Cobbers on the Brain

Most everyone has heard of Alzheimer’s Disease, far too often because of personal experience with loved ones. Although everyone associates the disease with someone losing their memory (and rightfully so), a physiological hallmark of Alzheimers is insulin resistance, which is thought of as the state of not having enough insulin, for one reason or another. 

Insulin is most commonly known for its role in regulating metabolism. Insulin however, does a whole host of other helpful things for our bodies, including the regulation of synaptic plasticity, being neuroprotective, acting on neuronal growth and survival, and has been proposed to regulate the gene expression required for the ability to consolidate long term memories. All of this alludes to the fact that if we don’t have enough insulin, as seen in Alzheimers, we have a problem. 

What can we do?

Insulin resistance has been observed to occur due to an inhibited insulin signalling pathway and an overactive pathway that leads that resistance called mTOR1 (mammalian target of rapamycin). However, with a drug called Rapamycin, mTOR can be inhibited and insulin resistance is abolished. Now, this doesn’t solve Alzheimers, but it’s certainly a step in the right direction for treatment if nothing else. 

Some researchers however are suggesting that rapamycin has additional beneficial effects than simply increasing insulin (although this still might be the mechanism, the benefits are broader than simply treating Alzheimers). One of the positive effects of rapamycin that was found was that, when intermittently administered, rapamycin led to stem cell regeneration. Considering some of the applications for stem cells, this is an amazing discovery that could have far reaching implications on the future of medicine. And that’s potentially just the tip of the iceberg. Because of the mTOR1 inhibition through rapamycin, it has been found that there is a decreased risk of cancer, since mTOR1 signaling can lead to cell proliferation. Tumor regression has also been observed to occur. It’s also been found that mTOR1 signalling sometimes leads to misfolded proteins. Using rapamycin, inhibiting mTOR1 led to greater autophagy and suppression of protein synthesis, which is important because this means that rapamycin can have neuroprotective effects in not just Alzheimers, but also Parkinson’s Disease and Huntington’s Disease. 

One of the most interesting positive effects found from administration of rapamycin was its ability to increase the lifespan of rats that were treated with the drug. It does this through slowing down the aging process along with inhibiting metabolic or neoplastic diseases. This also potentially includes cancer, as regulating cell proliferation through the drug means that cancer cells can’t spread as rapidly, and cancer cells may also happen less in the first place. 

Before we all start taking insulin, it’s important to remember however that one of the most consequential aspects of a drug’s effects and effectiveness is the dosage and how often its administration. With rapamycin, the appropriate ratios of both of these factors are still unknown as of yet, but research is being done to try decipher further how to access the perceived positive effects of the drug. It has been seen though that rapamycin doesn’t fully inhibit mTORC1 processes, and so a combination with another treatment would more effectively implement the positive effects of Rapamycin.

This being said, there are observed downsides, which shouldn’t ever be overlooked within any kind of drug treatment. Rapamycin has been sometimes seen to actually increase insulin resistance, but the mechanism for why this occurs is speculated to be known (inhibition of mTOR2). Other negative effects included increased hyperglycemia within type 2 diabetes mouse models, and the ability for tumors to start regrowing after treatment with rapamycin stopped.

To end on a positive note about rapamycin treatment, there are no known overdose deaths due, which could signify that the ability for researchers to manipulate administered dosage levels could be rather high. All in all, more research into the side-effects and anti-aging effects of rapamycin are needed, but some people even now think that rapamycin can be used as an effective anti-aging (or at least an anti-disease) drug with very few discovered side-effects. 

The snap-crunch of football pads & helmets colliding pulled my attention up from wrapping yet another blanket around myself as I watched my younger brother’s third high school football game of the COVID-modified season while sitting in cold, snow-covered, and socially distanced bleachers with about 30 other player family members. It was 19 degrees Fahrenheit. I was sitting on an inflatable camping sleeping pad with my mom as 22 high school students ran around the field in front of us, each student using the exercise as a somewhat futile attempt to stay warm while endeavoring valiantly to score more points than the other team. Yet, as these athletes gave all of their attention to the game, my mind as a scientist and concerned sibling was drawn to one of the physical perils of competitive varsity football: concussions. As my brother is the star first-string outside linebacker and running back of his team, he ends up involved in tackles on either the receiving or performing side of things on nearly every play.

Concussions are an insidiously common type of mild traumatic brain injury (mTBI) that occurs when the brain rapidly moves within the skull as the head is subjected to rapid acceleration and deceleration. For example – during a football tackle. While advances in protective technology for athletes helps reduce risk, the risk is never zero. This injury can result in both immediate symptoms – pain, ‘seeing stars,’ confusion, headaches – and symptoms lasting weeks – headaches, confusion, and inability to focus. This begs the question, what is happening on a fundamental biochemical level to cause these symptoms?

Inside the brain

Once the initial impact causing the concussion occurs, a cascade of events altering the chemical balance in the brain takes place. First, instead of the typical highly regulated signaling expected in a normal functioning brain, nonspecific depolarization and initiation of axon potentials occur. This causes the release of excitatory neurotransmitters to be widely released throughout the brain at a scale not seen under normal circumstances. This leads to the efflux of potassium ions from the brain and severe ion imbalance, leading to extremely high activity of ATPase, an enzyme responsible for maintaining ion balance in neurons. Since ATPase is powered by ATP, the brain enters an energy crisis trying to restore the ion balance and burns through stored glucose reserves to meet the need. When glucose runs out, the brain switches to other sources of energy which causes lactate to accumulate in the brain. At the same time, the physical injury to neurons results in Calcium entry into the cells. While the ATPase will help rebalance the Calcium entry eventually, in the short-term Calcium entry results in sequestration in the mitochondria. This Calcium imbalance both impairs the mitochondria’s ability to be the “powerhouse of the cell” by interfering with ATP production, further contributing to the brain’s energy crisis, but too much Calcium activates calpain proteins which then initiate apoptosis, or programmed cell death, which results in the dying back of neurons in concussed areas.

Additionally, scientists are building on this understanding of what happens in concussion by looking at what small chemical messengers that modulate inflammatory responses called cytokines do to change inflammation states in response to injury. After the injury, glial cells called microglia and astrocytes become activated and produce Glial Fibrillary Acidic Protein (GFAP, a biomarker of brain injury) and both pro- and anti-inflammatory cytokines. Due to the existence of both pro- and anti-inflammatory cytokines, teasing apart the differences in how these factors change inflammatory responses is pretty challenging. Interleukin 1 beta (IL-1b) offers an excellent case study in the challenges and opportunities presented by cytokine study.

IL-1b expression patterns after injury show a gradual rise in expression levels, with expression levels directly correlating with the severity of the injury. Interestingly, IL-1b causes the release of ciliary neurotrophic factor (CTNF) and nerve growth factor (NGF), two hormones associated with recovery from concussion. However, IL-1b also stimulates the release of high levels of other inflammation-causing cytokines such as tumor necrosis factor-alpha (TNF-a), which results in toxic inflammation. Therefore, some suggest that interrupting IL-1b after it stimulates growth factor release but before it can stimulate pro-inflammatory cascades may be an effective therapeutic target. Cytokines are incredibly important in regulating neuroinflammation and have both anti- and pro-inflammatory properties, therefore, parsing apart the exact cytokines associated with triggering hyperinflammatory cascades and interrupting their signaling cascades could serve as a therapeutic target in the treatment of concussion.

Clearly, a pharmacologic intervention for concussion treatment is still years away from becoming a reality for athletes. Currently, the best ‘treatment’ for concussions is prevention through educating players, coaches, and parents of all sports on methods that minimize risks of getting a concussion such as proper tackling and running technique, as expertly demonstrated by my brother in his game. While my brother’s team narrowly lost on Friday night, no player got a concussion. So, while not as immediately satisfying as a win, I take solace in the knowledge that through coaching and mentorship, everyone walked away safely.

Concussion is typically thought of as simply a hindrance to doing “normal” stuff, whether that be schoolwork, or getting back out onto the field, as most concussions happen through athletic means. But are the ramifications of a concussion just to feel a little dizzy and disoriented for a bit? Research into postcussed individuals suggests otherwise, as post concussion depression has been found to be a prevalent after-effect. 

When people generally think of concussion, their first thought is typically not in relation to other mental disorders such as depression, but it should be. One study found that at least 35% of individuals that experience a traumatic brain injury (TBI) develop depression. This means that at least a third of people who get a concussion develop depressive symptoms afterward, which is quite a dramatic number. Another fact that was found is equally concerning: one study found that after only a mild traumatic brain injury, there was a 15% chance that the person developed major depression. This is the lightest and least serious type of brain injury (which you can get simply by hitting your head slightly too hard) and the worst, most serious type of depression, occurring in more than 1 in 7 people who experience a concussion. This is significant not only because of the depression part, but because this points to concussion as being more than purely “an annoyance”. In fact, the total prevalence across all severities of TBIs for major depression is 14-29%. In other words, up to a third of people who experience a concussion develop the clinically-worst type of depression. 

This prevalence for depression isn’t universal however, there are certain people who develop more depressive symptoms than others post-concussion. Some risk factors are: being an older age when starting your first sport, having a history of substance abuse, and lower levels of education. Something that was found is that the severity of the TBI didn’t consistently lead to higher rates of depression, but losing consciousness was related to risk for developing major depression among mTBI patients. Some more demographic information reveals that ethnicities other than white experience greater post-concussion symptoms, and IQ has a negative correlation with such symptoms as well. These results are more speculative as to why they would be the case, but this highlights the need for greater concussion protocol and faculty in lower-socioeconomic areas, which unfortunately, by definition, have less access to such resources. 

Figuring out why these results are the case has the ability to help numerous concussion victims recover with more vigor and not have to deal with bouts of depression while trying to recover. Neurologically speaking, one culprit could be the “differential patterns of calcium flux” that can occur postconcussion, which could be leading to less brain-derived neurotrophic factor (BDNF), leading to depression. BDNF is essential for cell proliferation and so without adequate amounts of it, cell levels and signalling may be messed up enough to contribute to startling equilibrium and causing depressive symptoms. The article also states that BDNF is directly associated with NMDA receptor alteration, which concussion causes as well. Another factor that would seemingly lead to higher depressive symptoms post-concussion would be increased GABA levels and signalling, as that has been found to increase related to depression. This however, is not the case with concussion, as GABA levels have been observed to fall in post-concussed individuals. 

With the rates of depressive symptoms among concussed individuals being more than 1 in 3 people, more research should be done to figure out some of the mechanisms for bringing this number down. Preventing concussions in the first place would be the best option, but preventing post-concussion depression is also an important step in making things better for everyone who experiences this sort of thing, especially athletes. To loop back to my normal point, concussion is more than just an annoyance to be blown off as a headache, and more guidance should be brought into schools of all levels and education on the subject should continue so that everybody involved understands how to respond and properly help the individual heal.