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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

L-DOPA concentration-time profiles in brainECF in the control cerebral hemisphere (○; in total 12 rats: 10 mg/kg, n = 4; 25 mg/kg, n = 3; 50 mg/kg, n = 5) and in the rotenone-treated responder cerebral hemisphere (•; in total 7 rats: 10 mg/kg, n = 1; 25 mg/kg, n = 2; 50 mg/kg, n = 4), obtained after a 20-min intravenous infusion in Lewis rats.
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Figure 3: L-DOPA concentration-time profiles in brainECF in the control cerebral hemisphere (○; in total 12 rats: 10 mg/kg, n = 4; 25 mg/kg, n = 3; 50 mg/kg, n = 5) and in the rotenone-treated responder cerebral hemisphere (•; in total 7 rats: 10 mg/kg, n = 1; 25 mg/kg, n = 2; 50 mg/kg, n = 4), obtained after a 20-min intravenous infusion in Lewis rats.

Mentions: The plasma concentration-time profiles for each rat following intravenous infusion of 10, 25, and 50 mg/kg of L-DOPA are shown in Figure 2. The resulting brainECF concentration-time profiles of L-DOPA are shown in Figure 3, for both the control and the responder cerebral hemispheres. The L-DOPA concentrations in plasma and in brainECF were analysed simultaneously. All structural parameters of the population pharmacokinetic model for L-DOPA could be adequately estimated (Table 1). No dose-dependency was observed in the plasma pharmacokinetics for L-DOPA. No significant difference could be detected between the inter-compartmental clearances Q4 and Q5, the volumes of distribution V4 and V5 or the elimination rate constants k40 and k50 when these models were fitted to the L-DOPA brain concentration data. Table 2 shows a summary of the MVOF and parameter estimates after the different assumptions (Q4 = Q5, V4 = V5, k40 = k50 or a combination of any of these). Also, the separate estimate of endogenous brain production rate of L-DOPA (Kin) for compartment 4 and 5 resulted in similar estimated values (5.8 min-1). Striatal brainECF baseline L-DOPA levels in the rotenone-treated responder cerebral hemisphere were not statistically different (p = 0.07; Welch's t-test) from those in the control hemisphere and averaged 0.010 ± 0.004 pmol/mL and 0.024 ± 0.011 pmol/mL (mean ± SEM), respectively. Therefore, it can be concluded that no significant difference can be identified between the pharmacokinetics of L-DOPA in the control versus the rotenone-treated responder cerebral hemisphere.


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)

L-DOPA concentration-time profiles in brainECF in the control cerebral hemisphere (○; in total 12 rats: 10 mg/kg, n = 4; 25 mg/kg, n = 3; 50 mg/kg, n = 5) and in the rotenone-treated responder cerebral hemisphere (•; in total 7 rats: 10 mg/kg, n = 1; 25 mg/kg, n = 2; 50 mg/kg, n = 4), obtained after a 20-min intravenous infusion in Lewis rats.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: L-DOPA concentration-time profiles in brainECF in the control cerebral hemisphere (○; in total 12 rats: 10 mg/kg, n = 4; 25 mg/kg, n = 3; 50 mg/kg, n = 5) and in the rotenone-treated responder cerebral hemisphere (•; in total 7 rats: 10 mg/kg, n = 1; 25 mg/kg, n = 2; 50 mg/kg, n = 4), obtained after a 20-min intravenous infusion in Lewis rats.
Mentions: The plasma concentration-time profiles for each rat following intravenous infusion of 10, 25, and 50 mg/kg of L-DOPA are shown in Figure 2. The resulting brainECF concentration-time profiles of L-DOPA are shown in Figure 3, for both the control and the responder cerebral hemispheres. The L-DOPA concentrations in plasma and in brainECF were analysed simultaneously. All structural parameters of the population pharmacokinetic model for L-DOPA could be adequately estimated (Table 1). No dose-dependency was observed in the plasma pharmacokinetics for L-DOPA. No significant difference could be detected between the inter-compartmental clearances Q4 and Q5, the volumes of distribution V4 and V5 or the elimination rate constants k40 and k50 when these models were fitted to the L-DOPA brain concentration data. Table 2 shows a summary of the MVOF and parameter estimates after the different assumptions (Q4 = Q5, V4 = V5, k40 = k50 or a combination of any of these). Also, the separate estimate of endogenous brain production rate of L-DOPA (Kin) for compartment 4 and 5 resulted in similar estimated values (5.8 min-1). Striatal brainECF baseline L-DOPA levels in the rotenone-treated responder cerebral hemisphere were not statistically different (p = 0.07; Welch's t-test) from those in the control hemisphere and averaged 0.010 ± 0.004 pmol/mL and 0.024 ± 0.011 pmol/mL (mean ± SEM), respectively. Therefore, it can be concluded that no significant difference can be identified between the pharmacokinetics of L-DOPA in the control versus the rotenone-treated responder cerebral hemisphere.

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