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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 increase BDNF.BDNF protein levels were normalized to total protein in key basal ganglia structures of intact rats after a two-week stimulation interval. Data from each structure were normalized to the corresponding structure from the INACTIVE, contralateral (to 6-OHDA and electrode lead) hemisphere to control for the potential effect of dopamine denervation or electrode implantation on BDNF levels. Samples were obtained for the ipsilateral (Ipsi) and contralateral (Contra) substantia nigra (SN), striatum (STR), primary motor cortex (M1), thalamus and hippocampus. No significant difference was observed between ACTIVE and INACTIVE stimulation groups nor within animals between sides, though there was a trend toward significance between the Active and Inactive SN bilaterally.
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pone.0133957.g004: EP DBS does not increase BDNF.BDNF protein levels were normalized to total protein in key basal ganglia structures of intact rats after a two-week stimulation interval. Data from each structure were normalized to the corresponding structure from the INACTIVE, contralateral (to 6-OHDA and electrode lead) hemisphere to control for the potential effect of dopamine denervation or electrode implantation on BDNF levels. Samples were obtained for the ipsilateral (Ipsi) and contralateral (Contra) substantia nigra (SN), striatum (STR), primary motor cortex (M1), thalamus and hippocampus. No significant difference was observed between ACTIVE and INACTIVE stimulation groups nor within animals between sides, though there was a trend toward significance between the Active and Inactive SN bilaterally.

Mentions: Five structures—namely, the SN, striatum, M1 cortex, thalamus and hippocampus—were examined bilaterally for levels of BDNF protein expression in unlesioned rats that received unilateral EP stimulation for two weeks (ACTIVE) or INACTIVE electrode-implanted controls. ACTIVE stimulation of the rat EP was not associated with a significant increase in BDNF protein levels in any of the structures examined (viz., SN, thalamus, hippocampus, striatum and M1; p > 0.05k-o, respectively), although BDNF levels in the SN of ACTIVE rats displayed a trend toward increased BDNF (F(1,16) = 4.426, p = 0.052k). BDNF protein levels were not measured for the EP since they are below the detection threshold for an ELISA [21]. Of note, our raw data are generally of a similar magnitude as our previous work [21] and others [28], suggesting consistency with the assay. The comprehensive results are summarized in Table 2 and Fig 4.


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 increase BDNF.BDNF protein levels were normalized to total protein in key basal ganglia structures of intact rats after a two-week stimulation interval. Data from each structure were normalized to the corresponding structure from the INACTIVE, contralateral (to 6-OHDA and electrode lead) hemisphere to control for the potential effect of dopamine denervation or electrode implantation on BDNF levels. Samples were obtained for the ipsilateral (Ipsi) and contralateral (Contra) substantia nigra (SN), striatum (STR), primary motor cortex (M1), thalamus and hippocampus. No significant difference was observed between ACTIVE and INACTIVE stimulation groups nor within animals between sides, though there was a trend toward significance between the Active and Inactive SN bilaterally.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0133957.g004: EP DBS does not increase BDNF.BDNF protein levels were normalized to total protein in key basal ganglia structures of intact rats after a two-week stimulation interval. Data from each structure were normalized to the corresponding structure from the INACTIVE, contralateral (to 6-OHDA and electrode lead) hemisphere to control for the potential effect of dopamine denervation or electrode implantation on BDNF levels. Samples were obtained for the ipsilateral (Ipsi) and contralateral (Contra) substantia nigra (SN), striatum (STR), primary motor cortex (M1), thalamus and hippocampus. No significant difference was observed between ACTIVE and INACTIVE stimulation groups nor within animals between sides, though there was a trend toward significance between the Active and Inactive SN bilaterally.
Mentions: Five structures—namely, the SN, striatum, M1 cortex, thalamus and hippocampus—were examined bilaterally for levels of BDNF protein expression in unlesioned rats that received unilateral EP stimulation for two weeks (ACTIVE) or INACTIVE electrode-implanted controls. ACTIVE stimulation of the rat EP was not associated with a significant increase in BDNF protein levels in any of the structures examined (viz., SN, thalamus, hippocampus, striatum and M1; p > 0.05k-o, respectively), although BDNF levels in the SN of ACTIVE rats displayed a trend toward increased BDNF (F(1,16) = 4.426, p = 0.052k). BDNF protein levels were not measured for the EP since they are below the detection threshold for an ELISA [21]. Of note, our raw data are generally of a similar magnitude as our previous work [21] and others [28], suggesting consistency with the assay. The comprehensive results are summarized in Table 2 and Fig 4.

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