNF). However, whether DBS of the entopeduncular nucleus (EP), the homologous structure to the GPi in the rat, has similar neuroprotective potential in preclinical models has not been investigated. We investigated the impact of EP DBS on forelimb use asymmetry and SNpc degeneration induced by 6-hydroxydopamine (6-OHDA) and on BDNF levels. EP DBS in male rats received unilateral, intrastriatal 6-OHDA and ACTIVE or INACTIVE stimulation continuously for two weeks. Outcome measures included quantification of contralateral forelimb use, stereological assessment of SNpc neurons and BDNF levels. EP DBS 1) did not ameliorate forelimb impairments induced by 6-OHDA, 2) did not provide neuroprotection for SNpc neurons and 3) did not significantly increase BDNF levels in any of the structures examined. These results are in sharp contrast to the functional improvement, neuroprotection and BDNF-enhancing effects of STN DBS under identical experimental parameters in the rat. The lack of functional response to EP DBS suggests that stimulation of the rat EP may not represent an accurate model of clinical GPi stimulation.

No MeSH data available.


Related in: MedlinePlus

EP DBS does not correct forelimb asymmetry or provide neuroprotection from 6-OHDA.(A) Rats receiving intrastriatal 6-OHDA followed by either ACTIVE or INACTIVE EP DBS were analyzed for forelimb use asymmetry in the cylinder. 6-OHDA led to a significant decrease in contralateral forelimb use. However, ACTIVE EP DBS showed no difference compared to INACTIVE DBS at any time point. Of note, two weeks following electrode implantation in the EP, an improvement in contralateral forepaw use was observed. (B-E) EP DBS does not provide neuroprotection from 6-OHDA. Neither ACTIVE nor INACTIVE EP DBS halted ongoing nigral DA neuron loss normally observed between two and four weeks after intrastriatal 6-OHDA. (B-C) Representative nigral sections from both INACTIVE (B) and ACTIVE (C) EP DBS rats labeled with TH antisera reveal significant depletion of nigral DA neurons in the lesioned hemisphere. (D-E) At higher magnification, DA neuron loss appears equivalent between the INACTIVE (D) and ACTIVE (E) treatment groups. (F) Stereological assessment of THir neurons revealed a significant effect of 6-OHDA administration but no significant difference between ACTIVE and INACTIVE EP DBS groups.
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pone.0133957.g003: EP DBS does not correct forelimb asymmetry or provide neuroprotection from 6-OHDA.(A) Rats receiving intrastriatal 6-OHDA followed by either ACTIVE or INACTIVE EP DBS were analyzed for forelimb use asymmetry in the cylinder. 6-OHDA led to a significant decrease in contralateral forelimb use. However, ACTIVE EP DBS showed no difference compared to INACTIVE DBS at any time point. Of note, two weeks following electrode implantation in the EP, an improvement in contralateral forepaw use was observed. (B-E) EP DBS does not provide neuroprotection from 6-OHDA. Neither ACTIVE nor INACTIVE EP DBS halted ongoing nigral DA neuron loss normally observed between two and four weeks after intrastriatal 6-OHDA. (B-C) Representative nigral sections from both INACTIVE (B) and ACTIVE (C) EP DBS rats labeled with TH antisera reveal significant depletion of nigral DA neurons in the lesioned hemisphere. (D-E) At higher magnification, DA neuron loss appears equivalent between the INACTIVE (D) and ACTIVE (E) treatment groups. (F) Stereological assessment of THir neurons revealed a significant effect of 6-OHDA administration but no significant difference between ACTIVE and INACTIVE EP DBS groups.

Mentions: Two weeks following intrastriatal 6-OHDA, a significant decrease in contralateral forelimb use was observed in both ACTIVE and INACTIVE groups (F(3,6) = 5.403, p = 0.038a and F(1.718,18) = 21.137, p < 0.001b, respectively). Specifically, rats lesioned with 6-OHDA reduced contralateral forelimb use compared to baseline by over half as much. A two-way RM-ANOVA revealed no significant difference between treatment groups (F(1,8) = 0.147, p = 0.712c) but did reveal a significant main effect within subjects (F(3,24) = 20.335, p < 0.001d); therefore, the ACTIVE and INACTIVE treatment groups were combined for pairwise comparisons within subjects. Intrastriatal 6-OHDA resulted in deficits in contralateral forelimb use compared to baseline (p < 0.001e) that persisted for the duration of the study (p = 0.007f). However, contralateral forelimb use was significantly improved (compared to the two-week, post-lesion time point) at both four-week time points regardless of whether stimulation was ‘on’ or ‘off’ (p = 0.001g and p = 0.015h, respectively). These results demonstrate no functional impact of ACTIVE stimulation on contralateral forelimb use but a significant improvement over time in both treatment groups. These results are depicted in Fig 3A.


High-Frequency Stimulation of the Rat Entopeduncular Nucleus Does Not Provide Functional or Morphological Neuroprotection from 6-Hydroxydopamine.

Fischer DL, Collier TJ, Cole-Strauss A, Wohlgenant SL, Lipton JW, Steece-Collier K, Manfredsson FP, Kemp CJ, Sortwell CE - PLoS ONE (2015)

EP DBS does not correct forelimb asymmetry or provide neuroprotection from 6-OHDA.(A) Rats receiving intrastriatal 6-OHDA followed by either ACTIVE or INACTIVE EP DBS were analyzed for forelimb use asymmetry in the cylinder. 6-OHDA led to a significant decrease in contralateral forelimb use. However, ACTIVE EP DBS showed no difference compared to INACTIVE DBS at any time point. Of note, two weeks following electrode implantation in the EP, an improvement in contralateral forepaw use was observed. (B-E) EP DBS does not provide neuroprotection from 6-OHDA. Neither ACTIVE nor INACTIVE EP DBS halted ongoing nigral DA neuron loss normally observed between two and four weeks after intrastriatal 6-OHDA. (B-C) Representative nigral sections from both INACTIVE (B) and ACTIVE (C) EP DBS rats labeled with TH antisera reveal significant depletion of nigral DA neurons in the lesioned hemisphere. (D-E) At higher magnification, DA neuron loss appears equivalent between the INACTIVE (D) and ACTIVE (E) treatment groups. (F) Stereological assessment of THir neurons revealed a significant effect of 6-OHDA administration but no significant difference between ACTIVE and INACTIVE EP DBS groups.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4519335&req=5

pone.0133957.g003: EP DBS does not correct forelimb asymmetry or provide neuroprotection from 6-OHDA.(A) Rats receiving intrastriatal 6-OHDA followed by either ACTIVE or INACTIVE EP DBS were analyzed for forelimb use asymmetry in the cylinder. 6-OHDA led to a significant decrease in contralateral forelimb use. However, ACTIVE EP DBS showed no difference compared to INACTIVE DBS at any time point. Of note, two weeks following electrode implantation in the EP, an improvement in contralateral forepaw use was observed. (B-E) EP DBS does not provide neuroprotection from 6-OHDA. Neither ACTIVE nor INACTIVE EP DBS halted ongoing nigral DA neuron loss normally observed between two and four weeks after intrastriatal 6-OHDA. (B-C) Representative nigral sections from both INACTIVE (B) and ACTIVE (C) EP DBS rats labeled with TH antisera reveal significant depletion of nigral DA neurons in the lesioned hemisphere. (D-E) At higher magnification, DA neuron loss appears equivalent between the INACTIVE (D) and ACTIVE (E) treatment groups. (F) Stereological assessment of THir neurons revealed a significant effect of 6-OHDA administration but no significant difference between ACTIVE and INACTIVE EP DBS groups.
Mentions: Two weeks following intrastriatal 6-OHDA, a significant decrease in contralateral forelimb use was observed in both ACTIVE and INACTIVE groups (F(3,6) = 5.403, p = 0.038a and F(1.718,18) = 21.137, p < 0.001b, respectively). Specifically, rats lesioned with 6-OHDA reduced contralateral forelimb use compared to baseline by over half as much. A two-way RM-ANOVA revealed no significant difference between treatment groups (F(1,8) = 0.147, p = 0.712c) but did reveal a significant main effect within subjects (F(3,24) = 20.335, p < 0.001d); therefore, the ACTIVE and INACTIVE treatment groups were combined for pairwise comparisons within subjects. Intrastriatal 6-OHDA resulted in deficits in contralateral forelimb use compared to baseline (p < 0.001e) that persisted for the duration of the study (p = 0.007f). However, contralateral forelimb use was significantly improved (compared to the two-week, post-lesion time point) at both four-week time points regardless of whether stimulation was ‘on’ or ‘off’ (p = 0.001g and p = 0.015h, respectively). These results demonstrate no functional impact of ACTIVE stimulation on contralateral forelimb use but a significant improvement over time in both treatment groups. These results are depicted in Fig 3A.

Bottom Line: Outcome measures included quantification of contralateral forelimb use, stereological assessment of SNpc neurons and BDNF levels.EP DBS 1) did not ameliorate forelimb impairments induced by 6-OHDA, 2) did not provide neuroprotection for SNpc neurons and 3) did not significantly increase BDNF levels in any of the structures examined.These results are in sharp contrast to the functional improvement, neuroprotection and BDNF-enhancing effects of STN DBS under identical experimental parameters in the rat.

View Article: PubMed Central - PubMed

Affiliation: Department of Translational Science and Molecular Medicine, College of Human Medicine, Michigan State University, Grand Rapids, MI, United States of America; MD/PhD and Neuroscience Graduate Programs, College of Human Medicine, Michigan State University, Grand Rapids, MI, United States of America.

ABSTRACT
Deep brain stimulation (DBS) is the most common neurosurgical treatment for Parkinson's disease (PD). Whereas the globus pallidus interna (GPi) has been less commonly targeted than the subthalamic nucleus (STN), a recent clinical trial suggests that GPi DBS may provide better outcomes for patients with psychiatric comorbidities. Several laboratories have demonstrated that DBS of the STN provides neuroprotection of substantia nigra pars compacta (SNpc) dopamine neurons in preclinical neurotoxin models of PD and increases brain-derived neurotrophic factor (BDNF). However, whether DBS of the entopeduncular nucleus (EP), the homologous structure to the GPi in the rat, has similar neuroprotective potential in preclinical models has not been investigated. We investigated the impact of EP DBS on forelimb use asymmetry and SNpc degeneration induced by 6-hydroxydopamine (6-OHDA) and on BDNF levels. EP DBS in male rats received unilateral, intrastriatal 6-OHDA and ACTIVE or INACTIVE stimulation continuously for two weeks. Outcome measures included quantification of contralateral forelimb use, stereological assessment of SNpc neurons and BDNF levels. EP DBS 1) did not ameliorate forelimb impairments induced by 6-OHDA, 2) did not provide neuroprotection for SNpc neurons and 3) did not significantly increase BDNF levels in any of the structures examined. These results are in sharp contrast to the functional improvement, neuroprotection and BDNF-enhancing effects of STN DBS under identical experimental parameters in the rat. The lack of functional response to EP DBS suggests that stimulation of the rat EP may not represent an accurate model of clinical GPi stimulation.

No MeSH data available.


Related in: MedlinePlus