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Assessment of the Protection of Dopaminergic Neurons by an α7 Nicotinic Receptor Agonist, PHA 543613 Using [(18)F]LBT-999 in a Parkinson's Disease Rat Model.

Sérrière S, Doméné A, Vercouillie J, Mothes C, Bodard S, Rodrigues N, Guilloteau D, Routier S, Page G, Chalon S - Front Med (Lausanne) (2015)

Bottom Line: The DAT density reflecting the integrity of dopaminergic neurons was significantly decreased while the intensity of neuroinflammation measured by TSPO density was significantly increased in the lesioned compared to intact striatum in both groups.These findings indicate that PHA 543613 exerts neuroprotective effects on the striatal dopaminergic neurons associated with a reduction in microglial activation in this model of PD.This reinforces the hypothesis that an α7R agonist could provide beneficial effects for the treatment of PD.

View Article: PubMed Central - PubMed

Affiliation: UMR INSERM U930, Université François Rabelais , Tours , France.

ABSTRACT
The inverse association between nicotine intake and Parkinson's disease (PD) is well established and suggests that this molecule could be neuroprotective through anti-inflammatory action mediated by nicotinic receptors, including the α7-subtype (α7R). The objective of this study was to evaluate the effects of an agonist of α7R, PHA 543613, on striatal dopaminergic neurodegeneration and neuroinflammation in a rat model of PD induced by 6-hydroxydopamine (6-OHDA) lesion. Adult male Wistar rats were lesioned in the right striatum and assigned to either the PHA group (n = 7) or the Sham group (n = 5). PHA 543613 hydrochloride at the concentration of 6 mg/kg (PHA group) or vehicle (Sham group) was intra-peritoneally injected 2 h before 6-OHDA lesioning and then at days 2, 4, and 6 post-lesion. Positron emission tomography (PET) imaging was performed at 7 days post-lesion using [(18)F]LBT-999 to quantify the striatal dopamine transporter (DAT). After PET imaging, neuroinflammation was evaluated in same animals in vitro through the measurement of the microglial activation marker 18 kDa translocator protein (TSPO) by quantitative autoradiography with [(3)H]PK-11195. The DAT density reflecting the integrity of dopaminergic neurons was significantly decreased while the intensity of neuroinflammation measured by TSPO density was significantly increased in the lesioned compared to intact striatum in both groups. However, these both modifications were partially reversed in the PHA group compared to Sham. In addition, a significant positive correlation between the degree of lesion and the intensity of neuroinflammation was evidenced. These findings indicate that PHA 543613 exerts neuroprotective effects on the striatal dopaminergic neurons associated with a reduction in microglial activation in this model of PD. This reinforces the hypothesis that an α7R agonist could provide beneficial effects for the treatment of PD.

No MeSH data available.


Related in: MedlinePlus

Quantitative results from PET brain images with [18F]LBT-999. (A) Mean-time activity curves of [18F]LBT-999 SUVs in the IST, LST, and CE, in Sham (blue) and PHA (red) rats. (B) Mean-time activity curves of SUVr to CE of tracer accumulation in IST and LST in Sham (blue) and PHA (red) rats. (C) Percentage of lesion in Sham (blue) and PHA (red) rats. *p < 0.05 compared with Sham (Mann–Whitney test). Abbreviations: CE: cerebellum, IST: intact striatum, LST: lesioned striatum, SUV: standard uptake value, SUVr: standard uptake value ratio to CE.
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Figure 2: Quantitative results from PET brain images with [18F]LBT-999. (A) Mean-time activity curves of [18F]LBT-999 SUVs in the IST, LST, and CE, in Sham (blue) and PHA (red) rats. (B) Mean-time activity curves of SUVr to CE of tracer accumulation in IST and LST in Sham (blue) and PHA (red) rats. (C) Percentage of lesion in Sham (blue) and PHA (red) rats. *p < 0.05 compared with Sham (Mann–Whitney test). Abbreviations: CE: cerebellum, IST: intact striatum, LST: lesioned striatum, SUV: standard uptake value, SUVr: standard uptake value ratio to CE.

Mentions: The time activity curves (Figure 2A) showed a rapid uptake of [18F]LBT-999 in the ROIs (i.e., the IST, LST, and CE) after intravenous bolus injection. In the CE, the uptake decreased rapidly and remained low and stable after 20 min post-injection in both groups (SUV in the PHA group: 0.97 ± 0.06, and 0.99 ± 0.08 in the Sham group). The uptake remained high and stable in the IST in both groups (SUV in the PHA group: 3.99 ± 0.33, and 3.84 ± 0.31 in the Sham group). By contrast, the values observed in the LST were reduced in comparison to those in the IST in both groups (SUV in the PHA group: 1.41 ± 0.19, and 0.98 ± 0.11 in the Sham group).


Assessment of the Protection of Dopaminergic Neurons by an α7 Nicotinic Receptor Agonist, PHA 543613 Using [(18)F]LBT-999 in a Parkinson's Disease Rat Model.

Sérrière S, Doméné A, Vercouillie J, Mothes C, Bodard S, Rodrigues N, Guilloteau D, Routier S, Page G, Chalon S - Front Med (Lausanne) (2015)

Quantitative results from PET brain images with [18F]LBT-999. (A) Mean-time activity curves of [18F]LBT-999 SUVs in the IST, LST, and CE, in Sham (blue) and PHA (red) rats. (B) Mean-time activity curves of SUVr to CE of tracer accumulation in IST and LST in Sham (blue) and PHA (red) rats. (C) Percentage of lesion in Sham (blue) and PHA (red) rats. *p < 0.05 compared with Sham (Mann–Whitney test). Abbreviations: CE: cerebellum, IST: intact striatum, LST: lesioned striatum, SUV: standard uptake value, SUVr: standard uptake value ratio to CE.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4556971&req=5

Figure 2: Quantitative results from PET brain images with [18F]LBT-999. (A) Mean-time activity curves of [18F]LBT-999 SUVs in the IST, LST, and CE, in Sham (blue) and PHA (red) rats. (B) Mean-time activity curves of SUVr to CE of tracer accumulation in IST and LST in Sham (blue) and PHA (red) rats. (C) Percentage of lesion in Sham (blue) and PHA (red) rats. *p < 0.05 compared with Sham (Mann–Whitney test). Abbreviations: CE: cerebellum, IST: intact striatum, LST: lesioned striatum, SUV: standard uptake value, SUVr: standard uptake value ratio to CE.
Mentions: The time activity curves (Figure 2A) showed a rapid uptake of [18F]LBT-999 in the ROIs (i.e., the IST, LST, and CE) after intravenous bolus injection. In the CE, the uptake decreased rapidly and remained low and stable after 20 min post-injection in both groups (SUV in the PHA group: 0.97 ± 0.06, and 0.99 ± 0.08 in the Sham group). The uptake remained high and stable in the IST in both groups (SUV in the PHA group: 3.99 ± 0.33, and 3.84 ± 0.31 in the Sham group). By contrast, the values observed in the LST were reduced in comparison to those in the IST in both groups (SUV in the PHA group: 1.41 ± 0.19, and 0.98 ± 0.11 in the Sham group).

Bottom Line: The DAT density reflecting the integrity of dopaminergic neurons was significantly decreased while the intensity of neuroinflammation measured by TSPO density was significantly increased in the lesioned compared to intact striatum in both groups.These findings indicate that PHA 543613 exerts neuroprotective effects on the striatal dopaminergic neurons associated with a reduction in microglial activation in this model of PD.This reinforces the hypothesis that an α7R agonist could provide beneficial effects for the treatment of PD.

View Article: PubMed Central - PubMed

Affiliation: UMR INSERM U930, Université François Rabelais , Tours , France.

ABSTRACT
The inverse association between nicotine intake and Parkinson's disease (PD) is well established and suggests that this molecule could be neuroprotective through anti-inflammatory action mediated by nicotinic receptors, including the α7-subtype (α7R). The objective of this study was to evaluate the effects of an agonist of α7R, PHA 543613, on striatal dopaminergic neurodegeneration and neuroinflammation in a rat model of PD induced by 6-hydroxydopamine (6-OHDA) lesion. Adult male Wistar rats were lesioned in the right striatum and assigned to either the PHA group (n = 7) or the Sham group (n = 5). PHA 543613 hydrochloride at the concentration of 6 mg/kg (PHA group) or vehicle (Sham group) was intra-peritoneally injected 2 h before 6-OHDA lesioning and then at days 2, 4, and 6 post-lesion. Positron emission tomography (PET) imaging was performed at 7 days post-lesion using [(18)F]LBT-999 to quantify the striatal dopamine transporter (DAT). After PET imaging, neuroinflammation was evaluated in same animals in vitro through the measurement of the microglial activation marker 18 kDa translocator protein (TSPO) by quantitative autoradiography with [(3)H]PK-11195. The DAT density reflecting the integrity of dopaminergic neurons was significantly decreased while the intensity of neuroinflammation measured by TSPO density was significantly increased in the lesioned compared to intact striatum in both groups. However, these both modifications were partially reversed in the PHA group compared to Sham. In addition, a significant positive correlation between the degree of lesion and the intensity of neuroinflammation was evidenced. These findings indicate that PHA 543613 exerts neuroprotective effects on the striatal dopaminergic neurons associated with a reduction in microglial activation in this model of PD. This reinforces the hypothesis that an α7R agonist could provide beneficial effects for the treatment of PD.

No MeSH data available.


Related in: MedlinePlus