Caffeine effects on PD in Men vs. Women

Parkinson’s Disease is a disease involving the degeneration of neurons in the substantia nigra. Many of these neurons contain the neurotransmitter dopamine. The degeneration of these neurons decreases the level of dopamine leading to an imbalance in the way muscles work and problems with movement.

Cures for Parkinson’s are idiopathic, however, studies have found treatments to the disease. One such treatment in reducing the symptoms of (PD) is caffeine intake. Caffeine is known as an antagonist to adenosine receptors which causes an increase in dopamine levels in the brain. There have been many large studies proving that caffeine intake does, in fact, reduce the risk of (PD) in men, however, in women it is questionable. One reason for the difference in effects of caffeine is the hormonal factor. Interesting discoveries were made from many studies: 1) Postmenopausal women taking hormone replacement therapy (HRT) who also drank five cups of coffee or more per day showed an increased susceptibility in developing PD 2) Women taking HRT and drank small amounts of coffee per day did not appear at risk to PD 3) And according to Dr. Ascherio, women not taking HRT who also drank less than half a cup of coffee per day had a PD risk similar to that of men. Interestingly, the combination of coffee and hormones shows a drastic increase in risk of PD development in women. Yet, each factor individually is proven to protect against PD. Hmmm!!!

Researchers suggest that estrogen levels in women have “neuroprotective effects in PD.” Dr. Schwarzschild believes that caffeine and estrogen are competing in the body, as a result, canceling each other’s effect. Another theory of his is that estrogen is interfering with the break down of caffeine in the body.

Dopamine and Memory Loss

In class the question was brought up about how depression affects memory loss. In the article "In Search of Lost Time," the author mentions how memory loss can be caused by depression, anxiety, and trouble sleeping. I looked back at the PSIO480 notes and found out how dopamine is involved in depression, anxiety, and trouble sleeping. The dopamine is a neurotransmitter and the pathway begins in the midbrain. The midbrain controls all our automatic functions including sleep. The dopamine pathway ends in the hypothalamus, basal ganglia, and mesolimbic area. The hypothalamus controls our short-long term memory. And the mesolimbic area influences goal-directed behavior and also anxiety. The main problem would be a disturbance in the dopamine pathway. And memory loss would be associated with depression, anxiety, and trouble sleeping.

HLA-DR: Genetics and Autoimmune Conditions

In the "Inflammation in MS" review, the DR-17 haplotype was associated with autoimmune disorders such as diabetes, lupus, and thyroid disorders. In fact the more general Human Leukocyte Antigens (HLA) were found as the cell surface antigens mediating the rejection of tissue transplants in HLA mismatched donors. HLA-DR family is a major histocompatibility complex (MHC II) cell surface receptor and is a ligand for T-cell receptor.

HLA-DR is linked to many autoimmune conditions and disease susceptibility or resistance. In response to signalling, HLA-DR molecules are upregulated. In the instance of an infection, the peptide binds to a DR molecule and is presented to a few T-cell receptors found on T-helper cells. These cells then bind to antigens on the surface of B-cells stimulating B-cell proliferation. Upon activation, antibodies are produced, which can lead to autoimmune disorders or disease resistance.

Wikipedia has a very nice table of diseases associated with HLA-DR, displaying which specific DR is linked with which disease.
http://en.wikipedia.org/wiki/HLA-DR

Neurodegenerative disease: Alzheimer’s synopsis

Alzheimer’s disease is a neurodegenerative disease that I took interest in because people spend their whole lives using cognitive function to create who they are. For some people the latter years of life are spent loosing all that function that was meticulously fostered to define them.
Alzheimer’s is the most common cause for Dementia, its cause and progression are not clearly known and there are no treatments for the disease. Despite a lack of options, there are a few things that are known about Alzheimer’s, such as the target population, the general symptoms and the plaque and tangle significance.

The disease targets people who are 65 and older. The progression can go from 5 years to 20 years and unless symptoms are displayed it the beginning stages can be overlooked. The most common symptom that brings the disease to light is memory loss becomes a concern to the individual. Other symptoms that follow are mood swings, confusion, anger and long-term memory loss. Individuals that have been diagnosed with Alzheimer’s are associated with having large numbers of plaques and tangles in the brain. Plaques are extracellular deposits in the gray matter of the brain that are surrounded by an abundance of immune cells microglia and astrocytes that are associated with neural degenerative disease. Tangles are protein aggregates also seen in those with Alzheimer’s however their role is unknown.
Perhaps with further research new strides can be made.

Sea Bathing???

I was researching cures/relief mechanisms for arthritis and something really caught my eye. Sea bathing. I really don’t know if it’s fact or fiction. I’ve searched high and low and all I’ve gotten are mixed theories and beliefs. Many articles state that sea bathing is a beneficial treatment for arthritis. The main constituent in the sea water valuable for pain relief of arthritis is iodine. Accordingly, iodine is known for its regulatory effects on the acid-alkaline balance in the blood and tissues. It is absorbed through the pores of the skin and enters into the thyroid gland’s secretion. It’s purpose is to restore worn out tissues and correct internal imbalances. If someone wants to check up on this subject please do and let me know what you find.

P.S. They say that if you’re not next to a body of sea water the next best thing is 30 minutes every night in a tub of warm water with a cup of sea salt. Hopefully, this home remedy really does do the trick for arthritis relief.

Calorie Restriction: Protecting From Neurodegeneration

Calorie restriction seems it may have a neuroprotective effect in ageing or age-related diseases, though the mechanism is not quite clear. In a study from the National Institute on Ageing found that adult mice showed an increase in neuron generation in the hippocampus, than mice on a normal diet. The dietary restriction boosts factors such as brain-derived neurotrophic factor (BDNF), which increases the brain's ability to produce neurons from stem cells and resist damage. This seems to mean that brain is more protected from degeneration, like Parkinson's and Alzheimer's diseases. More studies should be done to see if supplementing BDNF will produce the same results without calorie restrictions.

A study at the University of Florida showed that calorie restriction might prevent brain cell death. As seen in rats, apoptosis increases with age, however caloric restriction reduces this increase by 36%. This is possibly explained that the restrictive diet helps prevent age-related decline of ARC (Apoptotic Regulatory Protein) which represses apoptosis.

There are many other ways that caloric restriction can protect the brain. like affecting the endocrine system. A study in Neurobiology of Aging showed that this caloric restriction suppressed levels of specific hormones involved in high-energy processes, such as reproduction and growth (in mice). The hippocampus also seems affected through mechanisms that are mostly not understood.

http://websites.afar.org/site/PageServer?pagename=IA_b_cal_19_r_brain

However, as said in the article "One for the Ages: A Prescription That May Extend Life" there is very little proof that caloric restriction will have as substantial an effect on humans. Experts say that this may only increase lifespan by 2-7%. So is it really worth adopting such a severe diet, to live a little longer or to enjoy all the delicious calories and sacrifice a few years?

Mason, Michael: "One for the Ages: A Prescription That May Extend Life," New York Times, October 31, 2006

Histology 101: Synovial Joints, a Possible Explanation to their Susceptibility to Infection

A synovial joint consists of articulating bone surfaces that are covered with hyaline cartilage (aka articular cartilage) separated with a fluid filled space surrounded by a joint capsule. The lining of the joint space is covered with a synovial membrane. Synovial membranes are composed of cuboidal collagenous cells called synoviocytes, they function to secrete synovial fluid that aid lubrication.

This anatomical set-up seems pretty safe, a dense layer of cells surrounds the underlying vasculature to protect from infection. Well, not quite... in most epithelium, such as our stratified squamous epithelium of our skin, there are tight junctions and basal lamina that aid in keeping propagators of inflammation out. However, the layer of synoviocytes do not come with this protective shield. This fact has lead scientists to group synoviocytes separate from the tradition epithelium cell type.

What's the connection to arthritis? One of the many causes of arthritis is inflammation that can be caused by a septic infection that can eventually make its way to the synovial fluid of joints. Since there are no tight junctions or basal lamina within the synovium, bacteria have the ability to enter the highly vasculature tissue and initiate inflammatory processes. The body's reaction to joint inflammation often leads to joint destruction and therefore arthritis.

The important role of tight junctions and the basal lamina can be seen in the comparison between epithelium and synoviocytes and their ability to react to Staphylococcus aureus. Staphylococcus aureus is a very common bacteria strain seen within the mucus membranes of the respiratory tract and basically any outer surface of our body. Within the mucus membranes, for example, the bacteria are essentially trapped outside the body. However, within the synovial membrane, Staphylococcus aureus can easily enter. Staphylococcus aureus is the most commone infection seen within infectious or septic arthritis.

Young, Barbara, James Lowe, Alan Stevens, and John Heath. Wheater's Functional Histology, a Text and Colour Atlas. 5th ed. Churchill Livingstone Elsevier.

"Septic Arthritis." MayoClinic.Com. 31 July 2006. Mayo Clinic. http://www.mayoclinic.com/health/bone-and-joint-infections/
DS00545/DSECTION=3.

Interleukin-1 and inflammatory degeneration

Inflammatory processes in the brain (and systemically) have been linked to neuron loss in CNS disease and injury, including Alzheimer’s Disease, Parkinson’s Disease, MS, stroke, etc. Inflammation in the brain can lead to increased expression of inflammatory mediators, cytokines being a primary one in the inflammatory response. The cytokine IL-1 has been shown to contribute to neuronal loss and may play an important role in neurodegenerative disease. IL-1 is expressed rapidly by microglia in response to injury, and increases brain injury by neutrophil mobilization and cell apoptosis by MMP-9.
Experimental brain insults, including ischaemia, trauma, inflammatory stimuli, etc, increased the expression of the IL-1 family. Administration of this cytokine causes a major increase in neuron cell death after brain injury. In models of Alzheimer’s in mice, B-amyloid- activated microglia produced IL-1, promoting the production of neurotoxic B-amyloid peptides. Furthermore, rat brains with high expression of IL-1 resulted in demyelinating lesions, similar to MS.
IL-1 is not toxic to pure neurons or when injected into healthy brains. Neurotoxicity typically requires cell contact interactions between astrocytes and neurons. IL-1 up-regulates genes in astrocytes that encode neurotoxic mediators, as well as survival-promoting factors. It also acts on endotheilial cells of the brain to up-reulate the expression of adhesion/chemoattractant substances and promote BBB breakdown, which are factors involved in leukocyte recruitment. There are many other examples in this paper of how IL-1 mediates neuron death, but the major focus should be on how we can modify or control this.
IL-1RA(receptor antagonist) is a major player , providing neuroprotection, that researchers are studying. It has been a success in treatment of rheumatoid arthritis, and has shown promise in the Phase II trial in stroke patients. It inhibits ischaemic, excitotoxic and brain injury in rats. There is still a lot of studying to be done on this but with high hopes. Brain injury creates a therapeutic challenge and it is still unclear whether inflammation promotes CNS diseases or is merely a coincidence. With the increased awareness of many neurodegenerative diseases today, I predict that we will know a lot more in the near future.

Gold salts anyone?

Dr. David Pisetsky, chief of the division of rheumatology and immunology at Duke University Medical Center have recently found the curative property of gold salts for rheumatoid arthritis and other inflammatory diseases. Dr. Pisetsky, working with other scientists at Karolinska Institute in Sweden and the University of Pittsburg, have been studying the functional properties of HMGB1 molecules, which converts DNA to RNA inside the nucleus and is released from the cell either through normal processes or cell death. This molecule is released from the cell by the help of interferon-beta and nitric oxide. HMBG1 belongs to the High Mobility Group proteins that not only act on DNA transcription but also play a role on DNA repair. HMGB1, once released by the cell, attracts neutrophils and other inflammatory cells to infected tissue. This (HMGB1) molecule is found to be high in the synovial tissue and joint fluid where arthritis commonly occurs. Pisetsky and colleagues conducted their research on the properties of gold by stimulating mouse and human immune cells to release HMGB1 then treat them with gold salts. What they found was that when the immune cells were exposed to gold salts, there was an inhibition in the release of HMGB1 molecules from the nucleus. The implication is that if you block the release of HMGB1 molecules (which stimulates the aggregation of inflammatory cells in one location) then it should decrease the immune response. The gold salts inhibits the release of HMGB1 by blocking the helper molecules (interferon-beta and nitric oxide) so it is sequestered inside the nucleus and therefore cannot stimulate the immune system.

But like all the other treatments (for any disease), gold salts has its own side effects, which includes rashes, kidney damage and bone marrow's ability to synthesize blood cells and its ability to decrease immune system response via HMGB1 inhibition takes months to take effect. So until they figure out how to decrease some of the side effects and also decrease the time for gold salts to work, it could be awhile before this treatment would be as effective as one would hope. Still, it looks like Pisetsky and colleagues are going in the right direction in searching for another possible treatment for arthritis.

More information about HMGB1 protein:
HMGB1 proteins is secreted by macrophages and monocytes that were activated by IL-1 or TNF-alpha and act as a chemoattractant for myeloid and muscle cells. These proteins stimulates the expression of adhesion molecules in the endothelial cells, making it easy for inflammatory cells to bind and migrate to infected sites. This molecule also impairs the barrier function of intestinal epithelia (inhibiting the protective activity of intestine against pathogens). HMGB1 activity is initiated by binding to RAGE (receptor for advanced glycation end products), which is present in many immunoglobulin cells. The binding of HMGB1 to RAGE activates the chemoattractant capabilities of HMGB1 proteins thus stimulating the inflammatory response.


www.sciencedaily.com/releases/2007/10/071022153109.htm (from Science Daily)
'Role of Toll-like Receptors in HMGB1 release from Macrophages' by David Pisetsky and Weiwen Jiang (from Annals of the New York Academy of Sciences)