Файл: Extracellular and Intracellular Signaling (книга).pdf

extracellular antagonists and agonists as well as the balance of intracellular synergizing and dysynergizing signal transduction networks. Drugs can help restore the balance of endogenous agonist/antagonist activity. Drugs do not cure diseases, but facilitate the ability of the body to cure itself. This is similar to the American Indian theory of balance in health and the Chinese theory of health that depends on the proper balance of yin (cold) and yang (hot). Yin is also the female or inhibiting aspect of the body. Yang is the male or activating aspect of the body.

The receptor approach is further complicated by the following factors. Typical receptor-based research has reasonably focused on the ligand binding site of the receptor. As in enzymology, there may well be alternate sites on the receptor that are amenable to drug action.1 An example in the GPCR realm is the interface between receptor and G protein.2 Agonist or antagonist substances binding to any of a number of available regulatory sites between receptor and G protein could influence tra cking through the coupled signal transduction system.

Further downstream in the transducing system there could be drug targets that influence other enzymes or targets in the pathway, and in these targets a multiplicity of possible interactive locations, from ligand binding sites to allosteric sites, could occur. Specificity has long been a concern and goal of pharmacology, and for some disorders this approach is likely to be the best. In other cases, and migraine headache may be one of these, an agent or agents that hit in many locations may be preferable. Natural products like cannabis come to mind in this regard. Tetrahydrocannabinol (THC) or cannabidiol (CBD) alone or even THC and CBD in combination may not be the most e ective therapeutic approach. Rather the combination of cannabinoids, terpenoids and other substances found in crude cannabis preparations may allow for the greatest coverage of useful target sites.

1.2 Experimental Approaches to Disease Treatment

The Chinese have experimentally found ways to stimulate yin and yang in order to restore balance between proinflammatory and anti-inflammatory factors and treat disease.3 Too much yin can be caused by an insu cient flow of vital forces, such as blood, lymph and chi. Too much yang can be caused by excessive flow of vital forces. Chi is the source of life and is a life force carried in the body by the acupuncture channels. Chi is required to regulate the balance between yin and yang. It is possible that chi and the intracellular signal transduction networks accomplish the same purposes. Regulation of gene transcription is also involved in chi. It is also possible that endogenous extracellular ligands accomplish the same purposes as yin and yang.

The brain and nervous system depend on endogenous ligands and signal transduction networks, just like other organs. In addition, neurons modify each other’s signals through synaptic interactions. Therefore, the brain has

intracellular signal transduction networks, extracellular ligands and synaptic interactions that are important in the production of neuronal impulses.

However, the brain also depends on perceptions that alter signal transduction networks. Perceptions come from a variety of stimuli outside or inside the body and are translated into neural signals and synaptic impulses in the brain. Perceptions are important in anxiety disorders, delusions, depression and other disorders. Even Parkinson’s disease is more common in people who are more prone to anxiety. Unfortunately, very little is understood about how perceptions are involved in altering signal transduction networks and endogenous ligands in the brain. It is possible that a balance exists between perceptions of comfort and discomfort that is needed for proper brain health.

The involvement of perceptions in pain processing can be taken another step into the realm of an a ective component of pain. In gate theory4 once the original nociceptive signal is processed in a perceptual sense in the brain, an a ective or emotional component of feedback is sent to the periphery to further gate in other words allow for increased or decreased movement of sensory information into the input pathway. Additionally, in this context, local signals in the periphery that involve non-pain input may further influence the strength of the pain signal. All of these aspects of pain processing suggest multiple sites for therapeutic intervention either alone or in some complex interacting fashion. These aspects are probably also important in the placebo e ect that is prominent in pain treatment.

Before antibiotics were discovered, the treatment of infectious fevers involved aspirin and cold baths to bring down the fever. The patient usually died anyway because only the symptom was being treated, not the cause. This is true of many diseases today. Only the symptoms are known, not the causes. However, advances are being made that will be discussed in the current work. Diseases for which no cures (and sometimes no causes) are known include hypertension, heart disease, diabetes, arthritis, Alzheimer’s disease, Parkinson’s disease, migraine headache, neuropathic pain, fibromyalgia and others. Advances are being made with hypertension, heart disease, diabetes and arthritis. However, it is important to realize with all of these diseases that the most powerful drugs available to treat the symptoms do not cure the diseases.

1.3 Adipokines and Disease Causation

Recently, fat cells, especially visceral fat cells, have been found to secrete adipokines, such as visfatin, leptin, resistin, C-reactive protein, angiotensin II, tumor necrosis factor alpha, and interleukin 6, that are released into the blood and have e ects throughout the body (proinflammatory factors). Macrophages, in obese patients, can also secrete adipokines. Obesity, caused by a sedentary and overindulgent lifestyle, produces more fat, more adipokines and more toxic lipids, such as ceramide and endocannabinoids. These adipokines and toxic lipids induce inflammation and alter the balance of signal

transduction networks necessary for normal health. In addition, many adipokines alter the secretion of other adipokines.

Interleukin-6, tumor necrosis factor alpha, resistin, C-reactive protein, angiotensin II, ceramide and other ligands are involved in altering the balance of signal transduction mechanisms that leads to heart disease.5,6 Lipotoxicity, from ceramide, causes iNOS dysfunction resulting in oxygen radical production in the kidney leading to increased blood pressure. Adiponectin decreases due to increased endocannabinoids. Low adiponectin causes NO production to decrease. In endothelial cells, eNOS dysfunction leads to oxygen radical production. Angiotensin II and endothelin-1 increase, leading to increased peripheral resistance and more eNOS dysfunction. Resistin, TNFa and IL-6 decrease NO production. Wall defects develop in arteries, and are partially caused by leptin. Platelet, neutrophil and monocyte adhesion occurs due to increased production of adhesion proteins. TNFa, resistin and C-reactive protein may stimulate adhesion protein synthesis. Neutrophils invade arterial walls and start the inflammatory process. Monocytes and more neutrophils are activated and are stimulated to make oxygen radicals by visfatin and leptin. Oxidized LDL-C is taken up by macrophages making foam cells and plaque. Smooth muscle cell proliferation occurs due to the e ects of PDGF, angiotensin II and heparin binding epidermal growth factor-like growth factor. Plaque instability occurs due to C-reactive protein induced matrix metalloproteinase activity in macrophages.

Hypertension is caused by angiotensin II, resistin, visfatin, C-reactive protein, tumor necrosis factor alpha and other endogenous ligands.7,8 Vascular tone (blood pressure) is decreased by PGI2, NO, acetylcholine and vagal nerve stimulation (decreased cardiac output). Blood pressure is increased by adrenergic nerve stimulation, endothelin, angiotensin, renin, aldosterone and other factors. Adiponectin levels decrease in obesity leading to impaired vasorelaxation, due to less NO production, and higher levels of endothelin-1. CRP decreases eNOS and prostacyclin synthase activities leading to increased blood pressure. TNFa decreases iNOS activity and NO production. Visfatin inhibits vasodilation through an unknown mechanism. Resistin inhibits vasodilation induced by bradykinin and induces endothelin-1 transcription. Angiotensinogen is secreted to some extent by visceral fat, increases angiotensin II and blood pressure.

Diabetes is caused by endocannabinoids, ceramide, resistin, visfatin, inter- leukin-6, tumor necrosis factor alpha and others.9,10 Endocannabinoids decrease adiponectin production, and increase visfatin and TNFa production. Ceramide inhibits insulin receptor phosphorylation causing short-term insulin resistance. Ceramide also makes iNOS dysfunction, making oxygen radicals that destroy b cells. Resistin, RELMs and lipotoxicity cause short-term insulin resistance. Visfatin, IL-6 and TNFa are involved in long-term insulin receptor resistance.

Osteoarthritis is caused by endocannabinoids, leptin, resistin, TNFa, IL-6 and others.8,11,12 Endocannabinoids decrease adiponectin production and increase the production of other adipokines. However, rheumatoid arthritis

patients have high adiponectin levels perhaps as a compensatory mechanism. Leptin levels increase and activate macrophages, T cells and chondrocytes, leading to increased production of oxygen radicals and cytokines that are inflammatory. Inflammation follows with macrophages and monocytes di erentiating into osteoclasts. This di erentiation is caused by colony stimulating factor-1 (CSF-1) from fibroblasts. TNFa is involved in the stimulation of CSF-1 production. Neutrophils are activated by leptin and visfatin and induce more inflammation. Macrophages secrete resistin that induces TNFa and IL-6 in a vicious cycle.

Clearly, a large portion of the economically important diseases in developed countries are caused by toxic lifestyles that produce toxic extracellular ligands that alter the normal balance of signal transduction networks in the body. It is also clear that a number of genes are involved in these disease processes to produce the adipokines and toxic lipids. Therefore, these diseases have a number of potential drug targets. In addition, it is clear that re-establishing a healthy lifestyle can alter the activities of many genes, leading to better disease treatment.

The current approach to many chronic diseases is to treat symptoms, such as hypercholesterolemia in heart disease, pain in arthritis and high blood glucose in diabetes. In Alzheimer’s disease, billions of dollars are being spent to try to find ways to prevent or reverse plaque formation in the brain. Treating symptoms can sometimes slow down the disease process and may be of benefit to patients. However, the chronic disease is not cured or reversed. Lifestyle changes may be able to prevent or reverse chronic diseases, by re-establishing the proper balance between proinflammatory and antiinflammatory factors.

1.4 Questions in Disease Treatment

A question that remains unanswered for many drugs is: Do drugs alter the activities of endogenous agonists and antagonists such that recovery from a disease is impeded? For instance, opioids cause receptor desensitization through receptor of G protein signaling (RGS) and other mechanisms. When patients try to stop taking opioids, the pain returns and is much worse than before. The pain is worse because the endogenous opioid agonists cannot function normally due to opioid receptor desensitization. Are there similar processes with other drugs, such that the normal balance of endogenous agonist and antagonist activity is so disturbed that proper health cannot be restored?

Despite recent advances, there is still much that is not known. For instance, muscles are vital to proper health. Do muscles secrete myokines that are involved in maintaining health? How does exercise promote the health of stem cells throughout the body? The guts produce hormones that are important for health. The guts are associated with a large array of immune tissue and nervous tissue. Are there unknown enterokines that are involved in the health of organs, the nervous system and the immune system? Similarly, it is not known if bone secretes osteokines that might maintain health in other organs. The brain,

ganglia and other nervous tissues secrete a variety of hormonal ligands. There are undoubtedly more neurokines still to be discovered. Immune cells secrete a huge array of cytokines with a variety of e ects throughout the body. Many of these ligands are not fully understood. The kidneys, liver, pancreas, thyroid, adrenal glands, heart, vascular system, lymphatic system, reproductive organs, skin and other organs may also produce unknown extracellular ligands that are vital to proper health.

Drug development currently involves the carpenter approach: if the hammer does not work, get a bigger hammer. A good example of this approach is if aspirin does not work for rheumatoid arthritis, use methotrexate. Unfortunately, patients can die from improper use of methotrexate. A corollary of the carpenter approach is the search for more specific receptors. For instance, if antihistamines produce drowsiness by interacting with too many receptors (brain H1 and H2), find a more specific receptor (peripheral H1) that will not cause drowsiness. Similarly, if non-steroidal anti-inflammatory agents cause ulcers by interacting with too many receptors (Cox-1 and Cox-2), find a drug for a more specific receptor (Cox-2) that will not lead to ulcers. Unfortunately, the more specific receptor approach has resulted in catastrophic events with many thousands of people su ering major toxic e ects and death. Some of the peripheral H1 blockers caused arrhythmias. Some of the Cox-2 inhibitors caused thrombosis leading to heart attacks and strokes. Despite all of the powerful drugs available, there are no drugs that cure hypertension, heart disease, diabetes, arthritis and other chronic conditions. Currently available drugs can only manage these diseases. It is possible that finding drugs to re-establish the proper balance of agonist/antagonist and signal transduction networks may be a better approach. Better yet, promoting healthy lifestyles may help maintain or re-establish good health.

1.5 Toxic Lifestyles and Disease Treatment

Healthcare in the future will depend on helping people maintain proper lifestyles that promote a healthy balance of extracellular agonists and antagonists as well as signal transduction networks. Lifestyles are far more powerful than most drugs in terms of maintaining health, since lifestyle can alter many endogenous ligands and signal transduction networks at once. Commonly prescribed drugs tend to be magic bullets that a ect only one mechanism at a time. The magic bullet approach to drugs makes drugs far too specific and renders them useful only for managing one aspect at a time of a disease. However, drugs will always be needed to treat ill patients. Drugs that alter signal transduction pathways, such as protein kinase inhibitors, tend to have many e ects throughout the body. Some of these e ects are unwanted and therefore toxic. However, by using a model of matrix interactions that produces drug e ects, as presented above, it is possible that ways of decreasing toxicity may be found. Another approach may be to find drugs that help re-establish normal endogenous ligand synthesis and release.

For instance, a drug that stimulates endorphin synthesis and release may be useful in pain therapy.

There are four statements that patients want to hear. 1. You do not have to lose weight and exercise, because we have powerful drugs to control blood cholesterol. 2. You do not have to lose weight and exercise, because we have powerful drugs to control blood pressure. 3. You do not have to lose weight and exercise, because we have powerful drugs to control blood glucose. 4. You should not exercise, because exercise, especially running, causes arthritis. All four of these statements are false. Drugs that control cholesterol slow down, but do not stop, atherosclerotic processes. Heart attacks and strokes are delayed by drug therapy, but not prevented. Drugs that control blood pressure delay, but do not prevent, the onset of congestive heart failure. Drugs that control blood glucose delay, but do not prevent, the loss of vision, loss of toes, loss of kidney function and other consequences of diabetes. Exercise, especially

running, has been shown in several studies to slow down the progression of arthritis.13–16

Recommendations for lifestyle changes are not accepted readily by patients who are more interested in maintaining their toxic lifestyles, and adding drugs to manage their chronic conditions. In addition, healthcare professionals cannot make a living by teaching patients about healthy lifestyles. They make their livings by selling drugs and carrying out surgery. However, lifestyle changes are suggested for many chronic conditions, especially hypertension and diabetes. Patients are encouraged to lose weight, alter their diets, decrease sodium intake to no more than 2.4 g daily, stop smoking, decrease alcohol intake to no more than 15 ml (1 drink) daily for women or no more than 30 ml (2 drinks) daily for men, and to exercise. Among athletes, optimal body composition is about 4% body fat for men and 12% body fat for women. Women become amenorrheic and osteoporotic below 12% body fat. Optimal diets contain vegetables, whole grains and five servings of fruit daily. Recommended diets may have about 60% caloric intake from carbohydrate, 20% from protein and 20% from fat. Exercise should be moderate, not strenuous, and should be enjoyable. Walking, running, cycling, swimming and other forms of aerobic exercise are encouraged.17 Yoga, tai chi, meditation and spiritual practices are becoming popular among health-conscious adults and seniors. Patients may start with about 20 minutes of physical exercise daily and should increase this over a year or more to about an hour each day. Spirituality and its health e ects are poorly understood by science.18 Yet many patients seem to benefit from increased spirituality during their recovery processes. As mentioned in the discussion on migraine headache later in the book, a form of homeostatic regulation introduced by Bruce McEwen, known as allostasis, fits nicely into the holistic concepts introduced in this opening chapter.19 Daily physical exercise, meditation and spiritual practices should be maintained throughout life. The goals of lifestyle alterations are to maintain a productive personality, decrease abdominal fat, decrease osteoporosis, decrease inflammation of the joints, decrease blood cholesterol and glucose levels, decrease blood pressure and increase the exercise endurance of the heart.