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Neurological Diseases see also antioxidant products and oxidation and Alzheimer's Disease US Patents for transgenic mice models: U.S. Patent 5,387,742 U.S. Patent No. 5,602,299 Alzheimer's is a neurodegenerative disease associated with aging affecting more than 5% of the population over the age of 65 years. More than 20 million people are affected world-wide. The disease is characterized by increased deposition of amyloid-beta peptide and neurofibrilary tanges in the brain. The histopathological hallmarks are senile plaques and neurofibrillary tanges, which cause progressive synaptic dysfunction and, eventually, death of neurons, especially in the limbic and association cortices, which have roles in memory and navigation. Senile plaques consist of a core of amyloid-B peptide deposits surrounded by degenerative presynaptic endings together with astroyctes and microgial cells. Possible Causes: TLR4 and MD2 form a complex through which LPS and its receptor, CD14, can initiate an intracellular signal that induces pro-inflammatory presonses. in Alzheimer's disease, amyloid-beta is highly hydrophobic and therefore could induce innate immune reponses similar to those triggered by LPS. It has been shownt that acute or chronic administration of LPS into the brain ventricles of rats can result in gliosis, cyotkine production, increased APP concentrations and, in some caes, cognitive deficits. Glial activation due to LPS administration has been thought to mimic some features of Alzheimer's disease. Under certain circumstances, immune cells in the brain, known as microglia, promote the inflammatory and destructive process that can lead to Alzheimer's disease. It has been reported that once a specific molecule on the surface of microglia, CD40, get activated by its partner, CD40 ligand, the scene is set for microglial injury to the main cells in the brain; the nuerons. In Alzheimer's disease there is an increase in the production of ROS, an increase in cytosolic calcium influx, and in an increase in the phosphorylation of tau protein. Treatment Strategies: Researchers are currently administering anti-CD40 ligand antibody to mice so as to develop symptoms similar to Alzheimer's disease. The mice can then be immunized with an investigational anti-Alzheimer's vacine shown to remove beta amyloid plaques that accumulate in the brain, thereby leading to nerve damage and memory loss (Morgan). Lou Gehrig's disease (ALS): ALS is a disease of the central nervous system. It involves the progressive degeneration of the nerves that carry impulses to muscles. ALS is characterized by the death of the nerves that control motor function (also called motor neurons). This occurs after the motor neuron cell bodies shrivel and harden, a process called sclerosis. The clinical symptoms of ALS may firt appear in the skeletal muscles, referred to as "limb onset" ALS, or in the bulbar muscles of the throat, tongue, and respiratory system, referred to as "bulbar onset" ALS. Multiple Sclerosis (MS) MS is an autoimmune human disease without fully effective treatment and alrgely unkown pathogenesis. Who gets MS/risk factors MS affects about one million people worldwide with 350,000 cases in North America alone. It ranks as a major cause of nervous-system disability in young adults between the ages of 15 and 45 years. Women are affected two times more frequently than men. Since the 1960s, a possible linke between MS and mercury exposure from amalgam used to fill dental caries has been explored. What happens with MS? MS is usually a sporadic disease and is characterized as a variably progressive human disease of the nervous system in which patchy degenerative and inflammatory changes occur within the brain and spinal cord. MS is a chronic inflammatory disease characterized by lymphocyte infiltration and inflammation of the central nervous systen (CNS) white matter. T cells recognizing myelin protein pepetides are likely involved in the pathogenesis of the disease. Myelin is a fatty substance which covers the axons of nerve cells and is important for proper nerve conduction. The disease often beings in young adulthood with recurrent inflammatory attacks against the white matter of the brain, producing a myriad of neurological impairments, including blindness, loss of senstation, lack of coordination, bowel and bladder incontinence and diffculty walking. Abnormalities and Causes of MS Inflammation and autoimmunity: In MS, certain T cells trigger inflammatory processes when they encounter myelin, stimulating other immune cells and soluble factors like cytokines and antibodies. Normally there is a tight barrier between the blood and brain called the blood brain barrier, built up of endothelial cells lining the blood vessel walls. The inflammatory processes triggered by the T cells creat leaks in the blood brain barrier which causes swelling, activation of macrophages and more activation of cytokines and destructive proteins like matrix metalloproteinases. The final result is demyelination or destruction of myelin. The hallmark pathology in MS is the plaque- an area of myelin that has been denuded by inflammation and subsequent scarring by non-neural cells in the brain, including bone marrow derived microglia and brain derived star shaped astroglia. The cause of MS is enigmatic, although most investigators believe that immune attack against white matter is paramount, with the resulting degeneration of axons and nyelin being secondary to this inflammatory process. T Regulatory Cell Dysfuction: There are few reports on functional analysis of CD4+CD25high cells isolated form patients with autoimmune disease. One reports finds no difference in the frequency of these cells between patients and healthy controls but T-reg cells derived form patients as compared to healthy controls did exhibit significantly less suppressive function. Th1/Th2 Imbalance: MS is believed to be an autoimmune disease in which Th1 immune responses predominant. This response is associated with an increased production of IFNy and IL12 produced by T cells and by cells of the monocyte lineage. An increased expression of costimulatory molecules by T cells and APCs Amyloid cascade: A significant body of evidence point to an amyloid cascase event in the pathogenesis of AD, where amyloid precursor protein (APP) is processed to AB, by B- and y-secretases, which spontaneously self-aggregate in the presence of divalent metals (Fe2+, Cu2+) into nuerotoxic amyloid fibrils in the neocortex. Experimental Models Experimental autoimmune encephalomyelitis (EAE), an inflammatory CNS demyelinating disorder which serves as the prime animal model for MS can be induced in a number of species by immunization with myelin components or injection of autoimmune T lymphocytes. Treatment Interferon treatment: In the US, there are currently five FDA approved treatments for patients with relapsing-remitting MS. Three are interferons: Interferon beta-1a (Avonex and Rebif) or beta-1b (Betaseron). Part of there mechanism may be to reduce MO CD86 and CD40L expression as well as IL-12 secretion. IFN-B induces IL-10 secretion and suppresses IFN-y-inducible MHC class II up regulation an APC. A fourth approved medication is glatiramer acetate (Coaxone), a mixture of polypeptides which may protect important meylin proteins by substituting itself as the target of immune system attack. A fifth medication, mitoxantrone is effective but is limited by cardiac toxicity. All of the medications cited require frequent injections and are expensive. MS patients are usually given high doses of intravenous corticosteroids, such as methylprednisolone to end the attack sooner. This corticosteroid treatment however does not appear to have a significant impact on long term recovery. During symptomatic attacks, patients may be hospitalized. Bone marrow transplant and total lymphoid irradiation have been studied and are currently reserved for the most dire cases. TNF-alpha treatment: Proposed methods of using TNF-alpha or in the alternative down regulating TNF-alpha have been proposed (see for example. US Patent Publication 2003/0228276A1). Apparently, the level of TNF-alpha in a pateint suffering from a neurological disease is important. Low concentration may provide a neuroprotective activity whereas high concentraiton of TNF provides a nuerodegerative effect. natural products: Among natural products, a recent study found that women who took vitamin D supplments were 40% less likely to develop MS than women who did not take supplements. There were, however, some controversy regarding whether or not the beneficial effects were due to vitamin D or multivitamin supplments including vitamin E and various B vitamins, which may also exert a protective effect. An extracellular adherence protein (Eap) of Staphylococcus aureus reprotedly exerts antinflammatory activities by interacting with ICAM-1 and blocking beta2-integrin-dependent neutrophil recruitment. Huntington's disease (HD): is an inherited degenerative brain disease characterized by intellectual decline and involuntary movement of limbs. The onset of the ultimately fatal disease occurs later in life and is associated with the death of a population of neurons in the basal ganglia of the brain. A trinucleotide repeat (CAG repeat) of variable but abnormal lenght is specifically related to HD and to the protein "huntingtin" the role of which is still not clear. Parkinson's Disease (PD): is a slowly progressive neurodegenerative disease of the substantia nigra, an area localized in the basal ganglia of the CNS. The disease is characterized by muscular tremor, slowing of movement, partial facial paralysis, peculiarity of gait and posture, and weakness. Typically, when patients present iwth first clinical signs, the vast majority of nigral neurons that synthesize dopamine have perished. In most cases, the causes of the disease remian unkown. Natural Products for Neurodegeneritive Diseases generally: Folate, Vitamin E, and ALCAR: A nutriceutical formulation which contains at least 2 of the natural products folate, vitamin E, and ALCAR has been reported effective to amerliorate the effects of nuerodegeneration. ALCAR is an ester of the trimethylated amino acid L-carnitive, which is normally synthesized in human brain, liver and kidney. It facilitates the uptake of acetyl-CoA to mitochondria during fatty acid oxidation and thus enhances cellular energy production. Folate has been shown to buffer oxidative damages in the CNS and its absence is associated with nuerodegerenation. See US Patent Publication # US2005/0043312. |
