Oxidative stress? Let’s take a look at DOPAC…

In the past several weeks, there have been a number of posts about oxidative stress and the effects that it can have on neurotransmitter pathways, including the tryptophan pathway and catecholamine synthesis. Dopamine metabolism can also contribute to oxidative stress.

Figure 1. The breakdown of dopamine by MAOB creates hydrogen peroxide and a hydroxide ion, both free radicals.

Figure 1. The breakdown of dopamine by MAOB creates hydrogen peroxide and a hydroxide ion, both free radicals.

Dopamine is created from L-DOPA by the enzyme aromatic L-amino acid decarboxylase (AADC) (Figure 1). Dopamine is then broken down into DOPAL by monoamine oxidase B (MAOB) and DOPAC by aldehyde dehydrogenase (ALDH). The breakdown of dopamine to DOPAL creates a hydrogen peroxide molecule (H2O2). Hydrogen peroxide is a free radical and is also broken down into a hydroxide ion (HO), which is also a free radical. Normally, free radical synthesis through the breakdown of dopamine is well controlled by the body. If the body becomes overwhelmed with free radicals, illness or disease symptoms can occur. An elevated DOPAC level can indicate increased dopamine breakdown, leading to increased levels of free radicals. This oxidative stress can affect neurotransmitter pathways. The neurotransmitter pathways, in turn, can also impact the total oxidative stress in a patient.

So, if you see elevated DOPAC levels in a patient, make sure you think about oxidative stress as a contributing factor.

References:
Meiser, J., Weindl, D., Hiller, K. (2013). Complexity of dopamine metabolism. Cell Commun Signal, 11(1): 34-52.
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Neuropharmacology: How do your drugs work?

Almost everyone uses medications at some point in their life, but what are they actually doing in the nervous system? Neuropharmacology is a branch of medical science dealing with the properties and actions of a drug on and in the nervous system. Drugs are grouped into one of the following based on how they work: neurotransmitter substrates, reuptake inhibition, receptor modification, and enzyme modulation (Figure 1).

Figure 1. Drugs can be classified into one of the following based on their mechanism of action: reuptake inhibition (1), receptor modification (2), neurotransmitter substrates (3), or enzyme modification.

Figure 1. Drugs can be classified into one of the following based on their mechanism of action: reuptake inhibition (1), receptor modification (2), neurotransmitter substrates (3), or enzyme modification.

Neurotransmitter substrates

Neurotransmitter substrates are amino acids that act as precursors for neurotransmitter synthesis. Neurotransmitter substrates, such as the drug Levodopa, will affect the amount of neurotransmitters available.

Reuptake inhibition

Reuptake inhibition is the prevention of neurotransmitter transport from the synapse back into the neuron that released it. This increases neurotransmitter levels outside the cells. These substances are commonly referred to as reuptake inhibitors. Examples of reuptake inhibitors include selective serotonin reuptake inhibitors (SSRI) like citalopram or fluoxetine, serotonin and norepinephrine reuptake inhibitors (SNRI) like venlafaxine and duloxetine, and norepinephrine and dopamine reuptake inhibitors (NDRI) like bupropion.

Receptor modification

Neuronal receptor modification includes the mimicry, enhancement, or blocking of neurotransmitter binding to its receptor. Therapeutic agents in this category include receptor agonists and receptor antagonists.

Receptor agonists can either act like or enhance the action of neurotransmitters. Mimics bind to a specific neurotransmitter receptor and cause a similar action. Agents that enhance the action of neurotransmitters bind to the neurotransmitter receptor along with the neurotransmitter. This amplifies the effect of the neurotransmitter. Clonazepam, diazepam, and zolpidem are all classified as receptor agonists.

Receptor antagonists have the opposite effect of agonists. They bind to neurotransmitter receptors, blocking the neurotransmitter from activating the receptor. This decreases neurotransmission. One common example of a receptor antagonist is diphenhydramine, which is commonly used to treat allergies. It is a histamine receptor antagonist. It reduces the symptoms of allergies by blocking peripheral histamine receptors. Diphenhydramine also blocks central histamine receptors that are involved in wakefulness. When it blocks receptors in the central nervous system, the drowsiness often felt with the use of this drug can occur.

Enzyme modulation

Enzyme modulators alter the activity of an enzyme. Some enzymes break neurotransmitters down into their inactive metabolites. Pharmaceutical enzyme inhibitors can slow the breakdown of neurotransmitters, leaving more neurotransmitters to transmit signals. Examples are monoamine oxidase inhibitors (MAOI) such as selegiline or phenelzine or acetylcholinesterase inhibitors (AChEI) such as carbamates.

Many pharmaceuticals affect the nervous system by altering the levels or activity of neurotransmitters. Identifying which neurotransmitters are out of balance will help to determine the appropriate therapy to improve patient outcomes. For more information on which neurotransmitters are affected by different pharmaceuticals, please see the Prescribing Information for Select Drugs reference document.

References:
http://www.merriam-webster.com
Muller, W.E., et al. (1998) Pharmcopsych. 31:16-21.
Turner, E.H., et al. (2006) Pharmcol Ther. 109:325-338.
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What to expect when you’re expecting: do you expect environmental toxins?

Earth Day was first celebrated in 1970 and is meant to bring awareness to environmental protection. Ironically, since then, the amount of chemicals (i.e., insecticides, pesticides, manufacturing) used in the environment has increased. US industries make and import around 80,000 chemicals with an average of seven new chemicals approved each day. Of the top 20 chemicals discharged into the environment, nearly 75% are known or suspected to be toxic to the developing human brain.

A 2005 EWG study identified 287 different chemical in umbilical cord blood. 180 are known to cause cancer in humans and animals, 217 are toxic to the brain and nervous system, and 208 cause birth defects or abnormal development in animal tests.

A 2005 EWG study identified 287 different chemical in umbilical cord blood. 180 are known to cause cancer in humans and animals, 217 are toxic to the brain and nervous system, and 208 cause birth defects or abnormal development in animal tests.

This increase in exposure to toxic chemicals in the environment, including the home, can have drastic effects on children. Kids are more vulnerable to the effects of toxins than adults. Their ability to detoxify is not as well-developed as an adult’s. Kids also have more risk of toxic exposure from water, food, and air. This is because, pound-for-pound, kids drink, eat, and breathe more than adults. Kids also touch the ground more often and engage in more hand-to-mouth behaviors, making the risk even greater.

Exposure to toxic chemicals begins in the womb. The Environmental Working Group (EWG) ordered a study in 2004 to identify industrial chemicals, pollutants, and pesticides in human umbilical cord blood. The study, printed in 2005, found 287 different chemicals in the cord blood. Of these, 180 are known to cause cancer in humans and animals, 217 are toxic to the brain and nervous system, and 208 cause birth defects or abnormal development in animal tests.

Research has also found that acute leukemia is significantly linked with home and garden insecticide and fungicide use during pregnancy and childhood. Phthalates, substances added to plastics to increase flexibility, have been associated with increased allergies in children. Prenatal exposure to phthalates has also been linked to autistic behaviors. There have been reports that DDT exposure is associated with early menarche and shortened menstrual cycles. The National Academy of Sciences has also determined that environmental factors contribute to 28% of developmental disorders in children.

Industrial pollutants and toxins have become abundant in our environment, and prenatal and childhood exposure to these toxins is increasing. The total body burden of toxins should be kept as low as possible to support optimal health. Removal of toxins is important, including staying hydrated to flush out toxins as well as regular bowel movements. Maximizing children’s antioxidant reserves can also be beneficial to support their ability to detoxify. Neurotransmitter testing can also be of benefit to identify imbalances in the nervous system that may be due to toxic chemicals. Above all, the most important aspect is to minimize toxin exposure.

References:
Bornehag, CG., et al (2004). The Association between Asthma and Allergic Symptoms in Children and Phthalates in House Dust: A Nested Case-Control Study. Environ Health Perspect, 112(14): 1393-7.
Houlihan, J., et al. (2005). Body Burden: The Pollution in Newborns. Environmental Working Group. http://www.ewg.org/research/body-burden-pollution-newborns.
Menegaux, F, et al. (2006). Household exposure to pesticides and risk of childhood acute leukaemia. Occup Environ Med, 63: 131-4.
Miodovnik, A, et al. (2011). Endocrine disruptors and childhood social impairment. Neurotoxicology, 32(2): 261-7.
Ouyang, F, et al. (2005). Serum DDT, age at menarche, and abnormal menstrual cycle length. Occup Environ Med, 62: 878-84.
Posted in Immunology | Tagged , , , , , , , , , , | 2 Comments

Flu bugs aren’t the only infection that cause stomach problems: Viruses may worsen IBD

As Easter approaches and kids eagerly wait for candy from the Easter Bunny, parents will be watching to make sure they don’t eat too much at once and get a stomachache.  All of us have experienced stomach upset from time-to-time and regardless of what caused it, it was an unpleasant experience. Unfortunately, unpleasant GI experiences occur on a much more frequent basis for individuals with Crohn’s disease or ulcerative colitis.

Crohn’s disease and ulcerative colitis are both inflammatory bowel diseases (IBD) that cause inflammation of the lining of the digestive tract. Resulting inflammation can lead to abdominal pain, severe diarrhea, and even malnutrition. In Crohn’s disease, the inflammation often spreads deep into the layers of the affected tissue and can affect various areas of the digestive tract1. Ulcerative colitis, on the other hand, tends to only affect the colon and rectum2.

While the initial cause of IBD remains unclear, some literature suggests that viral infections are associated with the onset and aggravation of IBD. Of these viral infections, cytomegalovirus (CMV) is of particular interest to the development and worsening of the conditions. Mucosal injury, or damage to the intestinal tract, is also a component of the chronic nature of these diseases3.

Figure 1. IBD, CMV infection, and mucosal injury can all contribute to symptoms that plague patients.

Figure 1. IBD, CMV infection, and mucosal injury can all contribute to symptoms that plague patients.

IBD, CMV infection, and mucosal injury can all contribute to the symptoms that plague patients(Figure 1).

  • Patients with IBD are often treated with immunosuppressive medications to reduce symptoms.  These patients may also suffer from poor nutrition due to damaged intestinal tissues.  The combination of immunosuppressive medications and poor nutrition make it easier for CMV to infect or re-infect a host.
  • IBD can also worsen mucosal injury.  Inflamed mucosa may play a crucial role in inducing and sustaining CMV reactivation as epithelial cells can serve as permissive hosts for CMV during inflammatory responses.  This means they could possibly create a friendly environment for CMV reactivation and replication which in turn enhances the chance of chronic viral infection. This process can result in an increase in CMV infections over time.
  • CMV infection may be a result of mucosal injury, but it may also be a cause.  Reactivation of or new CMV infection is thought to cause severe colitis, particularly in patients with ulcerative colitis that are treated with immunosuppressive agents.

In addition to the physical symptoms IBD and CMV infection can cause, poor nutrient absorption by the damaged intestinal tract can also lead to malnutrition. This lack of nutrients may mean that the necessary building blocks for neurotransmitters and hormones are insufficient.  This deficiency can lead to symptoms like anxiousness, sleep difficulty, or fatigue. Identifying and addressing neurotransmitter and hormonal imbalances with targeted support may help ease a patient’s secondary symptoms.

Guest author: Rachel Rixmann is a manager of the Clinical Support & Education Department at NeuroScience, Inc. and the resident expert in gastroenterology and nutrition.

References:
  1. http://www.mayoclinic.org/diseases-conditions/crohns-disease/basics/definition/con-20032061
  2. http://www.mayoclinic.org/diseases-conditions/ulcerative-colitis/basics/definition/con-20043763
  3. Cytomegalovirus (CMV)-Specific Perforin and Granzyme B ELISPOT Assays Detect Reactivation of CMV Infection in Inflammatory Bowel Disease.  Nowacki, Tobias M et. al.  Cells 2012, 1, 35-50; doi:10.3390/cells1020035.
Posted in Immunology | Tagged , , , , , , , , | 1 Comment

Carpe diem! Can you seize the day if seizures are contributing to your low mood?

Epilepsy is a brain disorder in which seizures occur as a result of abnormal neuron signaling.

Epilepsy is a brain disorder in which seizures occur as a result of abnormal neuron signaling.

Epilepsy is a brain disorder in which seizures occur as a result of abnormal neuron signaling. This irregular signaling may briefly alter a person’s consciousness, movements, or actions. However, having a seizure does not necessarily mean that a person has epilepsy. People are considered to have epilepsy when they have had two or more unprovoked seizures. Seizure symptoms can include convulsions, loss of consciousness, blank staring, lip smacking and/or jerking movements of the arms and legs.

One of the most-studied neurotransmitters that plays a role in epilepsy is GABA. Many of the drugs used to treat epilepsy affect GABA. These drugs alter the amount of GABA in the brain or change how the brain responds to it.

Another area of study in relation to epilepsy is depression. It’s estimated that 22% of epileptics have depression compared to 12% of the general population. This is believed to be due to the effect chronic epilepsy has on the hypothalamic-pituitary-adrenal (HPA) axis, specifically cortisol. Activity in the hippocampus leads to higher cortisol levels secreted from the adrenal glands. Elevated cortisol levels and hyperactivity of the HPA axis impair serotonin 5-HT1A receptors. This leads to decreased serotoninergic activity in the hippocampus. The resulting deficit in serotonergic activity can lead to the development of depression.

For patients with epilepsy, neurotransmitter and adrenal assessments can provide an important look at which neurotransmitters and hormones are out of balance and potentially contributing to the seizures or associated symptoms. Providing therapy that targets individual imbalances can help to improve symptoms and quality of life for a patient.

References:
http://www.ninds.nih.gov/disorders/epilepsy/epilepsy.htm
E Pineda, D Shin, R Sankar, A Mazarati. (2010). Comorbidity between epilepsy and depression: Experimental evidence for the involvement of serotonergic, glucocorticoid and neuroinflammatory mechanisms. Epilepsia, 51.
M Mula, B Schmitz. (1990). Depression in epilepsy: mechanisms and therapeutic approach. Ther Adv Neurol Disord, 2(5): 337-344.
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Epigenetics: more than “there’s a gene for that”

As we increasingly look to our personal electronic devices for help with our daily tasks, we’ve been assured they can help us address nearly any issue we may encounter. Companies like Apple that there is no problem they cannot address with their’s trademark mantra, “There’s an app for that.”  With the decoding of the human genome, which was expected to shed light on health issues ranging from weight to depression or addiction to the continuing rise of autism and other disorders, the medical community has taken a similar approach, being driven by the belief, “There’s a gene for that.”

Figure 1: The flow of information from DNA to protein is largely influenced by regulatory factors acting on the processes of transcription and translation. Environmental factors also influence protein expression.

Figure 1: The flow of information from DNA to protein is largely influenced by regulatory factors acting on the processes of transcription and translation. Environmental factors also influence protein expression.

While in many cases there may be “a gene for that”, this may not be the end of the story. Until recently, it was believed that our genes were the primary determining factors in how we look, think, and behave. Within the past decade however, this paradigm has shifted. It is increasingly apparent that the expression and function of our genes are largely influenced by a network of regulatory and environmental factors. Exploration into how internal regulation and environmental factors influence the expression of genes has given rise to a new field called epigenetics.

Epigenetic studies provide insight into how a person’s genetic makeup interacts with environmental, dietary, and lifestyle factors. The application of these insights has led to a new paradigm in medicine known as functional genetics. The fundamental tenet of this emerging field is that environmental triggers play a major role in whether a particular gene is expressed in a way that favors sickness or health, ease or disease.

The insight into human heredity has come a long way from Mendel’s discoveries in 1866 to the completion of the reference sequence for the human genome in 2003. Advances in current technology allow for studies that look deeper into our genetic code. These advances help determine how our genes are regulated and how they interact in response to various environmental factors. The enormous amounts of data obtained from these studies give us the potential to create truly personalized approaches to managing our well-being.

Guest author: Curtis Christian is a member of the Clinical Support & Education Department at NeuroScience, Inc. and the resident expert in genetics.

References:
Baranov, V. S. (2009). Genome paths: A way to personalized and predictive medicine. Acta Naturae, 3, 70-80.
Becker, F., van El, C. G., Ibarreta, D., Zika, E., Hogarth, S., Borry, P… Cornel, M. C. (2011). Genetic testing and common disorders in a public health framework: How to assess relevance and possibilities. European Journal of Human Genetics, 19, S6-S44.
Knight, J. C. (2009). Genetics and the general physician: Insights, applications and future challenges.  Q J Med, 102, 757-772. doi:10.1093/qjmed/hcp115
Rose, M. R., Mueller, L. D., & Burke, M. K. (2011). Anecdotal, historical and critical commentaries on genetics: New experiments for an undivided genetics. Genetics Society of America
Young, E., & Alper, H. (2010). Synthetic biology: Tools to design, build, and optimize cellular processes. Journal of Biomedicine and Biotechnology, 2010, 130781. doi:10.1155/2010/130781
Posted in Genetics | Tagged , , , , | 1 Comment