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Evaluation of blood-brain barrier transport and CNS drug metabolism in diseased and control brain after intravenous L-DOPA in a unilateral rat model of Parkinson's disease.

Ravenstijn PG, Drenth HJ, O'Neill MJ, Danhof M, de Lange EC - Fluids Barriers CNS (2012)

Bottom Line: In rotenone responders (71%), no difference in L-DOPA BBB transport was found between diseased and control cerebral hemisphere.Parkinson's disease-like pathology, indicated by a huge reduction of tyrosine hydroxylase as well as by substantially reduced levels and higher elimination rates of DOPAC and HVA, does not result in changes in BBB transport of L-DOPA.Taking the results of this study and that of previous ones, it can be concluded that changes in BBB functionality are not a specific characteristic of Parkinson's disease, and cannot account for the decreased benefit of L-DOPA at later stages of Parkinson's disease.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Pharmacology, LACDR Leiden University, Leiden, The Netherlands. l.lange@lacdr.leidenuniv.nl.

ABSTRACT

Background: Changes in blood-brain barrier (BBB) functionality have been implicated in Parkinson's disease. This study aimed to investigate BBB transport of L-DOPA transport in conjunction with its intra-brain conversion, in both control and diseased cerebral hemispheres in the unilateral rat rotenone model of Parkinson's disease.

Methods: In Lewis rats, at 14 days after unilateral infusion of rotenone into the medial forebrain bundle, L-DOPA was administered intravenously (10, 25 or 50 mg/kg). Serial blood samples and brain striatal microdialysates were analysed for L-DOPA, and the dopamine metabolites DOPAC and HVA. Ex-vivo brain tissue was analyzed for changes in tyrosine hydroxylase staining as a biomarker for Parkinson's disease severity. Data were analysed by population pharmacokinetic analysis (NONMEM) to compare BBB transport of L-DOPA in conjunction with the conversion of L-DOPA into DOPAC and HVA, in control and diseased cerebral hemisphere.

Results: Plasma pharmacokinetics of L-DOPA could be described by a 3-compartmental model. In rotenone responders (71%), no difference in L-DOPA BBB transport was found between diseased and control cerebral hemisphere. However, in the diseased compared with the control side, basal microdialysate levels of DOPAC and HVA were substantially lower, whereas following L-DOPA administration their elimination rates were higher.

Conclusions: Parkinson's disease-like pathology, indicated by a huge reduction of tyrosine hydroxylase as well as by substantially reduced levels and higher elimination rates of DOPAC and HVA, does not result in changes in BBB transport of L-DOPA. Taking the results of this study and that of previous ones, it can be concluded that changes in BBB functionality are not a specific characteristic of Parkinson's disease, and cannot account for the decreased benefit of L-DOPA at later stages of Parkinson's disease.

No MeSH data available.


Related in: MedlinePlus

Population predicted concentrations of DOPAC (panel A) and HVA (panel B) in the control cerebral hemisphere (-) and rotenone-treated responder cerebral hemisphere in responders (---) according to the model as described in Figure 1, at three doses of L-DOPA.
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Figure 4: Population predicted concentrations of DOPAC (panel A) and HVA (panel B) in the control cerebral hemisphere (-) and rotenone-treated responder cerebral hemisphere in responders (---) according to the model as described in Figure 1, at three doses of L-DOPA.

Mentions: Striatal microdialysate baseline DOPAC levels in the rotenone-treated responder cerebral hemisphere were about 6 times lower than in the control cerebral hemisphere and averaged 0.2 ± 0.19 pmol/mL and 1.3 ± 0.17 pmol/mL (mean ± SEM), respectively (p-value < 0.01; Welch's t-test). Also, striatal microdialysate baseline HVA dialysate levels in the rotenone-treated responder cerebral hemisphere were lower (approximately 4 times) than in the control cerebral hemisphere with respective values of 0.25 ± 0.14 pmol/mL and 0.9 ± 0.08 pmol/mL (mean ± SEM), respectively (p-value = 0.02; Welch's t-test). Figure 4 shows the population predicted microdialysate concentrations of DOPAC and HVA versus time for a typical rat per dose group. All structural parameters of the population kinetic model for DOPAC as well as for HVA could be adequately estimated (Table 1). No dose-dependency was found in any of the parameters for DOPAC or HVA. For DOPAC, k46 and k58 (rate constants which describe the conversion of L-DOPA, via dopamine, to DOPAC) do not significantly differ, which means that there appears to be no effect of disease on the metabolism of L-DOPA via dopamine to DOPAC. The same can be said for HVA for which k47 and k59 do not significantly differ. On the other hand, the elimination rate constants were found to be 7-fold and 2.5-fold higher in the rotenone-treated responder compared to the control side for DOPAC (k60 and k80) and HVA (k70 and k90), respectively.


Evaluation of blood-brain barrier transport and CNS drug metabolism in diseased and control brain after intravenous L-DOPA in a unilateral rat model of Parkinson's disease.

Ravenstijn PG, Drenth HJ, O'Neill MJ, Danhof M, de Lange EC - Fluids Barriers CNS (2012)

Population predicted concentrations of DOPAC (panel A) and HVA (panel B) in the control cerebral hemisphere (-) and rotenone-treated responder cerebral hemisphere in responders (---) according to the model as described in Figure 1, at three doses of L-DOPA.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3298802&req=5

Figure 4: Population predicted concentrations of DOPAC (panel A) and HVA (panel B) in the control cerebral hemisphere (-) and rotenone-treated responder cerebral hemisphere in responders (---) according to the model as described in Figure 1, at three doses of L-DOPA.
Mentions: Striatal microdialysate baseline DOPAC levels in the rotenone-treated responder cerebral hemisphere were about 6 times lower than in the control cerebral hemisphere and averaged 0.2 ± 0.19 pmol/mL and 1.3 ± 0.17 pmol/mL (mean ± SEM), respectively (p-value < 0.01; Welch's t-test). Also, striatal microdialysate baseline HVA dialysate levels in the rotenone-treated responder cerebral hemisphere were lower (approximately 4 times) than in the control cerebral hemisphere with respective values of 0.25 ± 0.14 pmol/mL and 0.9 ± 0.08 pmol/mL (mean ± SEM), respectively (p-value = 0.02; Welch's t-test). Figure 4 shows the population predicted microdialysate concentrations of DOPAC and HVA versus time for a typical rat per dose group. All structural parameters of the population kinetic model for DOPAC as well as for HVA could be adequately estimated (Table 1). No dose-dependency was found in any of the parameters for DOPAC or HVA. For DOPAC, k46 and k58 (rate constants which describe the conversion of L-DOPA, via dopamine, to DOPAC) do not significantly differ, which means that there appears to be no effect of disease on the metabolism of L-DOPA via dopamine to DOPAC. The same can be said for HVA for which k47 and k59 do not significantly differ. On the other hand, the elimination rate constants were found to be 7-fold and 2.5-fold higher in the rotenone-treated responder compared to the control side for DOPAC (k60 and k80) and HVA (k70 and k90), respectively.

Bottom Line: In rotenone responders (71%), no difference in L-DOPA BBB transport was found between diseased and control cerebral hemisphere.Parkinson's disease-like pathology, indicated by a huge reduction of tyrosine hydroxylase as well as by substantially reduced levels and higher elimination rates of DOPAC and HVA, does not result in changes in BBB transport of L-DOPA.Taking the results of this study and that of previous ones, it can be concluded that changes in BBB functionality are not a specific characteristic of Parkinson's disease, and cannot account for the decreased benefit of L-DOPA at later stages of Parkinson's disease.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Pharmacology, LACDR Leiden University, Leiden, The Netherlands. l.lange@lacdr.leidenuniv.nl.

ABSTRACT

Background: Changes in blood-brain barrier (BBB) functionality have been implicated in Parkinson's disease. This study aimed to investigate BBB transport of L-DOPA transport in conjunction with its intra-brain conversion, in both control and diseased cerebral hemispheres in the unilateral rat rotenone model of Parkinson's disease.

Methods: In Lewis rats, at 14 days after unilateral infusion of rotenone into the medial forebrain bundle, L-DOPA was administered intravenously (10, 25 or 50 mg/kg). Serial blood samples and brain striatal microdialysates were analysed for L-DOPA, and the dopamine metabolites DOPAC and HVA. Ex-vivo brain tissue was analyzed for changes in tyrosine hydroxylase staining as a biomarker for Parkinson's disease severity. Data were analysed by population pharmacokinetic analysis (NONMEM) to compare BBB transport of L-DOPA in conjunction with the conversion of L-DOPA into DOPAC and HVA, in control and diseased cerebral hemisphere.

Results: Plasma pharmacokinetics of L-DOPA could be described by a 3-compartmental model. In rotenone responders (71%), no difference in L-DOPA BBB transport was found between diseased and control cerebral hemisphere. However, in the diseased compared with the control side, basal microdialysate levels of DOPAC and HVA were substantially lower, whereas following L-DOPA administration their elimination rates were higher.

Conclusions: Parkinson's disease-like pathology, indicated by a huge reduction of tyrosine hydroxylase as well as by substantially reduced levels and higher elimination rates of DOPAC and HVA, does not result in changes in BBB transport of L-DOPA. Taking the results of this study and that of previous ones, it can be concluded that changes in BBB functionality are not a specific characteristic of Parkinson's disease, and cannot account for the decreased benefit of L-DOPA at later stages of Parkinson's disease.

No MeSH data available.


Related in: MedlinePlus