Minocycline and Brain Trauma 2

Welcome to another blog post!

Link to the First Blog Post about Minocycline: Minocycline 1

If you want to see the link to the article immediately: Direct Link to the Paper

Quote of the Post:

Let's Get Back to It

So, it’s time to learn about the results of the experiment.

The researchers tell us that there are 15 patients, and none of them have undergone neurosurgery. The results of the experiment were not affected by the different ways neurosurgery can be performed. Nice.

What's not so nice is that the patients showed cognitive impairment. The subjects of the trial had white matter reductions all over their brains compared to the controls. Controls are normal people, so they have no impairments. By measuring the brains of controls, it becomes apparent how the brains of traumatic brain injury patients have changed. Traumatic brain injury patients also had less grey matter in the “frontal and temporal cortex, hippocampus and subcortical structures.” My guess is that microglia have been wreaking havoc, destroying regions of the brain important for memory and cognitive function.

After 12 weeks and some complicated calculations, the researchers can say…that they think minocycline reduces chronic microglial activation. Let me explain how. So, the researcher used PET scanning to measure microglial activation. They used a chemical called C-PBR28 as a signaling molecule for a protein present in overactive microglia. The volume of distribution was measured to find out how the C-PBR28 distributed itself in the body of the patients. The volume of distribution tells us how widely a drug is distributed in the body. The volume of distribution for C-PBR28 fell for patients given minocycline, and what do you think happened to the patients who did not receive minocycline? Yes, you guessed correctly, their volume of distribution levels did not fall. So, it seems like minocycline results in more microglia activation in the body.

I wish they had some sort of explanation for why minocycline would only affect microglia. I feel like they should have measured other molecular markers to see what else happened to cells of the brain. I also have no idea how minocycline affected microglia that were not overactive in the brain (are there specific microglia for regions of the brain?).

Side effects of the minocycline? Mild vomiting and hearing loss.

Now we’ll take a look at the discussion.

Patients with traumatic brain injury and higher levels of chronic microglial activation also have more progressive neurodegeneration. However, minocycline, which reduced microglial activation, also increases the amount of neurodegeneration? I’m just as confused as you guys, let’s hope they clarify this later.

Microglial activation can repair brain tissue, but it can also lead to neurodegeneration. What circumstances lead to either repair or destruction are unknown.

The tracer that recognizes high microglia activation was also found in damaged white matter. Also, microglia may be attracted to the damaged parts of neurons stemming from the initial traumatic brain injury, resulting in a cycle in which microglia continue to destroy neurons and then more microglia come to clean up the mess.

In addition, the researchers argue that during the chronic phase of traumatic brain injury, microglia are reparative in the months after the initial injury, before taking on a role that involves a lot more destruction than repair. As microglia perform different functions at different times according to the stage of the traumatic brain injury, minocycline may have different effects if it is given to patients at an earlier stage. It seems clear that before this drug can be effective, we need to understand how microglia operate at different stages of the injury.

A quick question: What is released by the neuron when it faces the mechanical destruction caused by a traumatic brain injury. Do the chemicals released by the neuron activate microglia, and how does the neuron secrete different amounts of these chemicals depending on whether it can still be repaired, or it will undergo apoptosis (cell destruction)?

Anyway, the researchers decide that they believe that by stopping microglial activation after brain injury, neurodegeneration occurs. This feels very murky, but I feel like in another read this research will make more sense.

I need to learn more about the plasma neurofilament light chain (NFL). This is a marker of axonal injury, and higher levels of this substance are associated with ALS and Alzheimer’s. The researchers used this marker as evidence a brain region had high microglial activation.

Alright, let’s move on to some of the issues with this study. The biggest study in which minocycline was the drug of study showed “an adverse effect on the progression” of patients with ALS. So, take the results of this study with a grain of salt, as it clearly can’t be reproduced for other neural diseases involving inflammation.

They also based most of their results on the changes in plasma neurofilament light chain, so a study with more subjects and wider array of measurements of chemicals affecting brain neurodegeneration would be more beneficial.

In this paper, we learned a lot about how the plasma neurofilament light chain relates to brain damage, how microglia can either repair or destroy white matter tracts, and the effects of the drug minocycline. Of course, this is just scratching the surface of this field, but it was an interesting read nevertheless. Thanks for reading!

Links

• Direct Link to the Paper