Cobbers on the Brain

Lou Gehrig’s disease is also called ALS. It is a motor neuron disease that impairs the physical activities in the life of the patients with ALS.
 
ALS begins with muscles weakness, stiffness, softness, tightness, or spastic. The patients with ALS feels fatigue, poor balance, slurred words, weak grip, or tripping. These symptoms may be so subtle they occur before diagnosis. The next stage of ALS presents with more widespread symptoms from above, paralyzed muscle groups, deformed and rigid joints, weakness in swallowing, unable to drive, weakness in breathing when lying down, and bouts of inappropriate laughing or crying. The final stage of ALS presents with most all voluntary muscles paralyzed such as speech, eating, drinking, limited ability to move air into and out of lungs (breathing) and poor respiration leads to fatigue, scattered thoughts, headaches, and pneumonia. In the last stage, the patient with ALS have a high risk of death.
 

 
Unfortunately, the diagnosis process of ALS usually takes 2 to 3 years, implying that the patients are usually at the late stage when they find out that they have ALS. The treatments are also limited. The treatments do not target to the specific area in the growth of ALS. Instead, they just try to slow down the progression of ALS disease.
 
In a current study, the oxidative stress, the mitochondrial damage and the RNA dysfunction are the important mechanisms contributing to the initiation and progression of ALS:
The mutant Fuse in Sarcoma (FUS) and TAR-DNA binding protein (TDP43) protein tend to aggregate and trap within the cytoplasm, leading to the impairment transcription and growth of motor neuron. This creates more oxidative stress in the cell. The autophagy and protein degradation, such as SOD1 and UPR, help to keep the oxidative stress at the normal level. When they are unable to resolve the oxidative stress in a timely manner, they shift their function to destroy the cells. Apoptosis is now the goal.
 
The key players in ALS disease:

1. Fuse in Sarcoma (FUS) is essential in the nucleus and cytoplasm. In the nucleus, it is a transcription factor, a pre-mRNA splicing, and bringing other transcription factors together to initiate the transcription process. In the cytosol, FUS has less functions, so small amount of FUS is present in cytoplasm. FUS importantly acts as a mRNA transporter, bringing mRNA out of the nucleus. When FUS is mutated, it tends to aggregate and accumulate in the cytosol, leading to the inability for mRNA to be spliced properly, less miRNA produced, transcription issues, lack of mRNA transport to the dendrites in the cell that require it and destabilization of important mRNA.
2. TAR-DNA binding protein (TDP43) is a DNA/RNA binding protein. It has the similar functions like FUS. It plays an important role in transcription and translation process. It also involves in stress granule response under condition of stress.
3. SOD1 is a mainly cytosolic antioxidant enzyme that convert superoxide (O₂^–) into hydrogen peroxide (H₂O₂). Its important function in the complex defense against reactive oxygen species that are produced by the cell during normal cellular metabolism. Mutation SOD1 increase protein and lipid oxidation, making the metabolism work more and producing more ROS. In addition, mutant SOD1 sometimes runs in reverse, catalyzing the conversion of H₂O₂ into O₂^–, and worse, allows the nascent O₂^– to react with nitric oxide (NO) to yield peroxynitrite (ONOO^–). Peroxynitrite intitate the oxidative stress in the cell and ultimately leading to motor neuron death.
4. Oxidative stress may also lead the formation of unfolded protein. Unfolded Protein Response (UPR) is a cells response to restore normal function of the cells, breakdown of the misfolded proteins and increasing the production of chaperones in protein folding.

 
More studies are needed to understand in depth the mechanism of ALS disease to come up with the better treatments as well as improving the diagnosis process that is able to diagnose at the early stage in order to suppress effectively the growth of ALS.
 

Marijuana, and all of the cannabinoid compounds found in it, are listed as schedule one drugs according to the DEA. Other drugs found in the schedule one class are heroin, LSD, and ecstasy; these drugs are considered to be the most addictive and dangerous, and are not considered to have any valid medical purposes (1). This is why they have been placed in the schedule one category.
 
But does marijuana really belong in the same class as heroin and other highly dangerous substances? There is little to no evidence that suggests marijuana is even close to being as addictive as heroin, or even alcohol and tobacco for that matter. Other highly addictive and dangerous drugs, such as cocaine and fentanyl (a type of opiate), are listed one class below marijuana in schedule two (1), indicating that the DEA considers marijuana to be more dangerous than drugs like cocaine, methamphetamine, and even fentanyl.
 
Given the current scientific knowledge about marijuana and its active ingredient, THC, marijuana probably doesn’t belong in the same category as drugs like heroin and LSD. Marijuana simply isn’t as addictive or lethal as these other drugs are. There are also numerous legitimate medical uses for marijuana and some of the cannabinoids contained within it, making its placement in the schedule one category even less logical.
 

 
 
However, this doesn’t automatically mean that marijuana is completely safe for recreational use. To determine how safe marijuana really is, it is necessary to weigh the known benefits of smoking marijuana against the known detriments. Here is a list of the known effects of marijuana, and more specifically THC, on the human brain and body:
 
Potential Benefits:
1. Analgesia: THC is well-known for its analgesic, or pain relieving, effects in the human brain. This effect is one of the main reasons why marijuana is used for medicinal purposes (2), and this is definitely a beneficial use of marijuana.
2. Anti-cancer: A study found that consuming THC is linked to the death of cancer cells in one type of cancer, known as glioma (3). In this study, THC induced the death of human glioma cells through a process known as autophagy, in which cells basically ‘recycle’ or ‘eat’ their organelles until they die (3). This process is often beneficial in patients who suffer from cancer.
3. Anti-seizure effects (4)
4. Anti-inflammatory effects (4)
 
 
Adverse Effects:
1. Addiction: It is possible to become addicted to marijuana, and an estimated 9% of individuals who try marijuana eventually become addicted to it (4).
2. Problems with brain development: Adolescents who smoke marijuana regularly are at risk of developing minor brain abnormalities, such as the decreased size or connectivity of some regions of the brain. One region that can be adversely affected is the prefrontal cortex, which is involved with decision-making (4).
3. Mental Illness Related Effects: Marijuana use has been found to increase the likelihood of the development of schizophrenia, but genetic factors that make the individual susceptible to schizophrenia must be present as well (4).
4. Memory impairment: Some studies have shown a clear link between THC consumption and both short-term and long-term impairment of memory formation (4).
5. Negative effects on cognitive functioning: Some studies have established a link between regular marijuana use among adolescents and poor achievement in school, indicating that regular marijuana use may inhibit cognitive functions such as learning (4).
 
 
Although some of the effects of marijuana and THC have been well-documented, research on marijuana is difficult to conduct due to heavy restrictions, and more research needs to be done on marijuana in order to fully understand the effects it has on the human body. Other compounds found in Marijuana, like cannabidiol, have much therapeutic potential, and these chemicals need to be researched as well.
 
 

Sources

1. https://www.dea.gov/druginfo/ds.shtml

2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4827335/

3. https://www.jci.org/articles/view/37948

4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4827335/

 

Image Credits

 
1. https://www.cbsnews.com/marijuana-nation/
2. https://longhorns7770.wikispaces.com/
 

Legalize marijuana? Medicinal or recreational? Is marijuana good or bad for you? These are the questions our society is currently facing when discussing the legal stance on marijuana. Right now, the legal climate is fairly rocky as some states have decided to legalize this drug for recreational use. However, it is still currently illegal under the federal government. This is because we don’t fully understand the impacts and effects of cannabis on the brain/body and how this can effect us long term. The FDA classifies this drug as a schedule I drug which makes research on cannabis nearly impossible. This makes it extremely difficult to learn more about this potentially very beneficial drug. Here is what we do know about how the cannabinoids in our brain impact us right now:
Endocannabinoids:
Endocannabinoids (eCB’s) are the molecules that we find naturally occurring in the brain. The most abundant eCB’s in the brain are N-Arachidonoylethanolamine (anandamide, AEA) and 2-arachidonoylclycerol (2-AG). In the brain, these molecules bind to the CB1 and CB2 receptors. These are also the same receptors that we think exogenous cannabinoids bind to, like THC in marijuana. The CB1 receptor is a g-protein coupled receptor (GPCR) which is paired to a Gi protein. This means that when activated this molecule will decrease the activity of adenylyl cyclase which in turn leads to lower levels of cAMP and PKA which are important molecules for cell functioning and working memory. This pathway also has the ability to activate the ERK, JNK, FAK and p38 pathways along with the control of ceramide and ion concentrations within the cell. I would specifically like to talk about the role of the JNK pathway and the CB1 receptor.
JNK and CB1 activation:
The JNK pathway is normally turned on in response to stress which leads to DNA repair, transcription factor changes or even cell death in extreme cases. Due to the CB1 receptor being coupled to the Gi g-protein, the activation of this GPCR has the ability to turn on Ras (one of the first proteins involved in the activation of the JNK pathway). Ras activates Raf activates MEK activates MKK which activates JNK in the nucleus. All of these molecules phosphorylate the next protein in the chain leading to its activation. It is also interesting to note that MEK is responsible for activating the MAPK pathway and the MEKK pathway. Therefore, the activation of the CB1 receptors can have three different outcomes just from activating the Ras protein. JNK leads to DNA repair and cell apoptosis. This could explain some of the healing effects of marijuana. We see that it has the ability to aid in the decline of growth of cancer cells while also giving patients an appetite needed during treatment.

Figure shows the activation of CB1 which in turn activates the JNK pathway.
Legalize it?
Although we don’t necessarily have enough evidence telling us whether the extended use of medicinal marijuana is bad or good. It has been shown to have remarkable beneficial impacts on diseases like cancer, glaucoma and epilepsy (seizures). Cannabis definitely changes the chemical balances in the brain and can in some cases be seen as addictive which could lead to negative side effects in the future. However, it may be logical to use medical marijuana as a treatment for these diseases to give people pain relief, appetite and relaxation for now.
For more information about the role of eCBs in the body read:
https://moodle.cord.edu/pluginfile.php/625296/mod_resource/content/0/endocannabinoids.pdf
Figure from:
http://molpharm.aspetjournals.org/content/molpharm/58/4/814.full.pdf
Cover Photo from:
https://www.hcillinois.com/learn/endocannabinoid-system/