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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

Lightmicroscopic images of wild-type and Plp1 transgenic controls and curcumin-treated Plp1 transgenic mice showing OLIG2 and CC1 (oligodendrocytes), MAC3 (microglia) and CD3 (lymphocytes) (A; DAB staining) as well as GFAP-immunopositive cells (astrocytes) in the spinal cord (F; fluorescent staining). Curcumin diet preserved the number of oligodendrocytes (B and C), reduced the microgliosis (D), the lymphocyte infiltration (E) and astrocytosis in Plp1 transgenic mice (G). WT, wildtype; Plp1 tg, Plp1 transgenic homozygous line #72; mean ± SD; ns, not significant; *P < 0.05, **P < 0.01, ***P < 0.001, scale bar = 10 μm.
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fig03: Lightmicroscopic images of wild-type and Plp1 transgenic controls and curcumin-treated Plp1 transgenic mice showing OLIG2 and CC1 (oligodendrocytes), MAC3 (microglia) and CD3 (lymphocytes) (A; DAB staining) as well as GFAP-immunopositive cells (astrocytes) in the spinal cord (F; fluorescent staining). Curcumin diet preserved the number of oligodendrocytes (B and C), reduced the microgliosis (D), the lymphocyte infiltration (E) and astrocytosis in Plp1 transgenic mice (G). WT, wildtype; Plp1 tg, Plp1 transgenic homozygous line #72; mean ± SD; ns, not significant; *P < 0.05, **P < 0.01, ***P < 0.001, scale bar = 10 μm.

Mentions: Oligodendrocytes (identified by their immunopositivity for the marker OLIG2 staining both, mature myelinating oligodendrocytes and progenitors or CC1 which stains only mature myelinating oligodendrocytes), activated microglia (MAC3), lymphocytes (CD3), and astrocytes (GFAP) were quantified in the CST area or the CST including the dorsal tracts (dorsal white matter); representative images are shown in Figure3A and F. Plp1 transgenic mice displayed fewer OLIG2-positive cells when compared to wild-type controls (7 ± 2 and 16 ± 1, P < 0.001), which were restored to wild-type levels by the curcumin diet (13 ± 4, P < 0.01) (Fig.3B). Similarly, CC1-positive cells were reduced in Plp1 transgenic mice compared to wild-type controls (22 ± 2 and 28 ± 2, P < 0.01), which were also restored to the wild-type level after chronic curcumin diet in Plp1 transgenic mice (30 ± 6, P < 0.01) (Fig.3C). The number of MAC3-immunopositive cells was increased in Plp1 transgenic mice compared to wild-types (92 ± 37 and 5 ± 2, P < 0.01). Curcumin diet reduced the number of activated macrophages (34 ± 16, P < 0.01) although not reaching wild-type levels (P < 0.05; Fig.3D). CD3-immunopositive cells were never observed in wild-type mice but were present in Plp1 transgenic controls (0 ± 0 and 3 ± 2, P < 0.05). Curcumin diet in Plp1 transgenic mice also reduced the number of CD3-immunopositive cells (0.6 ± 0.2, P < 0.01) to wild-type levels (not significant; Fig.3E). Finally, curcumin diet in Plp1 transgenic mice reduced the number of GFAP-positive cells when compared to the Plp1 transgenic controls (38 ± 2 and 53 ± 6, P < 0.05) which still showed astrocytosis exceeding wild-type levels (26 ± 4, P < 0.05; Fig.3G).


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)

Lightmicroscopic images of wild-type and Plp1 transgenic controls and curcumin-treated Plp1 transgenic mice showing OLIG2 and CC1 (oligodendrocytes), MAC3 (microglia) and CD3 (lymphocytes) (A; DAB staining) as well as GFAP-immunopositive cells (astrocytes) in the spinal cord (F; fluorescent staining). Curcumin diet preserved the number of oligodendrocytes (B and C), reduced the microgliosis (D), the lymphocyte infiltration (E) and astrocytosis in Plp1 transgenic mice (G). WT, wildtype; Plp1 tg, Plp1 transgenic homozygous line #72; mean ± SD; ns, not significant; *P < 0.05, **P < 0.01, ***P < 0.001, scale bar = 10 μm.
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Related In: Results  -  Collection

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fig03: Lightmicroscopic images of wild-type and Plp1 transgenic controls and curcumin-treated Plp1 transgenic mice showing OLIG2 and CC1 (oligodendrocytes), MAC3 (microglia) and CD3 (lymphocytes) (A; DAB staining) as well as GFAP-immunopositive cells (astrocytes) in the spinal cord (F; fluorescent staining). Curcumin diet preserved the number of oligodendrocytes (B and C), reduced the microgliosis (D), the lymphocyte infiltration (E) and astrocytosis in Plp1 transgenic mice (G). WT, wildtype; Plp1 tg, Plp1 transgenic homozygous line #72; mean ± SD; ns, not significant; *P < 0.05, **P < 0.01, ***P < 0.001, scale bar = 10 μm.
Mentions: Oligodendrocytes (identified by their immunopositivity for the marker OLIG2 staining both, mature myelinating oligodendrocytes and progenitors or CC1 which stains only mature myelinating oligodendrocytes), activated microglia (MAC3), lymphocytes (CD3), and astrocytes (GFAP) were quantified in the CST area or the CST including the dorsal tracts (dorsal white matter); representative images are shown in Figure3A and F. Plp1 transgenic mice displayed fewer OLIG2-positive cells when compared to wild-type controls (7 ± 2 and 16 ± 1, P < 0.001), which were restored to wild-type levels by the curcumin diet (13 ± 4, P < 0.01) (Fig.3B). Similarly, CC1-positive cells were reduced in Plp1 transgenic mice compared to wild-type controls (22 ± 2 and 28 ± 2, P < 0.01), which were also restored to the wild-type level after chronic curcumin diet in Plp1 transgenic mice (30 ± 6, P < 0.01) (Fig.3C). The number of MAC3-immunopositive cells was increased in Plp1 transgenic mice compared to wild-types (92 ± 37 and 5 ± 2, P < 0.01). Curcumin diet reduced the number of activated macrophages (34 ± 16, P < 0.01) although not reaching wild-type levels (P < 0.05; Fig.3D). CD3-immunopositive cells were never observed in wild-type mice but were present in Plp1 transgenic controls (0 ± 0 and 3 ± 2, P < 0.05). Curcumin diet in Plp1 transgenic mice also reduced the number of CD3-immunopositive cells (0.6 ± 0.2, P < 0.01) to wild-type levels (not significant; Fig.3E). Finally, curcumin diet in Plp1 transgenic mice reduced the number of GFAP-positive cells when compared to the Plp1 transgenic controls (38 ± 2 and 53 ± 6, P < 0.05) which still showed astrocytosis exceeding wild-type levels (26 ± 4, P < 0.05; Fig.3G).

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