Endogenous Anti-Inflammatory Neuropeptides and Proresolving Lipid Mediators: A New Therapeutic Approach for Immune Disorders

This is a review article that I found interesting given the fact that at the Barbara Davis Center I hear a lot of talks about autoimmune disease. The paper discussed factors affecting the balance between pro-inflammatory and anti-inflammatory signals in the body, including regulatory T cells and T cell effectors. Mainly discussed were the regulatory abilities of endogenous neuropeptides (such as vasoactive intestinal peptide, α-melanocyte stimulating hormone, urocortin, adrenomedullin, cortistatin and ghrelin) and lipid mediators (omega-3 and omega-6 polyunsaturated fatty acids--PUFAs).

Endogenous neuropeptides have been observed to do the following:
1. Counterbalance inflammatory response
2. Downregulate Th1 response
3. Generate regulatory T cells (Tregs)

What especially caught my eye during my reading about the neuropeptides is that they induce the peripheral expansion of antigen-specific Tregs, which have a suppressive activity on self-reactive T cells. The suppressive mechanism of Tregs is mainly dependent on cytotoxic T-lymphocyte-associated protein 4 (CTLA4), or through production of immunosuppressive cytokines. Trialnet, the large diabetes prevention/amelioration study which I participate in (doing HLA typing) has a CTLA4 study going on using the drug Abatacept, which is a fusion protein of the extracellular domain of CTLA4 bound to immunoglobulin. Abatacept prevents T cells from getting activated when the CTLA4 domain binds to B7 on the antigen presenting cell. If the B7 is bound by the CTLA4 domain, then CD28 on the T cell cannot bind B7 and receive the costimulation necessary to activate the T cell. The drug Abatacept is currently approved for the treatment of Rheumatoid Arthritis.

Omega-3 and Omega-6 PUFAs are precursors for tons of different molecules, both pro-and anti-inflammatory. Some of the molecules Omega-6 PUFAs make are prostaglandins and leukotrienes, which are strongly pro-inflammatory molecules. I had been under the impression that Omega-6 PUFAs were exclusively pro-inflammatory, but according to this review, they can also stimulate pathways that lead to inflammation resolution. I have read some material that indicates the American diet has a too high Omega-6 to Omega-3 PUFA ratio which ruins our health (heart disease, cancer, etc.) So I was surprised to find that it is possible for them to aid inflammation resolution as well. I wonder if there is a way to make Omega-6 PUFAs be anti- rather than pro-inflammatory?

The article concluded with some analysis on how these molecules could be developed into novel therapeutics. Some have been successfully tested in animal models. Advantages of these molecules include that fact that they have a wide spectrum of action in vivo. However, neuropeptides are extremely unstable and side effects of most of the molecules are unknown. For example, I recently found out that ghrelin is involved in hunger and satiety, so would use of this neuropeptide therapeutically affect patient weight? I’m sure there are many such questions that could only be answered with animal experiments and clinical trials. In view of other natural human compounds that have been found to be therapeutic such as insulin and cortisone, these substances may present an attractive therapeutic option, but as usual, much work needs to be done.

Resource: Anderson, P., Delgado, M. ENDOGENOUS ANTI-INFLAMMATORY NEUROPEPTIDES AND PRORESOLVING LIPID MEDIATORS: A NEW THERAPEUTIC APPROACH FOR IMMUNE DISORDERS.
J Cell Mol Med. 2008 Jun 12. [Epub ahead of print]

High Times with Alzheimer"s

As we all know there is no cure for the degenerative Alzheimer's. But there is evidence according to Spanish studies that marijuana helps. The drug's active ingredients, cannabinoids have been shown to help prevent inflammation and protect the brain. No tests have been performed on people living with the disease, but researchers have studied human brain tissue, of normal and Alzheimer's, and conducted cannibinoid experiments on rats.

The rats were injected with beta-amyloid, a protein which simulated Alzheimer-like effects on their brain. They were also injected with the marijuana ingredient--cannibinoid. For comparison, other rats were injected with another protein along with the cannibinoid. Then they were tested for memory, learning, and mental function. The cannibinoid was shown to prevent the trigger of inflammation in the cells around the Alzheimer "plaque" which is believed to be involved in development. "Our results indicate that cannabinoid receptors are important in the pathology of Alzheimer's disease and that cannabinoids succeed in preventing the neurodegenerative process occurring in the disease," write the researchers in the journal.

SOURCES: Ramirez, B. The Journal of Neuroscience, Feb. 23, 2005; vol 25: pp 1904-1913. WebMD Medical Reference from Healthwise: "Alzheimer's Disease: Topic Overview." News release, Society for Neuroscience.

Alzheimer's Disease

Alzheimer's Disease was first discovered in 1906 by Alois Alzheimer's. This disease is the 6th leading cause of death in the United States. It effects individuals by killing brain cells which leads to memory loss, thinking, and behavioral processes. Alzheimer's is just one of a number of forms of dementia, which is the general term used for memory loss and the loss of other abilities that effects everyday life. Alzheimer's can occur in conjunction with another form of dementia known as vascular dementia. Vascular dementia destroys the brain by constricting blood flow ultimately leading to cell death. There is sadly no cure for dementia but there are numberous treatments available to alleviate the symptoms and improve the quality of life for those effected with this disease.

For more information on Alzheimer's Disease please visit www.alz.org
(all information provided above was from this website as well)

Neurodegenerative Disease: Parkinson's Disease

Parkinson's Disease is a neurodegenerative disorder that affects nerve cells in the brain that control muscle movement.  The disease results from the lack of the chemical messenger dopamine in the brain.  Dopamine is produced in the substantia nigra of the brain.  Parkinson

s Disease causes the cells that produce dopamine to either become impaired or die.  What sets this in motion is yet to be determined.  

Signs and Symptoms

The symptoms of PD are often described using the acronym: TRAP.

T = Tremor: The characteristic tremor of PD often begins in a hand.

R = Rigidity: Muscle stiffness often occurs in the limbs or neck.  This stiffness can be so severe that range of motion and/or pain can result

A = Akinseia: this is the lack of movement or slowness in initiating/maintaining movement.

P = Posture Instability: Characteristic bending or flexion of the body.  It is associated with difficulty in balance and disturbances when walking.

Other symptoms that can appear with the progression of the disease include the loss of automatic movements, speech changes, and dementia.

Risk Factors

There are a few known risk factors for the development of PD.  First and foremost, it is very uncommon for young adults to experience the disease and risk of development increases with the progression of age.  Also, men are more likely to develop Parkinson's Disease than women.  Finally, if you have one or more close relatives have PD your chances of developing it increase.  However, your risk is still less than 5%.  Again, what sets off the initial events towards the development of PD is still unknown.

Diagnosis

Currently there are no definitive tests towards the diagnosis of PD.  This makes it incredibly difficult to diagnosis, especially in the early stages of disease progression.  Often, a diagnosis is made based on your medical history and neurological exam.  This exam includes an evaluation of walking and coordination.  Finally, with a diagnosis, a patient will normally have 2 out of the 3 cardinal Parkinson's Symptoms as mentioned earlier:  either tremor, akinesia, or rigidity.  

Treatment Options

Currently there are two major drugs on the market to treat PD.  First, there is Levodopa.  This is a natural substance that everyone has in their bodies.  When it is taken in a pill form, it passes into the brain and is converted into dopamine.  As PD progresses, medication adjustments will have to occur due to the tendency of the drug to wear off.  Dopamine antagonists are also used to treat PD.  Unlike levodopa, these are not converted into dopamine.  Instead, they mimic the effects of dopamine causing neurons to react as if dopamine were present.  However, they are not nearly as effective in treating the symptoms of PD and are often used to smooth the on-off effect of levodopa.  Other forms of drugs are: MAO B Inhibitors, COMT Inhibitors, Anticholinergics, and Antivirals.  Accompanying drug treatment is physical therapy.  This helps to improve range of motion and muscle tone.  Finally, the most common surgical procedure to treat PD is deep brain stimulation in which an electrode is place in the area of the brain that controls movement.  Stimulation is controlled by a pacemaker-like device placed under the skin in the upper chest.  This form of treatment is often used with patients in advanced stages of the disease.   Although the above treatment options have proven to be beneficial in helping with the symptoms of PD, there still is no cure for the condition.

References:  www.mayoclinic.com

Stress and Neurodegenerative Disease

Just like most diseases and disorders we have discussed thus far in class, stress presents itself once again as an agent for distruction. Chronic stress will intensify inflammation and increase the risk for developing neurodegenerative diseases, such as Multiple Sclerosis. Researchers presenting at the 115th Annual Convention of the American Psychological Association (APA) have revealed that stress-related increases in the central nervous system inflammation are prevalent in animal models with multiple sclerosis. Researchers have found that stress-induced increases of proinflammatory cytokines will inhibit the clearing of a virus and allow the inflammatory process to run amok, ultimately increasing the vulnerability of the body to be overrun with a neurodegenerative diseases, like MS. Studies have also revealed that patients already presenting with MS will have severly worsened symptoms in reasponse to stressful events. The specific cytokine found guilty for this vulnerability to nuerodegenerative diseases is interleukin-6 (IL-6). Researchers used a social disruption model to simulate stress for mice and what they found is stress appears to elevate levels of IL-6 which subsequently increases the severity of MS symptoms. On a lighter note, they have also found that this worsening can be prevented through neutralizing antibody treatments. Furthermore, interventions that prevented or reversed the stress-induced increases in IL-6 in the mouse model may have implications for humans and recent evidence suggests that some potential interventions include certain anti-inflammatory drugs, exercise, antidepressant medication, omega-3 fatty acids, and mindfulness relaxation training.

Resources:
Exam Health-http://www.emaxhealth.com/32/15106.html

Neurodegenerative disease: Multiple Sclerosis

MS is an autoimmune disease in which antibodies attack the white matter in the brain. The white matter is made up of oligodendrocytes that wrap around the axons in the central nervous system (brain and spinal cord) and form a fatty layer called the myelin sheath which helps in signal transduction. When demyelination occurs, the axons of neurons can't effectively conduct action potentials. If you have multiple sclerosis, you’re not alone. MS affects over 400,000 people in the United States and may affect 2.5 million people worldwide. Multiple sclerosis affects 2-3 times as many women as men. No two people get MS in the exact same way as in it differs in timing, location, and severity. In general, people with MS can experience partial or complete loss of any function that is controlled by, or passes through, the brain or spinal cord.

There are 4 different types of MS:

1. Relapsing/Remitting (RRMS):
This is characterized by relapses (also known as exacerbations) during which time new symptoms can appear and old ones resurface or worsen. The relapses are followed by periods of remission, during which time the person fully or partially recovers from the deficits acquired during the relapse. Relapses can last for days, weeks or months and recovery can be slow and gradual or almost instantaneous. The vast majority of people presenting with Multiple Sclerosis are first diagnosed with relapsing/remitting. This is typically when they are in their twenties or thirties, though diagnoses much earlier or later are known. Around twice as many women as men present with this variety.

2. Secondary Progressive (SPMS):
After a number of years many people who have had relapsing/remitting MS will pass into a secondary progressive phase of the disease. This is characterised by a gradual worsening of the disease between relapses. In the early phases of Secondary Progressive, the person may still experience a few relapses but after a while these merge into a general progression. People with secondary progressive may experience good and bad days or weeks, but, apart from some remission following relapsing episodes, no real recovery. After 10 years, 50% of people with relapsing/remitting MS will have developed secondary progressive

3. Progressive Relapsing Multiple Sclerosis (PRMS):
This form of MS follows a progressive course from onset, punctuated by relapses. There is significant recovery immediately following a relapse but between relapses there is a gradual worsening of symptoms.

4.Primary Progressive (PPMS):
This type of MS is characterised by a gradual progression of the disease from its onset with no remissions at all. There may be periods of a leveling off of disease activity and, as with secondary progressive, there may be good and bad days or weeks. PPMS differs from Relapsing/Remitting and Secondary Progressive in that onset is typically in the late thirties or early forties, men are as likely women to develop it and initial disease activity is in the spinal cord and not in the brain. Primary Progressive MS often migrates into the brain, but is less likely to damage brain areas than relapsing/remitting or secondary progressive - for example, people with Primary Progressive are less likely to develop cognitive problems.


There is no known cause for MS, however, factors such as heredity, the immune system, geography and climate, and viruses are being studied.

There is no cure for MS. The current treatment for MS is either injectable or infusion therapy.

Resources:
http://www.mult-sclerosis.org/whatisms.html
http://www.msactivesource.com/msavProject/msas.portal/_baseurl/twoColLayout/SCSRepository/en_US/msas/home/What-Is-Multiple-Sclerosis/index.xml