Limits...
Curcumin therapy in a Plp1 transgenic mouse model of Pelizaeus-Merzbacher disease.

Epplen DB, Prukop T, Nientiedt T, Albrecht P, Arlt FA, Stassart RM, Kassmann CM, Methner A, Nave KA, Werner HB, Sereda MW - Ann Clin Transl Neurol (2015)

Bottom Line: Furthermore, curcumin reduced astrocytosis, microgliosis and lymphocyte infiltration in Plp1 transgenic mice.Curcumin diet did not affect the pathologically increased Plp1 mRNA abundance.Curcumin may potentially serve as an antioxidant therapy of PMD caused by PLP1 gene duplication.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurogenetics, Max-Planck-Institute of Experimental Medicine Göttingen, Germany.

ABSTRACT

Objective: Pelizaeus-Merzbacher disease (PMD) is a progressive and lethal leukodystrophy caused by mutations affecting the proteolipid protein (PLP1) gene. The most common cause of PMD is a duplication of PLP1 and at present there is no curative therapy available.

Methods: By using transgenic mice carrying additional copies of Plp1, we investigated whether curcumin diet ameliorates PMD symptoms. The diet of Plp1 transgenic mice was supplemented with curcumin for 10 consecutive weeks followed by phenotypical, histological and immunohistochemical analyses of the central nervous system. Plp1 transgenic and wild-type mice fed with normal chow served as controls.

Results: Curcumin improved the motor phenotype performance of Plp1 transgenic mice by 50% toward wild-type level and preserved myelinated axons by 35% when compared to Plp1 transgenic controls. Furthermore, curcumin reduced astrocytosis, microgliosis and lymphocyte infiltration in Plp1 transgenic mice. Curcumin diet did not affect the pathologically increased Plp1 mRNA abundance. However, high glutathione levels indicating an oxidative misbalance in the white matter of Plp1 transgenic mice were restored by curcumin treatment.

Interpretation: Curcumin may potentially serve as an antioxidant therapy of PMD caused by PLP1 gene duplication.

No MeSH data available.


Related in: MedlinePlus

Curcumin treatment did not reduce the 1.8-fold Plp1 mRNA overexpression in Plp1 transgenic mice (A). However, we observed elevated glutathione (GSH) levels in primary oligodendrocytes of Plp1 transgenic mice (B) and in the white matter of Plp1 transgenic controls which were corrected by chronic curcumin diet (C). GSH levels were not increased in gray matter tissue of Plp1 transgenic mice and not altered by chronic curcumin treatment. WT, wildtype; Plp1 tg, Plp1 transgenic homozygous line #72; mean ± SD; ns, not significant; *P < 0.05, **P < 0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4554440&req=5

fig04: Curcumin treatment did not reduce the 1.8-fold Plp1 mRNA overexpression in Plp1 transgenic mice (A). However, we observed elevated glutathione (GSH) levels in primary oligodendrocytes of Plp1 transgenic mice (B) and in the white matter of Plp1 transgenic controls which were corrected by chronic curcumin diet (C). GSH levels were not increased in gray matter tissue of Plp1 transgenic mice and not altered by chronic curcumin treatment. WT, wildtype; Plp1 tg, Plp1 transgenic homozygous line #72; mean ± SD; ns, not significant; *P < 0.05, **P < 0.01.

Mentions: Based on previous pilot experiments (data not shown), curcumin was applied as a 1:6 mixture of turmeric powder in normal chow available ad libitum. Curcumin is the major active compound in turmeric powder and the proportion of curcumin is about 3% (corresponding to 0.5% curcumin in the given chow).21 Experimental treatment started in 3-week-old mice and was continued for 10 weeks. We additionally tested Meriva® (Indena S.p.A., Milan, Italy) curcumin which is formulated with phosphatidylcholine enabling a fivefold increased bioavailability compared to unformulated curcumin regarding Cmax and AUC in rodents and man,22,23 which is more favorable for future preclinical studies in PMD models and any translational approaches in patients as well. Therefore, for glutathione (GSH) measurements (shown in Fig. 4C and D) curcumin was applied ad libitum as a 1:1000 mixture of Meriva® curcumin in standard chow (corresponding to 0.1% Meriva® in the given chow) starting in 3-week-old mice and continued for 7.5 weeks aiming at similar curcumin blood levels as when turmeric was applied chronically. The treatment start point is most critical for comparable effects rather than the exact duration.14,24Plp1 transgenic and wild-type mice treated with normal chow served as controls for the present curcumin and recently published progesterone receptor antagonist treatment in Plp1 transgenic mice15 which were both tested in parallel within one common trial to minimize required animal numbers. All transgenic mice were assigned to treatment arms at random with respect to phenotype, weight, and litter. All analyses were performed in a blinded manner regarding genotype and treatment and each analysis was performed by the same investigator. Tissue samples for analysis were taken at the end of dietary supplementation.


Curcumin therapy in a Plp1 transgenic mouse model of Pelizaeus-Merzbacher disease.

Epplen DB, Prukop T, Nientiedt T, Albrecht P, Arlt FA, Stassart RM, Kassmann CM, Methner A, Nave KA, Werner HB, Sereda MW - Ann Clin Transl Neurol (2015)

Curcumin treatment did not reduce the 1.8-fold Plp1 mRNA overexpression in Plp1 transgenic mice (A). However, we observed elevated glutathione (GSH) levels in primary oligodendrocytes of Plp1 transgenic mice (B) and in the white matter of Plp1 transgenic controls which were corrected by chronic curcumin diet (C). GSH levels were not increased in gray matter tissue of Plp1 transgenic mice and not altered by chronic curcumin treatment. WT, wildtype; Plp1 tg, Plp1 transgenic homozygous line #72; mean ± SD; ns, not significant; *P < 0.05, **P < 0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4554440&req=5

fig04: Curcumin treatment did not reduce the 1.8-fold Plp1 mRNA overexpression in Plp1 transgenic mice (A). However, we observed elevated glutathione (GSH) levels in primary oligodendrocytes of Plp1 transgenic mice (B) and in the white matter of Plp1 transgenic controls which were corrected by chronic curcumin diet (C). GSH levels were not increased in gray matter tissue of Plp1 transgenic mice and not altered by chronic curcumin treatment. WT, wildtype; Plp1 tg, Plp1 transgenic homozygous line #72; mean ± SD; ns, not significant; *P < 0.05, **P < 0.01.
Mentions: Based on previous pilot experiments (data not shown), curcumin was applied as a 1:6 mixture of turmeric powder in normal chow available ad libitum. Curcumin is the major active compound in turmeric powder and the proportion of curcumin is about 3% (corresponding to 0.5% curcumin in the given chow).21 Experimental treatment started in 3-week-old mice and was continued for 10 weeks. We additionally tested Meriva® (Indena S.p.A., Milan, Italy) curcumin which is formulated with phosphatidylcholine enabling a fivefold increased bioavailability compared to unformulated curcumin regarding Cmax and AUC in rodents and man,22,23 which is more favorable for future preclinical studies in PMD models and any translational approaches in patients as well. Therefore, for glutathione (GSH) measurements (shown in Fig. 4C and D) curcumin was applied ad libitum as a 1:1000 mixture of Meriva® curcumin in standard chow (corresponding to 0.1% Meriva® in the given chow) starting in 3-week-old mice and continued for 7.5 weeks aiming at similar curcumin blood levels as when turmeric was applied chronically. The treatment start point is most critical for comparable effects rather than the exact duration.14,24Plp1 transgenic and wild-type mice treated with normal chow served as controls for the present curcumin and recently published progesterone receptor antagonist treatment in Plp1 transgenic mice15 which were both tested in parallel within one common trial to minimize required animal numbers. All transgenic mice were assigned to treatment arms at random with respect to phenotype, weight, and litter. All analyses were performed in a blinded manner regarding genotype and treatment and each analysis was performed by the same investigator. Tissue samples for analysis were taken at the end of dietary supplementation.

Bottom Line: Furthermore, curcumin reduced astrocytosis, microgliosis and lymphocyte infiltration in Plp1 transgenic mice.Curcumin diet did not affect the pathologically increased Plp1 mRNA abundance.Curcumin may potentially serve as an antioxidant therapy of PMD caused by PLP1 gene duplication.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurogenetics, Max-Planck-Institute of Experimental Medicine Göttingen, Germany.

ABSTRACT

Objective: Pelizaeus-Merzbacher disease (PMD) is a progressive and lethal leukodystrophy caused by mutations affecting the proteolipid protein (PLP1) gene. The most common cause of PMD is a duplication of PLP1 and at present there is no curative therapy available.

Methods: By using transgenic mice carrying additional copies of Plp1, we investigated whether curcumin diet ameliorates PMD symptoms. The diet of Plp1 transgenic mice was supplemented with curcumin for 10 consecutive weeks followed by phenotypical, histological and immunohistochemical analyses of the central nervous system. Plp1 transgenic and wild-type mice fed with normal chow served as controls.

Results: Curcumin improved the motor phenotype performance of Plp1 transgenic mice by 50% toward wild-type level and preserved myelinated axons by 35% when compared to Plp1 transgenic controls. Furthermore, curcumin reduced astrocytosis, microgliosis and lymphocyte infiltration in Plp1 transgenic mice. Curcumin diet did not affect the pathologically increased Plp1 mRNA abundance. However, high glutathione levels indicating an oxidative misbalance in the white matter of Plp1 transgenic mice were restored by curcumin treatment.

Interpretation: Curcumin may potentially serve as an antioxidant therapy of PMD caused by PLP1 gene duplication.

No MeSH data available.


Related in: MedlinePlus