The endocannabinoid system is one of the few pathways in the nervous system which send messages backwards. This uncommon occurrence always for the endogenous cannabinoids to regulate messages sent through the nervous system. This is important because if there is an overproduction of neurotransmitters the endocannabinoid system kicks in to suppress the overproduction of the neurotransmitters. Over productions of neurotransmitters cause a number of conditions like Parkinson. Such conditions involve uncontrollable shaking and motor lose. Studies show that these symptoms can be suppressed by the addition of cannabinoids. One of the most successful, but controversial methods of getting these compounds is by the use of medical marijuana. Although studies have shown marijuana has medical applications it is still classified as a schedule one controlled substance. With this classification it is illegal to carry it over state lines and has no medical benefits. These laws remain in place due to social stigmatisms and political/economic blockades. This doesn’t mean debate isn’t needed on the subject but the facts cannot be continuously over looked just because stigmas and blockades of the past continue to surface. For or against the subject, ignoring the facts would be a mistake, one in which could change people’s lives.
How is Type 2 Diabetes Affecting Your Ability to Learn and Form New Memories?
This week, our class discussed the detrimental effects of insulin resistance as seen in Type 2 diabetes mellitus. It has been established that Type 2 diabetes can be seen as a cofactor in the development of Alzheimer’s disease (AD). The defining characteristic of Type 2 diabetes is the body’s resistance to the effects of insulin. This differs from Type 1 diabetes mellitus in which insulin is simply not being produced, but can metabolized injected insulin without a problem. Insulin resistance makes it difficult for the body to perform insulin-mediated functions such as metabolism and regulation of other cellular processes. Like many people, I was unaware insulin played such a huge part in the brain. Recently, it has been established that insulin is involved in neuronal metabolism, cell survival, longevity, and learning and memory. This connection to learning and memory has led to research to determine insulin’s role in Alzheimer’s disease. The specific death of the cells in the brain’s memory center, called the hippocampus, leads to forgetfulness and inhibition of memory formation seen in Alzheimer’s disease. Insulin resistance facilitates this cell death through loss of intracellular transport of important nutrients, wastes, and other molecules.
The toxic β-amyloid plaques, typically seen in Alzheimer’s disease, can further decrease insulin activity by binding to insulin receptors. Neuronal insulin resistance contributes to the formation of these plaques as the enzyme that degrades both insulin and β-amyloid must work to degrade increased levels of both insulin resistance prevents the normal use and breakdown of insulin. This means that the same amount of enzyme would be responsible for the breakdown of an increasing amount of target molecules, which it is not intended to do.
So what does this mean for the population at large? Well, Type 2 diabetes can be caused by genetics, but also by poor diet (which causes obesity). With the obesity epidemic as of late, it is generally expected that frequency of Alzheimer’s disease will skyrocket in the coming years. As a society, the need for a quick fix has propagated and exacerbated the consumption of fast foods. This worsening in diet, along with people becoming more sedentary, has led to increasing obesity and also increased frequency of Type 2 diabetes. We should be concerned with this increased risk, per the previous discussion. It is difficult and expensive to maintain a healthy diet, but do a couple hours per day to make healthy food and exercise outweigh years of cognitive decline that will impact your family and your own quality of life? We, as a society, must change so as to be more conscious of our current health because it dictates our condition in the future. Stop spending so much on unnecessary things like multiple big televisions, movies you don’t need, or the up-and-coming Xbox One. Use your resources to enable your own well being as well as those for whom you are responsible. The benefits of a healthier lifestyle are plentiful and include more energy, more efficient cognition, and increased immune system function. The costs of not doing so are equally abundant and just as dire.
Akt/GSK3 Cascade: how important is it?
While reading the article “Beyond cAMP: the regulation of Akt and GSK3 by dopamine receptor” I thought to myself what on earth does all this technical jargon mean? as this article goes into explicit detail about how the Akt/GSK3 signalling cascade works, what it is intended for, and how understanding this pathway could lead to future pharmacological advances in dopamine-related disorders. The way the article was written made it very difficult for me to digest. By the end of the school week however, I could clearly grasp most of these concepts and most importantly why it was a relevant topic to be discussing.
Akt/GSK3 Pathway Break Down:
1. Initiating the cascade: Dopamine binds to a D2 receptor.
2. β-arrestin, Akt, and PP2A form a complex.
3. PP2A protein dephosphorylates, removing a phosphate group from Akt.
4. This causes Akt to be inhibited meaning Akt cannot phosphorylate GSK3. (When it is phosphorylated it is inhibited)
5. When GSK3 is not phosphorylated it means it will stay activated causing many other cellular responses in the brain.
Who cares about this pathway right?
Wrong! If you are unaware of how important this cascade is in our everyday lives, then you should probably start with the idea that this pathway is necessary for proper human functioning. If this cascade is “out of wack”, it can cause many neurological problems. It has a huge role in the actions of antidepressants, psychostimulants, and antipsychotics. Not only that, but it is involved in the psychopathology of schizophrenia, Parkinson’s disease, and bipolar disorder. Yikes! did you know all of that? I had no idea before reading and discussing this article. Scientists are doing many studies to grasp a better understanding of how this pathway works in hopes that we can find new strategies for the treatment of neurodegenerative disorders as well as finding treatments and cures for many other neurological diseases.
While I do not understand most of the technical jargon associated with the Akt/GSK3 pathway and the dopamine signalling, I do know now that it is extremely important for this pathway to be properly regulated. I also discovered that this is a sort of “hot topic” in the field of neurochemistry. Scientists are making huge discoveries on the role Akt/GSK3 signaling has in dopamine receptor functions and behavior as well as developing new theories as to how this pathway could one day be used to prevent-or at least treat- different neurological diseases. I personally did not know that this pathway was so important. It makes me think about the fact that tiny little molecules and cells in our brain can cause the biggest of problems with our cognition, development, movement, behavior, etc. It literally blows my mind! If one thing within this cascade gets disrupted (intentionally or accidentally) a number of things can happen within the brain, thus affecting the body. For example a person who has decreased dopamine activity in their brain could be at risk for ADHD, Parkinson’s disease, and depression. Is that not crazy how one neurotransmitter can a effect a person in such dramatic ways? This is why the research in this field is so crucial!
A Whole New Type of Diabetes
This week we discussed a topic that was completely new to me, Type III diabetes. According to “Possible implications of insulin resistance and glucose metabolism in Alzheimer’s disease pathogenesis,” Type 2 diabetes (T2D) is a significant risk factor for developing Alzheimer’s disease (AD). One of the key features of T2D is resistance to insulin-either the insulin receptors in the body do not respond to the insulin produced by the pancreas or there isn’t enough insulin produced. Insulin is an important regulatory molecule because it controls how much glucose enters the cells of the body and remains the blood. Glucose is an important energy source that cells use to create new molecules, transport molecules in and out of the cell, and store energy. Patients with Type 2 diabetes do not use insulin appropriately to reduce the blood sugar levels, which leads to hyperglycemia.
Hyperglycemia and insulin resistance are problematic body wide but particularly in the brain. Hyperglycemia causes the body to use more insulin, which leaves less insulin available for use in the brain. Insulin plays several important roles in the brain. First, low levels of insulin leads to increased brain glucose metabolism. Increased brain glucose metabolism changes the process of memory and cognition. Lack of insulin decreases the release of the signaling chemicals in the brain, neurotransmitters, which are responsible for cognition and memory. Amnesia can result from decreased neurotransmitter release. Also, insulin resistance has been found to down-regulate b-amyloid-derived-diffusible ligands (ADDL) binding sites in the brain. This causes the brain to hyperphosphorylate Tau proteins. This is a fancy way of saying that the brain activates proteins that are the hallmark of Alzheimer’s disease. Once the Tau proteins are phosphorylated and begin to accumulate as neurofibrillary tangles, the brain struggles to break down the proteins and get rid of them. Tau protein phosphorylation leads to oxidative stress. Oxidative stress is hard on neurons and causes neurons to stop communicating with each other. Eventually, the neurons die and contribute to the pathogenesis of Alzheimer’s disease. Theses are only a few of the effects that insulin may have in the brain. Insulin controls inflammatory responses in the brain as well. This is another reason that insulin is thought to contribute to the development of AD disease.
According to the Center for Disease Control and Prevention, as many as 1 in 3 U.S. adults could have T2D by 2050 if steps are not taken to reduce risk factors for this disease. This is an increase from the current estimation of 1 in 10 U.S. adults living with diabetes. These statistics do not reflect the increasing number of children that are developing type 2 diabetes, as a result of the increase of childhood obesity. Similarly, the Alzheimer’s association predicts that the prevalence of AD will triple to 13.8 people by 2050. With prevalence of both diseases on the rise, this should be a call for action. It should also give people hope that there is a realistic means to reduce an individual’s risk of developing AD. By eating healthy, exercising regularly, maintain proper sleep habits and other healthy lifestyle changes, an individual can significantly reduce their risk of T2D and AD. It is important to spread the word because choices made now can affect a person today and tomorrow. Living right is only half the fight!
Akt/GSK3 Protein signaling: The Other White Meat
If I’ve learned anything while at Concordia, it’s that there’s always something else I can learn. This week in neurochemistry only helped to make this more evident. After the first read-through of the article “Beyond cAMP: the regulation of Akt and GSK3 by dopamine receptors,” it really felt like I haven’t learned anything. However, after hashing it all out in class, we were able to piece together a very promising and intriguing protein signaling cascade. So why should we care about this pathway? Whether we realize it or not, every process that occurs in our body is ultimately the result of chemical reactions. When these reactions start to go wrong and processes start to fail we wind up in a pathological state.
So how does this all relate to Akt, GSK3, and dopamine? Dopamine is a chemical that acts within the brain and the rest of the body. Referred to as a neurotransmitter, dopamine is used to send signals between neurons. Dopamine is able to signal the occurrence of events in the body by binding to one of five dopamine receptors. When dopamine binds to the D2 receptor a signaling event involving Akt and GSK3 is initiated. Here’s how it works: dopamine binds the D2 receptor, a complex of β-arrestin, Akt and PP2A is formed, PP2A takes a phosphate group off of Akt (causing its inhibition), and GSK3 is activated. If you’re confused, that’s okay. Basically all you need to remember is that the binding of dopamine to D2 receptors causes the activation of GSK3.
Right about now, you’re probably thinking “Cool, and I care why?” Researchers have been studying this pathway, specifically GSK3 and the molecules it acts on after it is activated. It is now believed that a variety of disorders are associated with the Akt/GSK3 pathway. These conditions include: depression, schizophrenia, bipolar disorder, Parkinson’s Disease, and addiction. In addition, various cell processes are now believed to be implicated with this pathway. Studying pathways such as the Akt/GSK3 pathway offers a way to learn more about these conditions. In addition, a better understanding of the mechanism by which these pathologies present could bring to light novel treatments.
This pathway exemplifies the idea that there is always something else to learn. Although researchers have been studying these conditions for some time, they are just now beginning to discover a mechanism by which they MIGHT work. From a scientist’s perspective, the most exciting thing about this is not what they’ve already discovered about the Akt/GSK3, but the fact that it is just scratching the surface. There is undoubtedly a variety of targets that are downstream from the GSK3 protein that are involved in countless mechanisms. Even more, this is just one pathway; the body is filled with signaling pathways that make you function! While the discovery of the Akt/GSK3 pathway and its targets is exciting, it’s even more exciting to think of where it may take us.
I thought that was illegal….
When many people hear the acronym THC, they think of the illegal (in most places) drug marijuana. But the article Endogenous cannabinoids revisited: A biochemistry perspective sheds light on how this psychoactive chemical has led to research into naturally occurring cannabinoids in the human body and how their regulation can be beneficial. The system of receptors in the human brain that responds to THC and other cannabinoids is the endocannabinoid system. This system was discovered after researchers took a look at the way in which THC worked in the brain. As a result, many molecules were made to resemble THC and were used to help understand its psychotropic properties.
What I personally find most interesting from this article is the fact that researchers found a system of receptors, occurring naturally, in the brain that works by binding molecules very similar to THC. It makes one think, if there is a natural purpose for molecules similar to THC, is THC really all that bad for a human? The article goes on to describe pathways and signaling of two molecules very similar in structure to THC, AEA and 2-AG. These two molecules are present in human brains and are used for pain relief, motor control, stimulation of appetite, and inhibition of cell growth. The article goes on to talk about similarities between both the structures and effects of these naturally occurring compounds, AEA and 2-AG, and THC, the dangerous, illegal active ingredient in marijuana.
When looking at how similar these substances are, it wouldn’t be extraordinary to question why marijuana is not used more frequently for medical purposes. Since it shares many characteristics of naturally occurring molecules, the side effects of THC and marijuana on the body seem minimal when compared to other prescription drugs. Many drugs prescribed on a daily basis come with a long list of cautions warning people about possible negative side effects, but the review article we read for the week explained how there seem to be few consequences of consuming marijuana for pain relief or to help regulate appetite.
People opposed to the use of medical marijuana may combat the argument of its therapeutic effects with its addictive nature. The informed person knows that many prescription medications have a high risk of causing addiction. Many people become addicted to sleep aids and pain killers that were legitimately prescribed to them to deal with some sort of condition. But yet there is much less of a stigma of proper use of these drugs than there is for legitimate use of marijuana for medical purposes. It seems to me that by the general public insisting that marijuana is not suitable for actual medical use, we are missing out on a potent source of natural pain alleviation.
In my opinion, with all of the information this paper was able to provide about the naturally occurring endocannabiniod family of receptors, it would be more useful to figure out a way in which we can harvest the rich medicinal use of THC from marijuana (or other forms of THC) in a responsible manner. Worrying about the minimal side effects and possibility of addiction seem to be clouding the vision of many people who could be working towards more safe, natural drugs that can do the same things synthetic ones can do. So yes, you are correct in thinking marijuana is illegal in many of the states in the US, but according to the research presented in this week’s article, it would also be correct and easy to ask why it isn’t used more in modern medicine.
A New Look at Medical Marijuana
Last week, we tackled the topic of the endocannabinoid (EC) system and the implications of marijuana for medicinal purposes. Often only the recreational uses are acknowledged. However, the article “Endogenous cannabinoids revisited: A biochemistry perspective” describes the signal transduction pathways of ECs and physiological effects.
Researchers first realized that ECs existed when they discovered that Δ9-tetrahydrocannabinol (THC), the main psychoactive ingredient in cannabis, was able to bind to two types of receptors. CB1 receptors are found in the brain, immune system, vessel walls, intestine, liver, peripheral nervous system, and reproductive tissues and CB2 receptors are found in the immune system. This led the researchers to believe that there were molecules in the body that were structurally similar to THC. Further research showed that there are two main endocannabinoids produced in the body: anandamide or arachidonoylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG). AEA and 2-AG influence analgesia, motor response, inflammatory response, feeding behavior and other biological processes. More recently, it has been discovered that endocannabinoids have an effect on cell survival signaling. Cannabinoid signaling may induce apoptosis (cell death) through a number of pathways. This may prove useful in therapeutic treatments because it has been shown to be linked with anti-inflammatory, anti-proliferative and cytoprotective effects.
Now how does this all relate to medicinal marijuana use? Well, THC is similar in structure to 2-AG and AEA so it has may similar effects to these molecules. One of the main reasons that medical marijuana is used is to treat chronic pain in diseases such as cancer, diabetes, spinal cord injuries, and multiple sclerosis (MS). THC has also been shown to affect feeding behavior. Cannabis is being used to treat nausea associated with chemotherapy and increase food consumption in anorexic patients. CB1 and CB2 receptors are found in the immune system, which has led to the use of cannabinoids to treat MS, rheumatoid arthritis and inflammatory bowel disease. Researchers are looking into the molecule known as cannabidiol, another molecule in cannabis, because it has been shown to produce fewer psychoactive effects.
With new knowledge comes the responsibility to use it ethically. How should society approach the use of medical marijuana? Should it be legalized or should we approach the use of medical marijuana with caution? It is important to keep in mind that currently marijuana is considered by Drug Enforcement Administration (DEA) to be a Schedule I drug. According to this classification, schedule I drugs have no medical uses and a high potential for abuse. Research showing that cannabinoids are effective in treating symptoms associated with autoimmune diseases, neurodegenerative disorders, chronic pain, and cancer may be a reason to reconsider the current classification. Also, cost versus benefit must be weighed when considering therapy options. Many of the current medications used to treat diseases have harsh side effects. Much of the current research points to the positive effects of cannabinoids and few negative side effects. Further research will need to be done to fully understand the effects of cannabis. With proper regulation, it appears that medical marijuana may provide beneficial effects in a number of diseases.
What's Not to Love?
The article this week revolved around a topic that has been debated in many political and medicinal, as well as ethical, discussions. After reading and discussing this article, and doing some questionable Google searches, my understanding of cannabinoids and the pathways affected by them has increased drastically. Learning the basics of what becomes influenced was interesting, but what really captivated my attention was the side-effects cannabinoids produced, or rather lack thereof. Of course there are precautions that need to be taken when putting anything into our body. However, it amazes me the amount of stuff we can put into our bodies that are considered “medicine,” yet they have so many awful side-effects. It blows my mind that addictive pain killers are prescribed on the daily, but this natural pain killer is illegal almost everywhere in the United States. It’s fascinating how many medicines have been rushed to the market with only the minimal amount of research done for it to become a drug, but cannabinoid is still illegal despite all of the studies done inside, and outside, the lab where it has been proved to be beneficial to people’s ailments.
I’m not advocating for everyone to go and get baked on the daily, but I don’t see the problem with people being able to access a natural therapy for pain, eating disorders, etc. We have become a society that is obsessed with “fixing” everything, and if we have found a fix for all sorts of psychological problems, why not implement it? It’s not uncommon to have cabinets full of bottles we barely know what they do to our brain, yet this drug we know the pathway for and a lot of its positive side-effects for shouldn’t be among them. There must be a believable argument for why cannabinoids should not be allowed for medicinal uses, but I have yet to find it.
What Are We Really Affecting?
After a week of asking questions and asking the same questions again, the mystery of what the Akt/GSK3 pathways does for us has become a little clearer. Despite all of the questions I cannot answer related to this topic, I can say with confidence that many biological functions that rely on the activation of dopamine and G-protein coupled receptor’s signaling. I have also learned that the Akt/GSK3 pathway is important to neurological well-being and is a factor in many diseases. The article combines these pieces of information by informing us that the Atk/GSK3 pathway is controlled by a G-protein coupled receptor, and by manipulating that pathway there are changes in neural behaviors. However, it is still uncertain as to where in the pathway it is most beneficial to inhibit signaling in order to treat various diseases. With the discussion of this article it has also been established that there is still a lot to learn with the pathways of pharmaceuticals and just how selective these drugs are. This article helped us explore one pathway that is affected by dopamine receptors and how it could be affected various diseases.
I now have a better understanding of this particular pathway, but unfortunately this is only a very small piece to the puzzle to understanding the connections between pathways of neurological diseases, as well as the medications that are prescribed to help “fix” these diseases. The Akt/GSK3 pathway is only one pathway that is influential in diseases, but there is a lot of research that needs to be done to make sure pharmaceuticals are only acting on what they are supposed to.
At the end of the day, the past week has been informative and has opened my eyes to how much is unknown within our brains. I realize that a lot of that has to do with my own novice understanding, but I believe there is so much happening within the brain that progress with this type of research will take scientists a long time to quantify and actually make it useful to the public.
Akt and GSK3: Not Just Two Acronyms Someone Uses in a Lab
This week in class, we discussed the Akt-GSK3 pathway. The obscure name is enough to make most readers click on or scroll down, but before you do, I recommend you read just a little bit further. This pathway affects many aspects of your life and probably plays a role in a condition affecting someone in you know or maybe even you personally. The following list provides some examples of conditions associated with the Akt-GSK3 pathway:
- Addiction
- Parkinson’s Disease
- Schizophrenia
- Bipolar Disorder
- Depression
It’s incredible that one pathway can be implicated in and targeted for treatment for so many problems. Research into this pathway can lead to many important findings, improving the lives of many people in the process.
Research on the Akt-GSK3 pathway began when scientists found lithium to be an effective treatment for bipolar disorder. Lithium acts to disrupt GSK3 signaling inside the cell. Inhibiting of GSK3 activity has a variety of effects in the brain. Among them is the inhibition of serotonin-inhibiting receptors. Serotonin levels are often decreased in major depressive disorder. Antidepressants (specifically a class called SSRIs) act to increase the levels of serotonin in the brain. Inhibiting GSK3 has a similar effect to these SSRIs; therefore, lithium acts to decrease the lowness of the down periods in bipolar disorder. More selective GSK3 inhibitors are also being developed as depression treatments.
In schizophrenia, many atypical antipsychotics exist, but nearly all of them have the ability to act on the same class of receptors called D2-receptors. While it was thought this was the primary means of affecting psychotic behavior, it has been shown that other pathways are affected by these drugs. It is unknown whether the initial affected pathway, the newly-discovered affected pathways, or a mix of both cause the effects of antipsychotics. With further research, it may be possible to isolate a more specific target, producing more efficacious treatments with fewer side effects.
In Parkinson’s, the Akt-GSK3 pathway may contribute to brain cell degeneration, though the mechanism for this is unknown. Researchers discovered this link by examining the cellular effects of the neurotoxins used to create Parkinson’s-model rats in the laboratory. Further research into this pathway could be used both to treat and hopefully prevent or delay the onset of Parkinson’s disease.
Dopamine has been known to be an active part in the physiology of addiction. All reinforcing stimuli facilitate the release of dopamine in a certain part of the brain. Dopamine also acts on D2-receptors which, as stated previously, affect the GSK3 pathway. It is unknown whether addictive substances exert their effects through the Akt-GSK3 pathway or whether activation of this pathway from additional dopamine is merely an additional effect. It may be worth examining this to see if addiction can be curbed or even prevented in the future.
One other important thought we examined in our discussion is development of these new pharmaceuticals. It is important for them to be specific enough so as to avoid side effects, but also broad enough to address enough symptoms as they can. Also, a drug must be able to get to its target, which further complicates the process for researchers. Modern medicine is capable of many things, but innovation takes time and money. The human body also creates obstacles because not every drug can make its way into the brain or can be absorbed fast enough to provide relief. These concerns must be addressed when designing drugs.
Those are the facts we currently know. Facts, however, should bring questions to mind. We, as consumers and patients, must also ask ourselves the following questions: What separates “normal” from disorder-related behavior? What separates personality from irregularity? Is the behavior we see a result of something we can change by adjusting our lifestyle (e.g. exercising, maintaining a regular sleep schedule, eating healthier, lowering caffeine consumption, etc.) or is it the product of a genetic anomaly that would ideally be treated with medication?
Medical innovations are wonderful, but consumers must make decisions regarding what they put in their body based on their own NEED. Pharmaceuticals are not living beings that know to just go one place or only do one thing; they are chemicals designed to act on the body, many times to correct an imbalance. They act all over the body, not just in one place (though the action in one place produces the desired effect). The human body maintains a functional balance, each part affecting the whole. Putting one chemical in the brain affects one part of the balance, but because we cannot stop a chemical from circulating throughout the body, the chemical will act on other cells, causing additional effects. If we can naturally, through a lifestyle adjustment, correct an imbalance to alleviate symptoms while improving other bodily systems, it is clearly the better option because it usually does not produce negative side effects (except for less free time due to exercise, more sleep, preparing healthy food, etc.). Some problems arise from a lifestyle choice, but others are the result of things that are out of one’s control. This is where pharmaceuticals should find their niche. We have the ability to develop amazingly efficient drugs to help those in need, which is why research to help these people should continue. We must also be hesitant to attribute conditions to individual choices, but must also be careful not to immediately jump to the conclusion that pharmaceuticals are the best option. Natural remedies can alleviate symptoms and improve overall quality of life, but their maximum effect has a limit; drugs can treat the specific symptoms we need them to, but can cause side effects because of the need to get to the target area and the need to address certain symptoms. Patients acting as consumers and medical professionals acting as distributors must find a balance between the two to produce the best results for each patient.