Proteins in the brain

Chen G, Manji HK. Mood stabilizers regulate cytoprotective and mRNA binding proteins in the brain Long term effects on cell survival and transcript stability. Int J Neuropsychopharmacol 2001 4 47-64. 

Alzheimer s Disease This disease is due to the accumulation of j8-amyloid protein in the brain. The protein is believed to trigger brain degeneration through cell death of the neurons. Alzheimer s disease is characterized by loss of memory and intellectual performance, and slowness in thought. In the United States, a class of drugs called cholinesterase inhibitors is approved to treat Alzheimer s disease. Both Europe and the United States have approved a drug called memantine for treatment of Alzheimer s disease. 

Konishi, Y., Beach, T., Sue, L.I., et al. (2003) The temporal localization of frame-shift ubiq-uitin-B and amyloid precursor protein, and complement proteins in the brain of non-demented control patients with increasing Alzheimer s disease pathology. Neurosci. Lett., 348, 46-50. 

Rats exposed to 50 or 250ppmg-cymene 6 hours/day, 5 days/week for 4 weeks had a significantly decreased yield of synaptosomal protein in the brain, suggesting a decrease in the density and total number of synapses. ... 

Structure is also essential in complex biological molecules. A lot of medicines used for psychiatric illnesses such as depression rely on their ability to interact with certain proteins in the brain. For instance, a class of antidepressants—medications that alleviate the symptoms of depression—act on proteins involved with the collection (reuptake) of the chemical serotonin, and they are known as selective serotonin reuptake inhibitors (SSRIs). This class of antidepressants includes Prozac and Zoloft. Earlier medications were also effective and are still sometimes used though they produce a number of side effects, such as dietary problems. Although an SSRI can also generate potentially dangerous side effects, psychiatrists tend to observe these effects less often. (Brain chemistry is the subject of chapter 3.)... 

Figure 18.2 Redox proteomics and oxidatively modified proteins in the brain. Redox proteomics has the potential of detecting disease markers and identifying potential targets for drug therapy in neurodegenerative disorders. Redox proteomics involves the separation of brain proteins followed by detection, usually immunochemically, of oxidatively modified proteins, either from a two-dimensional western blot or from column eluents. Subsequent mass spectrometric analysis of tryptic digests and database searching leads to protein identification.

Angeletti RH, Novikoff PM, Juwadi SR, Fritschy JM, Meier PJ, Wolkoff AW. The choroids plexus epithelium is the site of the organic anion transport protein in the brain. PNAS 1994 94 283-286. 

Accumulation of P-amyloid proteins in the brain is one of the hallmarks of Alzheimer s disease. Dietary curcumin at low dose (160ppm) and high dose (5000ppm) significantly lowered oxidized proteins and interleukin 1-P, a pro-inflammatory cytokine... 

Table 13.2 Examples of drags demonstrating increased dissociation from plasma proteins in the brain microvasculature...

Zinc and Zinc Transport and Sequestration Proteins in the Brain in the Progression of Alzheimer s Disease... 

Prions also have the ability to trigger conformational change in their normal counterpart proteins in the brain, causing these to also adopt the improper configuration. In this fashion, the prion can essentially replicate itself. Because the conformational structure assumed during prion formation is thermodynamically stable, prions are exceedingly resistant to inactivation (128, 129). In addition, they can be transmitted orally. The effect of these traits is that the disease is not solely dependent on spontaneous generation to infect an individual or population, but it also can be acquired by consumption of infected tissue. 

Molecular mechanics calculations have proven to be enormously useful in organic chemistry, particularly in pharmaceutical research where the complementary fit between a drug molecule and a receptor molecule in the body is often a key to des ning new pharmaceutical agents. Morphine and other opium alkaloids, for instance, have a specific three-dimensional shape (Figure 4.26) that allows them to nestle into complementary-shaped cavities on opiate receptor proteins in the brain. Once this shape is known, other molecules calculated to have similar shapes can be des ned, leading to the possibility of enhanced biolc icsil activity. 

Bilberry extract 200 mg/(kg day) administered intraperitoneally to euthyroid rats increased radiolabeled triiodothyronine (T3) transport into the brain, compared to vehicle only (21). Postulated mechanisms include central or peripheral inhibition of L-thyroxine s (T4) deiodination to T3 inhibition of T3 protein binding or enhanced T3 binding to carrier proteins in the brain capillary wall (21). Whether bilberry could interact with thyroid replacement therapy remains to be seen. 

The pathogenesis of another well-known neurodegenerative disease (Jacob Creutzfeld disease) seems to be strongly linked to the presence of prion proteins in the brain. These macromolecules contain multiple Met residues, some of them in close vicinity. Such structure should favour stabilization of MetS as intramolecular (S.-.S) complexes. Since weak intramolecular non-bonded S O and S N interactions have been recently suggested in proteins [14], stabilization of MetS +through formation of S.-.N- and/or S.-.O-complexes might potentially accelerate oxidation processes in proteins.The first experimental evidence... 

Like other neurodegenerative disorders, such as Alzheimer s and Parkinson s disease, prion diseases are characterized by the formation and accumulation of an aberrantly folded protein in the brain. However, a unique feature of prion diseases is their transmissibility. Prions (acronym for proteinaceous infectious particles) are mainly composed of PrPSc, polysaccharides, and lipids, but lack nucleic acids longer than 25 nucleotides, arguing against an essential role for DNA/RNA in mediating infectivity [35, 36]. Indeed, recent experiments support the protein-only hypothesis recombinant PrP expressed in and purified from bacteria and subsequently misfolded in vitro can transmit the disease [37-40]. 

When a protein molecule gets misfolded for some reason, it is usually degraded. However, sometimes it escapes degradation and then it acts like a cheparon and causes the misfolding of the other protein molecules. This is the basis of the so-called infectivity of prions that causes mad cow disease and Creutzfeldt-Jakob disease. Once the healthy cow is exposed to misfolded protein or prions, it leads to the misfolding of the other proteins in the brain cells, which causes the disease. 

Other actions of methylene blue include monoamine oxidase inhibition, which can cause dangerous interactions with certain other drugs. Flowever, it also has potential to treat malaria and Alzheimer s disease, the latter as a formulation named Rember . Its activity in Alzheimer s disease is thought to depend on converting an abnormal tangled form of a protein in the brain back to the normal form, although the mechanism for this is not clear. 

In five of six half-genomic transgenic lines and one cosmid transgenic line, there was PrP expression as monitored by Northern analysis however, of eight lines tested for the cDNA construct, none, including those with >150 copy numbers, showed detectable levels of PrP protein in the brain and very weak to no mRNA expression. (Fischer et al, 1996). 

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