We live in a society where drugs (pharmaceuticals) dominate the medical world. Are you clinically depressed? Try Lexapro or Cymbalta. Is your cholesterol too high? Maybe Lipitor or Zocor will work for you. But don’t forget that drugs rarely work in the body without unwanted side effects! Why is this? How do pharmaceuticals work?
The majority of pharmaceuticals work by acting on receptors that are found on the surface of cells or enzymes (which regulate the rate of chemical reactions). The receptors have a high specificity for a particular substance, similar to a lock and key. If a molecule (the key) does not fit the receptor (the lock), it will not bind to the receptor. When a drug mimics the action of an endogenous compound, it is called an agonist. Essentially, the drug is encouraging a certain physiological response to transpire. For example, when Drug A binds a receptor, it may initiate a cascade of events to occur (called a signaling pathway) that leads to the synthesis Protein A. On the contrary, when a drug blocks a physiological response from occurring, it is called an antagonist or an inhibitor. By binding a receptor, it blocks an agonist of the receptor from binding and prevents that response from occurring. Continuing with the previous example: when Drug B binds the receptor, it prevents Drug A from binding and Protein A is not synthesized within the cell. The number of ways pharmaceuticals are used in the body is extraordinary and continues to grow each day.
The MAPK, or mitogen-activated protein kinase, pathway is recognized for its role in certain neurodegenerative diseases as well as certain cancers. Specifically, MAPK is identified for its role in Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS).
Scientists have determined that the MAPK pathway can induce neuronal apoptosis, or neuronal suicide. In Alzheimer’s disease, these pathways are upregulated and cause increased phosphorylation of certain proteins and increased expression of specific secretases that are known to induce AD. Similarly, these pathways are also affected in Parkinson’s disease. The activation of the MAPK, p38 and JNK pathways leads to the death of dopaminergic neurons in the brain, which characterizes the symptoms seen in patients with PD. Furthermore, the activation of the same pathways listed above may also prompt motor neuron death. As these motor neurons die, patients with ALS experience muscle atrophy, paralysis, and eventually die from the symptoms of the disease.
Unrelated to neurodegenerative diseases, but altogether related to diseases associated with the MAPK (and other listed) pathways are certain cancers, such as colon cancer. Scientists have focused on the ERK pathway in the cancer story. As certain proteins in the ERK pathway are phosphorylated, they encourage cell proliferation and growth as well as cancer cell migration.
You might be wondering why these pathways exist in the body if they can lead to such diseases, but as with most things, the danger comes in too MUCH activation of the pathway and not the existence of the pathway itself. In fact, the body NEEDS mechanisms that lead to the death of neurons. Similarly, it is vital that the body is able to grow and divide its cells to replenish dying ones.
However, as patients with these diseases do have pathways that function properly in a variety of ways, scientists are left to find ways to counter-act the problems specific to the disease. In the cases of AD, PD, ALS, and cancers, scientists look to inhibitors (or antagonists), drugs that suppress the physiological responses that are activated more often than they should be and cause excessive cell death or excessive cell growth. Ultimately, the goal of the research is to understand the mechanisms associated with the diseases and then to find ways to inhibit these mechanisms with accurate specificity. As always, negative side effects exist. Influencing a pathway, whether by activating or suppressing it, almost always leads to unwanted side effects. Nonetheless, at some point the symptoms of the disease override the unwanted side effects and this is when we rely on pharmaceuticals to “solve” all of our problems.