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The antiviral drug ganciclovir does not inhibit microglial proliferation and activation.

Skripuletz T, Salinas Tejedor L, Prajeeth CK, Hansmann F, Chhatbar C, Kucman V, Zhang N, Raddatz BB, Detje CN, Sühs KW, Pul R, Gudi V, Kalinke U, Baumgärtner W, Stangel M - Sci Rep (2015)

Bottom Line: Ganciclovir is effective in the treatment of human infections with viruses of the Herpesviridae family.The objective of this study was to determine potential inhibitory effects of ganciclovir in three different murine animal models of CNS neuroinflammation in which microglia play an important role: Theiler´s murine encephalomyelitis, the cuprizone model of de- and remyelination, and the vesicular stomatitis virus encephalitis model.In conclusion, our results show that the antiviral drug ganciclovir does not inhibit microglial activation and proliferation in the murine CNS.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Hannover Medical School, Hannover, Germany.

ABSTRACT
Ganciclovir is effective in the treatment of human infections with viruses of the Herpesviridae family. Beside antiviral properties, recently ganciclovir was described to inhibit microglial proliferation and disease severity of experimental autoimmune encephalomyelitis, an inflammatory model of multiple sclerosis. Microglial activation and proliferation are main characteristics of neuroinflammatory CNS diseases and inhibition of microglial functions might be beneficial in autoimmune diseases, or detrimental in infectious diseases. The objective of this study was to determine potential inhibitory effects of ganciclovir in three different murine animal models of CNS neuroinflammation in which microglia play an important role: Theiler´s murine encephalomyelitis, the cuprizone model of de- and remyelination, and the vesicular stomatitis virus encephalitis model. In addition, in vitro experiments with microglial cultures were performed to test the hypothesis that ganciclovir inhibits microglial proliferation. In all three animal models, neither microglial proliferation or recruitment nor disease activity was changed by ganciclovir. In vitro experiments confirmed that microglial proliferation was not affected by ganciclovir. In conclusion, our results show that the antiviral drug ganciclovir does not inhibit microglial activation and proliferation in the murine CNS.

No MeSH data available.


Related in: MedlinePlus

The effects of ganciclovir were investigated in the cuprizone model of de- and remyelination.After 5 weeks of cuprizone feeding, complete demyelination occurred as shown by the immunohistochemical staining for the myelin protein proteolipid protein (PLP) (A). One week after cuprizone withdrawal at week 6 remyelination was visible. Total microglia numbers were analyzed by Iba1 staining, while proliferating microglia were visualized by double staining for Iba1/Ki67 (B,C). No effects of ganciclovir on de- and remyelination and microglial numbers could be observed between cuprizone groups. Each bar represents the mean ± SEM, n = 6 per time point and group.
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f2: The effects of ganciclovir were investigated in the cuprizone model of de- and remyelination.After 5 weeks of cuprizone feeding, complete demyelination occurred as shown by the immunohistochemical staining for the myelin protein proteolipid protein (PLP) (A). One week after cuprizone withdrawal at week 6 remyelination was visible. Total microglia numbers were analyzed by Iba1 staining, while proliferating microglia were visualized by double staining for Iba1/Ki67 (B,C). No effects of ganciclovir on de- and remyelination and microglial numbers could be observed between cuprizone groups. Each bar represents the mean ± SEM, n = 6 per time point and group.

Mentions: In the toxic cuprizone model of de- and remyelination, oligodendrocytes are damaged within few days of cuprizone feeding and a nearly complete loss occurs after 3–4 weeks of treatment17. Clearance of damaged myelin is conducted by microglial cells that are recruited towards areas of demyelination such as the corpus callosum and hippocampus91819. To demonstrate myelin loss, brain sections were immunohistochemically stained for the myelin protein proteolipid protein (PLP). As expected, after five weeks of cuprizone treatment a nearly complete demyelination of the corpus callosum (Fig. 2A) and hippocampus (data not shown) was visible. Withdrawal of cuprizone resulted in remyelination at week 6 as shown by the re-expression of the myelin protein PLP (Fig. 2A and data not shown). Demyelination was accompanied by high numbers of proliferating microglia (Iba1+/Ki67+) and total microglia numbers (Iba1+) in both regions (Fig. 2B,C). The amounts and dynamics of microgliosis have been reported to be different in both regions, which might be explained by the amount of myelin to be cleared181920. In the hippocampus, numbers of proliferating microglia (Iba1+/Ki67+) and total microglia numbers (Iba1+) peaked at week 3 followed by a subsequent decrease. In the corpus callosum, higher numbers of microglial cells were found and microgliosis increased up to week 4 with subsequent decrease (Fig. 2B,C).


The antiviral drug ganciclovir does not inhibit microglial proliferation and activation.

Skripuletz T, Salinas Tejedor L, Prajeeth CK, Hansmann F, Chhatbar C, Kucman V, Zhang N, Raddatz BB, Detje CN, Sühs KW, Pul R, Gudi V, Kalinke U, Baumgärtner W, Stangel M - Sci Rep (2015)

The effects of ganciclovir were investigated in the cuprizone model of de- and remyelination.After 5 weeks of cuprizone feeding, complete demyelination occurred as shown by the immunohistochemical staining for the myelin protein proteolipid protein (PLP) (A). One week after cuprizone withdrawal at week 6 remyelination was visible. Total microglia numbers were analyzed by Iba1 staining, while proliferating microglia were visualized by double staining for Iba1/Ki67 (B,C). No effects of ganciclovir on de- and remyelination and microglial numbers could be observed between cuprizone groups. Each bar represents the mean ± SEM, n = 6 per time point and group.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4597339&req=5

f2: The effects of ganciclovir were investigated in the cuprizone model of de- and remyelination.After 5 weeks of cuprizone feeding, complete demyelination occurred as shown by the immunohistochemical staining for the myelin protein proteolipid protein (PLP) (A). One week after cuprizone withdrawal at week 6 remyelination was visible. Total microglia numbers were analyzed by Iba1 staining, while proliferating microglia were visualized by double staining for Iba1/Ki67 (B,C). No effects of ganciclovir on de- and remyelination and microglial numbers could be observed between cuprizone groups. Each bar represents the mean ± SEM, n = 6 per time point and group.
Mentions: In the toxic cuprizone model of de- and remyelination, oligodendrocytes are damaged within few days of cuprizone feeding and a nearly complete loss occurs after 3–4 weeks of treatment17. Clearance of damaged myelin is conducted by microglial cells that are recruited towards areas of demyelination such as the corpus callosum and hippocampus91819. To demonstrate myelin loss, brain sections were immunohistochemically stained for the myelin protein proteolipid protein (PLP). As expected, after five weeks of cuprizone treatment a nearly complete demyelination of the corpus callosum (Fig. 2A) and hippocampus (data not shown) was visible. Withdrawal of cuprizone resulted in remyelination at week 6 as shown by the re-expression of the myelin protein PLP (Fig. 2A and data not shown). Demyelination was accompanied by high numbers of proliferating microglia (Iba1+/Ki67+) and total microglia numbers (Iba1+) in both regions (Fig. 2B,C). The amounts and dynamics of microgliosis have been reported to be different in both regions, which might be explained by the amount of myelin to be cleared181920. In the hippocampus, numbers of proliferating microglia (Iba1+/Ki67+) and total microglia numbers (Iba1+) peaked at week 3 followed by a subsequent decrease. In the corpus callosum, higher numbers of microglial cells were found and microgliosis increased up to week 4 with subsequent decrease (Fig. 2B,C).

Bottom Line: Ganciclovir is effective in the treatment of human infections with viruses of the Herpesviridae family.The objective of this study was to determine potential inhibitory effects of ganciclovir in three different murine animal models of CNS neuroinflammation in which microglia play an important role: Theiler´s murine encephalomyelitis, the cuprizone model of de- and remyelination, and the vesicular stomatitis virus encephalitis model.In conclusion, our results show that the antiviral drug ganciclovir does not inhibit microglial activation and proliferation in the murine CNS.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Hannover Medical School, Hannover, Germany.

ABSTRACT
Ganciclovir is effective in the treatment of human infections with viruses of the Herpesviridae family. Beside antiviral properties, recently ganciclovir was described to inhibit microglial proliferation and disease severity of experimental autoimmune encephalomyelitis, an inflammatory model of multiple sclerosis. Microglial activation and proliferation are main characteristics of neuroinflammatory CNS diseases and inhibition of microglial functions might be beneficial in autoimmune diseases, or detrimental in infectious diseases. The objective of this study was to determine potential inhibitory effects of ganciclovir in three different murine animal models of CNS neuroinflammation in which microglia play an important role: Theiler´s murine encephalomyelitis, the cuprizone model of de- and remyelination, and the vesicular stomatitis virus encephalitis model. In addition, in vitro experiments with microglial cultures were performed to test the hypothesis that ganciclovir inhibits microglial proliferation. In all three animal models, neither microglial proliferation or recruitment nor disease activity was changed by ganciclovir. In vitro experiments confirmed that microglial proliferation was not affected by ganciclovir. In conclusion, our results show that the antiviral drug ganciclovir does not inhibit microglial activation and proliferation in the murine CNS.

No MeSH data available.


Related in: MedlinePlus