Cobbers on the Brain

Why do I personally enjoy this topic? Maybe because of my unknown personal connection to it? Traumatic brain injury (TBI) is usually caused by a mechanical impact on the head. This injury is usually followed by symptoms such as slow cognition, migraines, dizziness, and weakness. Young children may be at higher risks of having a TBI due to their involvement in sports. But most research have pointed out that after prevention, recovery time might hold a big key in restoring the health of a TBI patient. Therefore, due to the high risk TBI poses to younger people, recent research has looked into understanding the impact of TBI on a molecular level. 

Figure 1. Picture showing events that follow occurence of a TBI in the brain. Symptoms usually emerge from these events.

Research has shown that on a molecular scale, mechanical impact on the brain can lead to events such as neuroinflammation and axonal dysfuntion. In simpler terms, inflammation is the body’s response to injuries whereby chemicals are released to the site of an injury. Neuroinflammation is when inflammation happens in the CNS: brain or spinal cord. More importantly, significant imaging techniques such as Diffusion Tensor Imaging (DTI) [2] and Fractional anisotropy (FA)  [3].

While FA  serves as a sclae to understand levels of damage to white matter and axons after a TBI, researchers and physicians are able to gain some understanding on treatment and precautions for different TBI cases. Other factors that affect symptoms after a TBI occurence include timing after the injury, age of the subjects, severity of injury, age of subjects, and region of the brain affected. These symptoms may also affect DTI results. [4] Below are what DTI imaging may look like and what information they present. 

Figure 2. Picture showing DTI scan results comparing a healthy brain to a brain after a head trauma.

Figure 3. Picture showing effects of mechanical impact on a brain cell following a TBI.

Another major symptom of TBI is neurocognitive impairment. More interestingly, many cognitive impairments resulting from TBI do not get diagnosed until brain scans of the patients brain after they have died. My closest experience to TBI was my involvement in an auto accident as a young child. My head was impacted, but I was told I was fine although no brain scans were done on my brain. 

After learning about this topic at such level, I definitely think I should get a long awaited brain scan, just to be safe! 

Figure 4. Artstract made by student showing some basic information and awareness on brain injury.

References:

Rauchman, S. H., Zubair, A., Jacob, B., Rauchman, D., Pinkhasov, A., Placantonakis, D. G., & Reiss, A. B. (2023, February 6). Traumatic brain injury: Mechanisms, manifestations, and visual sequelae. Frontiers. https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2023.1090672/full — first picture shwing symptoms of tbi

Picture 1: Glioblastoma pictured in the brain.

Glioblastoma (GBM) is an aggressive and invariable lethal form of cancerous brain tumor, and it’s among the types of cancer with the worst survival rates. This type of cancer is extremely invasive, and spreads rapidly to neighbouring structures as well as extending into healthy brain tissue[1]. There are two main types of GMB, which is primary and secondary. Primary GBM develop without evidence of any pre-existing symptoms or tumor, while secondary arises from a lower grade tumor. Additionally, there is various molecular subtypes of GBM, which are classical, mesenchymal, proneural and neural GBM[2].

The current standard treatment for GBM is surgery, radiotherapy, and a singular drug called temozolomide. The limited therapy is associated with GSM being relatively resistant to therapy, and due to the drug needing to cross the Blood Brain Barrier (BBB), additionally exhibiting robust radio-resistance[3].

Three cellular transduction pathways have been found to play a role for GBM, these are the MAPK, PI3K, and cAMP pathways:

Figure 1: The MAPK pathway, from the activation by ligands to its downstream effects[4].

The MAPK pathway was found to be frequently altered in GBM, and high levels of phosphorylated (or activated) MAPK being linked to poor survival among patients with GBM. Multiple components of this pathway is transformed in cancer leading to the hyperactivation[5].

Figure 2: The PI3K pathway, visualized from ligand binding to promoting various factors such as cell survival[6].

The PI3K regulator multiple cellular functions, and is frequently disturbed in cancer whereas components may be mutated or amplified. In GBM, mutations or amplicitations can be found of the EGFR, and activated in PIK3CA  which is the gene that encodes p110 within the PI3K pathway, and inactivating of PTEN (a tumor suppressor)[7].

Figure 3: The cAMP pathway, from ligand bind to downstream effects[8].

The cAMP pathway had been less prominent, but tend to be lower in tumor cells. However, it has been shown that the elevation of cAMP levels inhibit growth, increase differentiation as well as promote apoptosis in GBM cells[9].

With the limited amount of treatment currently offered for GBM, opens the discussion for ideas on new therapies or areas of target for treatment. Targeting the different signaling pathways shown to play a role in GBM can be beneficial for treating the tumors. A review from Cellular Signaling brought up a couple of possible treatments, in which are inhibitors and activators that have shown increased apoptosis in cancer cells lines. Some of the various ones that target the three signaling pathways, are a PI3K inhibitor called Buparlisib, a MAPK inhibitor, Vemurafenib, as for cAMP a AC activator called forskolin and a PDE inhibitor, isobutylmethylxanthine[10]. It has however been found that targeting individual pathways is not always that effective. This is because of pathway redundancy, and the ability tumors have to adjust their signaling to other pathways in order to maintain growth and their function. Therefore, targeting areas where the pathways coverage may be effective, which can be cAMP response element-binding protein (CREB). CREB is a transcription factor that crosstalk between these three signaling pathways. The transcription factor is important in a number of downstream functions, which include neurogenesis and cancer. CREB is important for normal brain development. It was found that in mouse brains the deletion of CREB lead to neurodegeneration during development[11].

So, how can CREB be used as treatment for GBM? There has evidence suggesting that CREB is important for regulating tumor initiation, its progression and metastasis, and based on this it has been demonstrated therapeutic potential in possible inhibitors of gene transcription mediated by CREB[12]. The current approaches are termed “CREB inhibitors” and “CREB-related pathways inhibitors”, which can be shown in Figure 4, separated by direct inhibitors in the nucleus, and pathway inhibitors outside of the nucleus[13].

Figure 4: An overview of the main intracellular pathways involved in CREB activation: the red arrows being possible pharmacological hubs for its inhibition[14].

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Bibliography

[1] Fung, N.H., Grima, C. A., Widodo, S. S., Kaye, A. H., Whitehead, C. A., Stylli, S. S., & Mantamadiotis, T. (2019) Understanding and expliting cell signalling covergence nodes and pathway cross-talk in malignangt brain cancer. Cellular signalling, 57,2-9. https://doi.org/10.1016/j.cellsig.2019.01.011

[2]  Ibid.

[3]  Ibid.

[4]  Ibid.

[5]  Ibid.

[6] Ibid.

[7] Ibid.

[8] Ibid.

[9] Ibid.

[10] Ibid.

[11] Ibid.

[12] Xiao, X., Li, B. X., Mitton, B., Ikeda, A., & Sakamoto, K. M. (2010). Targeting CREB for cancer therapy: friend or foe. Current cancer drug targets, 10(4), 384–391. https://doi.org/10.2174/156800910791208535

[13] Sapio, L., Salzillo, A., Ragone, A., Illiano, M., Spina, A., & Naviglio, S. (2020). Targeting CREB in Cancer Therapy: A Key Candidate or One of Many? An Update. Cancers, 12(11), 3166. https://doi.org/10.3390/cancers12113166

[14] Ibid.

At Concordia, a liberal arts approach to learning is emphasized greatly and it is expected to help all students be exceptional contributors to the community, becoming responsibly engaged in the world. But what does this mean? Having the opportunity to learn in various different perspectives and looking at the world through different lenses is something I did not expect to appreciate coming into my college experience. As I would assume many first-year students feel, I thought these exploration courses were a waste of time and I just did not understand what the benefit was of taking these courses. Looking back at my time at Concordia, I cherish the fact that I was able to view the world through a religious perspective, a philosophical perspective, a scientific perspective, an arts perspective, and many more. It opens up your views and makes you see things from all angles which is the key to being a contributing member of society or any discipline that one may spend their life working in.

A key skill you learn through a diverse education that liberal arts provides is thinking critically and thinking of all possible perspectives. This allows you to recognize the best way to go about anything, what the best solution is to the problem at hand. One cannot possibly think of all possible approaches without being put in the position to think about problems in a completely different way that what might come naturally. Being a psychology major, thinking about behaviors and the way someone was brought up is where my mind goes naturally, but neuroscience and other natural sciences force me to think about what could be happening in the brain or the body that is causing certain personalities or actions. Without a liberal arts education, I would probably not be exposed to these ways of approaching ideas and problem solving, and I think having this experience makes me a more intelligent and well-rounded individual.

Critical thinking skills are definitely something that I improved on greatly during my time in Neurochemistry this semester. Going into discussions every week at the start of the semester was very difficult for me because the chemistry and really scientific ways of thinking are not where my mind goes immediately when talking about different disorders. My mind wants to go to the nurture side of the nature vs nurture debate, thinking about what is their early life is causing this disorder. Although this is still the way I approach these problems first, I have come to consider other reasonings or mechanisms for what is going wrong in each case.

Having this liberal arts education and being pushed cognitively to think critically is going to help me be a better collaborative partner going forward into the world which I think is one of the most appreciated qualities for someone to have not only in the workforce but it any relationships in life. Being able to see all perspectives and being flexible in how you think makes you work better in a group and have empathy for all people that you may interact with. I am incredibly grateful for this opportunity for me to grow and I am ready to become responsibly engaged in the world.

Concussions or traumatic brain injuries (TBI) occur when the head experiences an impact that causes structural damage to brain tissue. Depending on the severity of the injury, this damage may or may not be visible in images of the brain. Despite this, microstructural damage to neural tissue can have significant metabolic and neurochemical effects. This damage can induce chronic cell death and neurodegeneration. Alterations in cellular function can impair neurotransmission, induce metabolic changes, and trigger ionic shifts [1]. Even though these effects can be serious, there is not a universally accepted treatment protocol that modulates these altered pathways.

What Happens After TBI?

Immediately following a brain injury which results in damage to neural cell membranes, an ionic flux and hyperacute glutamate release can be observed. When the trauma alters the outer membrane of neurons, potassium ions rush out of the cell and sodium and calcium ions rush into the cell, due to the natural ionic gradient between the intracellular and extracellular regions. This initiates a depolarization within the cell, which induces a state of spreading depression which can be a major contributor to acute post-concussive symptoms such as headaches, migraines, and seizures [1].

Similarly, injury to axons of neural cells can promote extreme glutamate releases. Since glutamate is a major excitatory neurotransmitter, this can cause significant alterations to neurotransmission. Increased glutamate levels following TBI are associated with changes in the NMDA glutamate receptor which can affect memory, neuroplasticity, and electrophysiology of the brain. Glutamate release may also be related to increased cytokine and inflammatory gene responses following TBI which is associated with oxidative stress and cellular injury [1].

Alterations in GABA, the major inhibitory neurotransmitter, and its receptors have also been observed in TBI models. This could be correlated to the increased susceptibility to anxiety and PTSD following a TBI. GABA transmission is known to produce anti-anxiolytic effects. For this reason, decreased levels of GABA and GAD67 (the enzyme that turns glutamate into GABA) in the amygdala following TBI may specifically contribute to the long-term increases in anxiety observed after brain injury [1].

Likely related to the ionic alterations following structural damage is the metabolic shift that is observed immediately and sustained for 7-10 days following TBI. Immediately following structural damage which induces ionic flux, the cells enter a period of hyperglycolysis in their attempt to return ionic gradients to resting levels. Following this initial increase in glucose metabolism that lasts less than 24 hours, the brain enters a period of impaired glucose metabolism. During this time, it is suggested increased fatty acid consumption could decrease some of the axonal damage that occurs after a concussion [1].

Ketones and Concussions

Fatty acid supplementation could be beneficial following TBI because ketones from the metabolism of fats can be used for fuel instead of glucose in the hypometabolic state. For this reason, it appears that direct ketone supplementation or a ketogenic diet may have more advantageous effects than fatty acid supplementation because ketone body levels are raised more effectively [6].

The ketogenic diet (KD) is a high fat, low carbohydrate diet originally used to treat epilepsy. This diet initiates a metabolic state of ketosis where ketone bodies are used for fuel instead of glucose. In a study investigating the potential benefits of a KD following TBI it was shown that compared to a standard diet, a KD produced more ketone bodies, reduced loss of neurons, reduced inflammation, and increased SIRT1 protein following SIRT1 loss due to injury. SIRT1 is a neuroprotective protein that is active in the hippocampus where it activates Akt and inhibits GSK [7].

 

Given the significant neurochemical and metabolic changes observed following TBI, as well as the vast and serious symptoms this can cause, it is concerning that there are not any highly effective medications or treatments to help heal the structural and metabolic damage that has occurred. The structural damage leads to ionic fluxes which alters brain metabolism, leading to a wide range of behavioral and physiological symptoms. In light of the current understanding of the neural ionic flux and its alterations to neurometabolism, ketone supplementation or a ketogenic diet may be a viable treatment option following a concussion.

References:

What is Glioblastoma?

Glioblastoma (GBM) is a type of cancer that forms in the brain or spinal cord. GBM forms from astrocytes that support nerve cells. [1]

Classical GBM

Characterized by amplification or mutation of the EGFR gene. This type typically responds better to aggressive treatment compared to other types. 

Mesenchymal GBM

Characterized by mutations of NF1 and PTEN, and mutations of P53 are also common. This type is also responsive to aggressive treatment. 

Proneural GBM

Characterized by amplification of chromosome 4q12 and high levels of the PDGFRA gene. IDH1 and TP53 mutations are also typically present in this type. People with this type tend to live longer compared to other types, but it does not respond well to aggressive treatment. 

Neural GBM

This type does not have any obvious patterns of mutations or amplifications and typically has the worst prognosis of all types. [2]

Signal Transduction Pathways in Relation to GBM

MAPK 

High levels of MAPK signaling are connected to GBM. What could contribute to this is that in the mesenchymal type, NF1 is mutated which typically negatively regulates MAPK signaling by inactivating Ras. Another factor could be that in the classical type, the EGFR gene is amplified which hyperactives MAPK. 

PI3K 

The PI3K signaling pathway is hyperactive in GBM cases. What could cause this is the mutation of PTEN in the mesenchymal type which typically suppresses PI3K signaling by dephosphorylating PIP3. The EGFR gene amplification typical in the classical type also hyper-activates PI3K signaling. 

cAMP 

It has been found that cAMP signaling is hypoactive in GBM cases as there are low levels of cAMP and adenylyl cyclase in GBM tumor samples. CREB is a transcription factor that is activated through the cAMP signaling pathway, so if cAMP signaling is suppressed, CREB is inhibited which is connected to tumor growth.

Convergence of pathways

MAPK and PI3K cross regulate each other in many ways. For one, they are both activated by the same receptors and both activated by Ras proteins. ERK, a MAPK pathway, can downregulate PI3K by phosphorylating GAB1 which then reduces the activation of PI3K. ERK can also inhibit PI3K by activating mTOR. PI3K can also downregulate the MAPK signaling pathway by inhibiting Raf through the action of AKT and its phosphorylation of Raf. All three pathways involved, MAPK, PI3K, and cAMP seem to have some link to CREB and its inability to perform correctly which results in the modulation of tumor growth. [2]

Current Treatments for Glioblastoma

Surgery

Surgery can remove some of the tumor but it often spreads to healthy tissue, so typically surgery is not fully effective. After surgery, patients tend to have other treatments done to get whatever is left. 

Radiation

Radiation therapy uses energy beams from X-rays or protons to kill cancer cells. Radiation is typically used in combination with chemotherapy. 

Chemotherapy

Chemotherapy uses drugs to kill cancer cells and can be taken as a pill or through a vein. 

Tumor treating fields (TTF) therapy

TTF uses an electrical field to keep cancer cells from multiplying. [1]

References

[1] Mayo Clinic. (March 7, 2024). Glioblastoma. https://www.mayoclinic.org/diseases-conditions/glioblastoma/cdc-20350148#:~:text=It%20can%20form%20in%20the,can%20happen%20at%20any%20age

[2] Fung, N. H., Grima, C. A., Widodo, S. S., Kaye, A. H., Whitehead, C. A., Stylli, S. S., & Mantamadiotis, T. (2019). Understanding and exploiting cell signalling convergence nodes and pathway cross-talk in malignant brain cancer. Cellular Signaling, 57, 2-9. https://doi.org/10.1016/j.cellsig.2019.01.011

[3] Kwatra, G. (2021, August 30). Glioblastoma: What Every Patient Needs to Know. Glioblastoma Foundation. https://glioblastomafoundation.org/news/glioblastoma-multiforme

[4] Li, X., Oziel, M., & Rubinsky, B. (2022). Evaluating the therapeutic effect of tumor treating fields (TTFields) by monitoring the impedance across TTFields electrode arrays. PeerJ, 10. https://doi.org/10.7717/peerj.12877