Talk:Gancyclovir

Microglia

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Request for science help re: gancyclovir

I'm wondering if any more scientifically knowledgeable folks can help me with Gancyclovir. It's one of many pages that have no references at all and probably I'm best equipped just to tag them for cleanup, but since the entry only contains two claims, I thought I could track down refs to verify them. Ha ha. I found these studies which (if I understand them correctly) make opposing claims about its effect on microglial: "The antiviral drug ganciclovir does not inhibit microglial proliferation and activation" (2015) versus "Antiviral drug ganciclovir is a potent inhibitor of microglial proliferation and neuroinflammation" (2014). Is anyone available to help either revise the page (if I'm correct that maybe these are conflicting results that require qualification on the page) or confirm for me that the latter ref (or some other ref?) suffices to verify the entry's current claim that gancyclovir "also reduces microglial activation." Thanks much. Canele (talk) 17:45, 15 April 2019 (EDT)

Excellent question. I answer your question here. (Spoiler: it doesn’t reduce microglial activation after all.)

Pyrrhus (talk) 18:17, 15 April 2019 (EDT)

Oh, thank you so much Pyrrhus! Ok, I've updated both the gancyclovir and valgancyclovir. If you have a chance to look over and make sure I've presented it accurately, I'd be grateful! (Whew, glad we're fixing this! Def the kind of thing that argues for working hard to recruit and retain a lot more folks to comb the 2500+ pages for such issues...) Canele (talk) 20:57, 15 April 2019 (EDT)

Ah belatedly reading down the rest of that thread to see the follow-up STING paper from the first authors. I'm pretty well in over my head scientifically at this point. If you have guidance about if/how it should be incorporated, that'd be greatly appreciated but I don't want to assign you work (!); I can also just add it as a "Learn more" and eventually someone else can incorporate as far as explaining its implications. Canele (talk) 21:42, 15 April 2019 (EDT)

You covered the two papers very well in the two pages- succinctly, accurately, and objectively. I'll summarize the STING paper and then you can decide whether to include my summary in the page(s).

"The authors of the original 2014 paper published a follow-up paper which described in-vitro and in-vivo experiments where they observed evidence that ganciclovir, in sufficient doses, might stimulate a type-I interferon response in microglia. The authors attributed this response to a DNA-sensing protein called STING. Although this pro-inflammatory finding might appear to contradict the authors 2014 paper, the authors explain the contradiction by saying:

We show that GCV can exhibit dual function in microglia (Figure S10): in naïve state, GCV induces microglia to be “primed”; on the other hand, GCV reduces inflammation in active microglia.

"

Pyrrhus (talk) 00:07, 16 April 2019 (EDT)

Oh fab. For those of us with limited neuroscience background, can I take a stab at restating your explanation and you tell me if I understood it correctly?

The authors of the 2014 paper later published a follow-up paper (2017) based on in-vitro and in-vivo experiments using ganciclovir. This time they found a potentially pro-inflammatory response, specifically that ganciclovir, in sufficient doses, might stimulate a type-I interferon response in microglia. The authors attributed this response to a DNA-sensing protein called STING. While this result might appear to contradict their earlier anti-neuroinflammatory finding, they suggest it could indicate ganciclovir (GCV) "can exhibit dual function in microglia [...]: in naïve state, GCV induces microglia to be 'primed'; on the other hand, GCV reduces inflammation in active microglia."

If my lay-ified paraphrase gets it wrong tho, I say let's use yours; it does seem like a finding worth flagging for researchers even if some less scientifically literate readers (ha, yours truly) may not get it (although also you're definitely better qualified than I to judge whether the study rates mention. So whatever you think is best.) Canele (talk) 20:01, 16 April 2019 (EDT)

I‘ve made a few small changes to your text. Mainly, we have to be careful about our phrasing because there is currently a vicious fight over the very definition of “inflammation”. The old-timers stick stubbornly to the ancient greco-roman definition of inflammation, which does not recognize either the interferon response or neuroinflammation to have anything to do with what they consider to be “real” inflammation. Additionally, this is a hard paper to summarize because the authors themselves seem confused about their findings. Since you ask for my opinion, I don’t think their paper introduces anything new since their findings are perfectly consistent with the known toxicity of ganciclovir at high doses. But, in the interest of completeness, let’s include it. Hope this helps.

Pyrrhus (talk) 21:15, 16 April 2019 (EDT)

Ah thank you so much for your edits and your explanation Pyrrhus. This sounds like a good solution to me: the lay reader will def get the key take away that no, there's not firm evidence for this effect as the initial study suggested; and any scientist readers who want to get in the weeds will learn this study exists and they can go delve into its particulars if they wish. Cool! Thanks! Successful first use of the editor help desk! Canele (talk) 22:07, 16 April 2019 (EDT)

microglia A type of immune cell, called a macrophage, that lives in the brain. For historical reasons, macrophages have different names based on the part of the body that they normally live in. Macrophages that normally live in the blood are called monocytes. Macrophages that normally live in the skin are called Langerhans cells. Macrophages that normally live in the liver are called Kupffer cells. And macrophages that normally live in the central nervous system are called microglia. Microglia were originally classified as glial cells, under the assumption that the cells had a merely structural function, before it was realized that the cells were in fact immune cells. As the "sentinel cells" of the central nervous system, microglia survey their environment for abnormalities such as infection or tissue damage, and then initiate an immune response to fight the infection or repair the tissue damage.

microglia A type of immune cell, called a macrophage, that lives in the brain. For historical reasons, macrophages have different names based on the part of the body that they normally live in. Macrophages that normally live in the blood are called monocytes. Macrophages that normally live in the skin are called Langerhans cells. Macrophages that normally live in the liver are called Kupffer cells. And macrophages that normally live in the central nervous system are called microglia. Microglia were originally classified as glial cells, under the assumption that the cells had a merely structural function, before it was realized that the cells were in fact immune cells. As the "sentinel cells" of the central nervous system, microglia survey their environment for abnormalities such as infection or tissue damage, and then initiate an immune response to fight the infection or repair the tissue damage.

microglia A type of immune cell, called a macrophage, that lives in the brain. For historical reasons, macrophages have different names based on the part of the body that they normally live in. Macrophages that normally live in the blood are called monocytes. Macrophages that normally live in the skin are called Langerhans cells. Macrophages that normally live in the liver are called Kupffer cells. And macrophages that normally live in the central nervous system are called microglia. Microglia were originally classified as glial cells, under the assumption that the cells had a merely structural function, before it was realized that the cells were in fact immune cells. As the "sentinel cells" of the central nervous system, microglia survey their environment for abnormalities such as infection or tissue damage, and then initiate an immune response to fight the infection or repair the tissue damage.