We recently read an article about endocannabinoids. Yes, cannabinoids just like the active ingredient in marijuana, THC, or tetrahydrocannabinol. The part of the article that was most intriguing to me was the fact that these chemicals are completely natural in our body, as in we make them. Endocannabinoids act like a relay system in our body. Our neurotransmitters are released and bind post-synaptic neurons, which releases endocannabinoids. This tells the pre-synaptic neuron to stop releasing neurotransmitters. THC has a similar effect on the body. Here is where our discussions got interesting. THC acts exactly like a chemical our body already produces but has a huge stigma around it. Because of this stigma, one of the potentially beneficial parts of marijuana, cannabidiol, is often forgotten about. Cannabidiol is another cannabinoid, so it acts like the ones our body produces and THC. However, cannabidiol is far less psychoactive than THC. Cannabidiol is the part of marijuana that is often linked with the positive effects, such as preventing tumors and stopping seizures. In fact, a fairly recent article on CNN talked about how a specific strain of marijuana that was high in cannabidiol and low in THC was used to treat a girl with Davet’s Syndrome, a severe version of epilepsy. So we have natural endocannabiniods and cannabidiol that are generally helpful, but THC is the most commonly heard of and causes a lot of stigma for all cannabiniods. I wonder were the stigma came from in the first place. It does make you think, we have these chemicals are body uses for regulation that are also found in a plant. Some people use the plant to get high, others use it for health benefits. Should we be utilizing this plant, even though it is illegal now? Who knows, but cannabinoids are an interesting chemical nonetheless.
Akt, Gsk, Dopamine and how they can fix your brain
The other week in class we discussed the Akt/Gsk pathway and Dopamine receptors. To put it lightly the article we read was dense. Through all the scientific language and technical terms one general idea stood out. Your body releases dopamine, dopamine binds these receptors, and the receptors keep Akt inactive so Gsk can remain active and cause cellular responses. As exciting as that all sounds what does it matter? Well dopamine is one of the most important neurotransmitters in the brain and these proteins play a major role in its signaling pathway. Research is currently investigating the role of these signaling proteins in psychological disorders such as Bipolar and Schizophrenia. The antipsychotics we use now are effective but come with harsh side-effects. This is because these pharmaceuticals typically block dopamine receptors and while this works to stop the psychological problems, it causes a widespread effect on the body. The hope is that the issue with psychological disorders is that maybe the problem lies farther downstream from the dopamine receptor in the Akt/Gsk pathway. If we can find a protein or something that is causing the problem and can find a way to fix it we can hopefully manage psychological disorders without affecting something as major as dopamine receptors. This is easier said than done. The kind of research it takes to find what protein is causing the issue and figuring out a way to fix it costs huge amounts of money and takes a lot of time. But, nonetheless, the important of the Akt/Gsk pathway in the body cannot be undervalued. Some day it may lead to a better antipsychotic drug, or just a better understanding of dopamine.
Should we puff puff pass on the use of cannabinoids?
Despite its legal status, the use of marijuana is not uncommon. In fact, it is the most commonly used illegal drug in our society. In addition to its recreational use, marijuana has been used medically for hundreds of years. Although the use of marijuana might not be new, finding out how it works has just begun. This week in neurochem we discussed the article “Endogenous cannabinoids revisited: A biochemistry perspective.” As we discussed the intricacies of marijuana, THC, endocannabinoids and their receptors, it became apparent that THC and its natural analogues may be more beneficial than they are harmful.
The first step to understanding the benefits that cannabinoids can have comes through understanding how they work. The cannabinoid receptors were first discovered when researchers started looking into how THC and marijuana work in the body. They discovered certain receptors on cell membranes that specifically bind THC. As research continued, scientists discovered molecules that are naturally produced in your body that also bind these receptors. The most common of these molecules are known as 2-AG and AEA. The receptors are known as the CB-1 and CB-2 receptors. As research continues, more endogenous cannabinoids have been suggested as well as at least one more receptor type.
So what are the benefits that can be caused by cannabinoids? Medical marijuana has been used for Cancer, HIV/AIDS, multiple sclerosis, anorexia, anxiety, depression, and numerous other illnesses and conditions. In addition, it has been shown to have anti-proliferative and analgesic effects. In addition to the use of medical marijuana, researchers have been studying analogues of THC, the primary active compound found in marijuana. One of the most promising compounds is known as cannabidiol. Cannabidiol is second only to THC in the marijuana plant in terms of presence. It has been shown to have less psychoactive effects and may have more medical benefits than THC. Currently, a large amount of research is focused on cannabidiol in order to better understand how it works and the benefits it may have.
With the noted benefits of cannabinoids, the question then arises of how we should approach this knowledge. Although the use of marijuana is largely prohibited, its use may be beneficial in the treatment of a variety of neurodegenerative diseases. In addition, cannabinoids seem to alleviate a wide variety of problems without the side-effects of many pharmaceuticals. Cannabinoids might just be the answer to improvement of treatment for a variety of diseases; the knowledge we do have points to the positive effects that cannabinoids can have. So should we just take this knowledge and run with it? Although I can see and understand the benefits that cannabinoids can have, I think it is important that more research is done prior to widespread use. In addition, if marijuana or other cannabinoids are used for treatment, it is important that they are properly monitored by a physician as with any other medication. With proper research and monitoring, cannabinoids seem to be a promising treatment for a variety of disorders and diseases.
Iron: More than a Metal
Parkinson’s disease (PD) is a disease in which dopamanergic neurons experience substantial damage and even death. It affects 1-2% of people overage the age of 60, affecting more men than women. The causes of PD have typically been associated with oxidative stress and other toxic actions which lead to the build up of Lewy bodies in the brain which lead to death of neurons. A new study entitled, Targeting dysregulation of brain iron homeostasis in Parkinson’s disease by iron chelators, discusses the effect that iron might play in PD. One of the interesting things about this article is that it is able to supplement theories that are already in place about PD with a new idea. It doesn’t discount any of the old information about PD, but it adds a new piece to the puzzle that could help solve the problem.
Brain-iron homeostasis is regulated by interaction between two types of cells in the brain called endothelial cells and astrocytes. It is also regulated by two proteins called IPR1 and IPR2. These proteins help to regulate the amount of each type of iron in the brain. In the body, iron can take on two forms: one with a charge of +2 and one with a charge of +3. It is important to keep these two types of iron regulated because dysregulation of these two ions has been visible in PD. Too much iron in the brain has been studied and been shown to lead to PD, Alzheimer’s disease, and Multiple Sclerosis. Iron is important for the brain because it used to either reduce or oxidize molecules. Improper oxidation or reduction can lead to problems.
Like mentioned before, dysregulation of iron +2 and iron +3 has been seen in the brains of PD patients. One specific problem this causes in PD is the aggregation of alpha-synucleuin proteins due to iron radical molecules in the brain to form Lewy bodies. These Lewy bodies lead to death of neurons. One way this paper talked about treating the iron dysregulation is with iron chelators. Iron chelators are molecules which bind to iron and then remove it from the body. Iron chelators are therapeutic because they have antioxidant effects, prevent alpha-synucleuin aggregation, and can stabilize HIF (a molecule that is used to regulate transcription).
PD might not be as “hot” of a topic in terms of neurological disorders compared to others, but it still important to try to understand where it comes from and how it can be prevented and treated. Some people may feel disconnected from PD since it affects only a small part of the population. Further research into the mechanisms of PD could also bring about conclusions about other neurological disorders as well.
Since PD is diagnosed later in life, I think it may people don’t think much about preventing it. But, in my opinion, prevention is the best way to deal wit disease since it possibly alleviates having to treat the disease in the future. With the iron part of the PD story, it can be difficult since many women struggle with anemia. When trying to eat an iron-rich diet to control anemia, it would be unfortunate to develop PD as a consequence.
For people without anemia, in order to prevent PD it seems it would be important to eat a sufficient amount of iron to stay healthy, but keep the excess amount as low as possible.
The article also spoke about the positive effects of green tea in terms of PD. If this fact were made more public, it could be possible to help prevent/treat PD with the simple treatment of drinking or supplementation of green tea.
Type 2 Diabetes, a Precursor to Alzheimer’s Disease
Many people are aware of the connection between insulin resistance and type 2 diabetes. New research presented in the article, Possible Implications of insulin resistance and glucose metabolism in Alzheimer’s disease pathogenesis presents a link between insulin resistance, diabetes, and Alzheimer’s disease. When most people think of insulin, they think of blood glucose levels. This is a great association because insulin is a hormone released into the body which tells the body to absorb glucose when its levels are high, for example right after a meal. Before reading this article, I was unaware that insulin played any role in the brain. Recent studies have shown that insulin is produced in the brain and can have intense effects in the central nervous system. A specific receptor, IGF-1, was found in the brain that responds to insulin and can help regulate important neurological functions such as: energy homeostasis, survival of neurons, longevity, and learning/memory.
Alzheimer’s disease is a condition characterized by neurological degradation and memory loss. Just like insulin resistance is they “key word” to diabetes, accumulation of amyloid-Beta plaques in the brain is the “key word” to Alzheimer’s disease. Amyloid-Beta (AB) plaques form in the brain from the aggregation from AB proteins which are formed from the processing of amyloid precursor proteins (APP). APPs are found in membranes of the brain, but their natural function is still unknown. When they are cut with specific enzymes, AB proteins are formed. Abnormal folding of these proteins leads to their aggregation, which leads to brain deterioration and Alzheimer’s disease. AB plaques in the brain lead to a high level of inflammation in the brain which also contributes to the negative symptoms of Alzheimer’s disease.
The connection between diabetes and Alzheimer’s disease may not seem obvious, but one important link between the two is inflammation. Brain inflammation plays a large role in Alzheimer’s disease and is key in its pathology. The connection between insulin and Alzheimer’s is made because in the periphery, insulin plays an important role in inflammatory responses. Low does of insulin have been shown to have anti-inflammatory effects but high levels of insulin may increase inflammation and also activate oxidative stress (another factor in Alzheimer’s disease).
In summary, Alzheimer’s disease is associated with AB plaques, inflammation, and oxidative stress. Diabetes is associated with insulin resistance. Insulin in the brain is associated with regulation of inflammation. When these three concepts are connected, it leads to scary realities for the American public.
Type 2 diabetes is quickly infiltrating the American public at a younger and younger age. People of all ages are developing diabetes. If diabetes is a precursor to Alzheimer’s disease, and people are getting diabetes at younger age, this could lead to the onset of age of Alzheimer’s disease being lowered. This could be a huge problem for society. Many people with Alzheimer’s experience such severe memory loss that they cannot even recognize their own family members. Most people with Alzheimer’s disease are at an age where they are retired, have grown children, and are able to live in a facility that is able to accommodate their needs. But if people are to be diagnosed with Alzheimer’s at 50 years old because they contracted diabetes at a young age, the disease would be more taxing on their life. Most 50 year old people still have job and still have dependent children. Having a disease which so severely impacts memory would not make it easy to hold down a stable job or raise children. Alzheimer’s disease doesn’t necessarily quickly end a person’s life. Living with Alzheimer’s disease for 25 plus years would be extremely difficult for both the individual and their family.
Now that this research has come up, it is more than ever necessary to change the habits of the American public. Prevention of diabetes is even more important now that it is clear that prevention, or at least delay, of diabetes can prevent, or at least prolong, Alzheimer’s disease. One main way the American public should react to this article is with a change in diet. Unhealthy, sugary foods should be minimized in the American diet and foods high in antioxidants should replace them. Nutrition is an important factor in the development of type 2 diabetes. Increased nutritional values in the diets of Americans have been shown to help prevent type 2 diabetes. American health care occasionally struggles with preventative health care, but it is integral that people realize what kinds of negative problems can occur due to poor nutrition: type 2 diabetes, which recently has been identified as a precursor to Alzheimer’s disease.
You Want Me To Do Drink What…?
The focus of this week’s neurochemistry discussion was Parkinson’s disease. Parkinson’s disease is a progressive neurodegenerative disease that affects movement. Common symptoms of Parkinson’s disease include tremor, bradykinesia (slow movement), stiff limbs, and poor coordination and balance. Like many other neurodegenerative diseases, the cause of Parkinson’s disease is unknown and currently there is no known cure. However, it is known that patients with Parkinson’s disease experience cell death in an area of the brain known as the substantia nigra, which has high levels of a neurotransmitter (chemical signaling molecule) known as dopamine. Dopamine is the neurotransmitter used to regulate and coordinate movement in the body.
Recent research has shown that dysregulation of iron levels in the brain may play a role in the development of Parkinson’s disease (PD) as well as other neurodegenerative disorders. Iron levels have been found to be increased in the substantia nigra in Parkinson’s patients, which has led researchers to believe that regulation of this molecule is linked to PD. Iron is an important molecule in a number of biological processes such as DNA synthesis, cellular transport, storage and activation. A number of proteins are needed to maintain a consistent level of iron in the blood. Iron-regulatory proteins (IRP) and iron-responsive elements (IREs) are in charge of controlling the creation of proteins that regulate the amount of iron allowed in the blood and how much iron is taken into cells. When iron levels increase (not solely due to age) to the point that regulatory proteins are not able to handle the increased concentration, accumulation of iron can have disastrous effects. First, iron reacts with hydrogen peroxide and produces radicals, which cause oxidative stress. Oxidative stress in cells ultimately causes cell death. In other cases, iron causes proteins to accumulate in the cell. One of the hallmarks of Parkinson’s disease is the formation of Lewy bodies, which result from the accumulation of the protein of a-synuclein. Iron accumulation has been shown to contribute to two signs of Parkinson’s disease.
Now knowing that iron accumulation poses a serious threat, what can be done to lower levels of iron? One mechanism of decreasing the adverse effects is through chelation, or binding of iron ions to prevent iron from acting in cells. M30, a synthetic drug that is able to reach the brain, is showing promise in reducing iron levels in the brain and protecting dopaminergic neurons. However, M30 is not the only therapeutic option available for Parkinson’s patients. Surprisingly, there is a simple, natural way that everyone can reduce his or her levels of iron. (-)-epigallocatechin 3-galate (ECCG), an extract of green tea, has been found prevent neuron death in the substania nigra by binding to iron ions. Green tea is readily available and a natural therapy option that may reduce the harmful effects associated with excess iron. Green tea as a therapy option gives patients hope and motivation because they are capable of influencing their risk for Parkinson’s disease through accumulation of iron. Iron dysregulation offers a new, potential target for therapy. Further research is needed to continue looking for a cure for Parkinson’s disease.
Type 3 diabetes
Obesity is on the rise in the United States and with this comes a number of health issues. One of those issues is Alzheimer’s disease (AD). Obesity can lead to diabetes which is the body’s inability to regulate glucose. Insulin plays a vital role in the brain as shown in figure 1. It stops oxidative stress, one of the leading causes of aging, and apoptosis (cell death). In diabetes the insulin no longer bind to insulin receptors correctly. This causes the cell to perform acts otherwise not performed if working properly. In short, insulin isn’t able to bind to receptors causing things called neurofibrillary tangles. These tangles cause neurological death in the brain which causes AD. Because of this, many call AD type III diabetes, because of its link with insulin. This is just another reason why it is important to stay healthy and to fix the obesity problem in the country.
Changing stigmas for medical benefits
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!