Calpain Inhibitor

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Calpain Inhibitor

Postby Lyon » Tue Nov 21, 2006 4:45 pm

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Postby CureOrBust » Wed Nov 22, 2006 1:28 am

the link didnt work for me.
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Postby Melody » Wed Nov 22, 2006 5:22 am

Public release date: 21-Nov-2006
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Contact: Ron Najman
ron.najman@downstate.edu
718-270-2696
SUNY Downstate Medical Center

Downstate researchers target multiple sclerosis
Researchers at SUNY Downstate Medical Center have developed a substance that inhibits the progress of multiple sclerosis (MS) in an animal model. The agent, a novel calpain inhibitor, can be administered orally.

Calpains are a family of proteolytic enzymes naturally found in the human body. Inappropriate activation of calpain is associated with a number of neurodegenerative and autoimmune diseases such as MS. It is known to destroy the myelin sheath that coats and protects the nerves.

In a paper published in the Journal of Neuroimmunology, SUNY Downstate and Maimonides Medical Center researchers described the use of the calpain inhibitor for the treatment of a mouse model of MS. Whether administered by injection or by mouth, the inhibitor produced an almost complete cessation of the disease's progress.

The calpain inhibitor, developed at Downstate, was shown to reduce clinical illness signs and prevent demyelination and inflammatory infiltration in a dose- and time-dependant manner, and holds promise in treating both the acute and chronic phases of MS. The inhibitor may also prove beneficial for treating other degenerative illnesses, such as Alzheimer's, Huntington's and Parkinson's disease.


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The research was conducted by Getaw Hassen, MD, PhD, as his doctoral thesis in SUNY Downstate's School of Graduate Studies. Faroozan Mokhtarian, PhD, MPH, associate professor of medicine and of microbiology and immunology at Downstate, developed the mouse model. The inhibitor was developed by Leo Kesner, PhD, professor emeritus of biochemistry, and Alfred Stracher, PhD, distinguished professor of biochemistry.

The paper was published in the November edition of the journal, and is available via Science Direct at: <shortened url>.

SUNY Downstate Medical Center comprises a College of Medicine, Colleges of Nursing and Health Related Professions, a School of Graduate Studies, and University Hospital of Brooklyn.
http://www.eurekalert.org/pub_releases/ ... 112106.php
John was diagnosed Jan 2005. On lipitor 20mg .On Copaxone since July 4,2005. Vitamin D3 2000iu-4000iu (depending on sunshine months)June 10 2005(RX::Dr. O'Connor) Omega 3 as well Turmeric since April 2005. Q10 60mg. 1500mg liquid Glucosamine Nov 2005.
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Postby Melody » Wed Nov 22, 2006 5:39 am

Calpain
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Calpains are a family of calcium-dependent, non-lysosomal cysteine proteases (proteolytic enzymes) expressed ubiquitously in mammals and many lower organisms. Calpains constitute the C2 family of protease clan CA in the MEROPS database. The calpain proteolytic system includes the calpain proteases, the small regulatory subunit (calpain 4), and the endogenous calpain-specific inhibitor, calpastatin.

Historical Background
The history of calpain originates during the mid-1960s, when calcium-dependent proteolytic activities caused by a “calcium-activated neutral protease” (CAPN) were detected in brain, lens and other tissues. In the late 1960s the enzymes were isolated and characterised independently in both rat brain and skeletal muscle. These activities were caused by an intracellular cysteine protease not associated with the lysosome and having an optimum activity at neutral pH, which clearly distinguished it from the cathepsin family of proteases. The calcium-dependent activity, intracellular localization, along with the limited, specific proteolysis on its substrates, highlighted calpain’s role as a regulatory, rather than a digestive protease. When the sequence of this enzyme became known, it was given the name “calpain”, to recognize it as a hybrid of two well-known proteins at the time, the calcium-regulated signaling protein, calmodulin, and the cysteine protease of papaya, papain. Shortly thereafter, the activity was found to be attributable to two main isoforms, dubbed μ("mu")-calpain and m-calpain (a.k.a. calpain 1 and 2), that differed primarily in their calcium requirements in vitro. Their names reflect the fact that they are activated by micro- and millimolar concentrations of Ca2+ within the cell, respectively (Glass et al., 2002). To date, these two isoforms remain the best characterised members of the calpain family. Structurally, these two heterodimeric isoforms share an identical small (30k) subunit (calpain 4), but have distinct large (80k) subunits.

Recently, sequencing of the human genome has revealed genes for more than a dozen other calpain isoforms, some with multiple splice variants. As the first calpain whose almost complete three-dimensional structure was determined, m-calpain is the type-protease for the C2 (calpain) family in the MEROPS database.


[edit] Physiological Roles
Although the physiological roles of calpains are still poorly understood, they have been shown to be active participants in processes such as cell mobility, apoptosis/necrosis, and cell cycle progression, as well as cell-type specific functions such as long-term potentiation in neurons and cell fusion in myoblasts. Under these physiological conditions, a transient and localized influx of calcium activates a small local population of calpains (for example, those close to Ca2+ channels), which then advance the signal transduction pathway by catalyzing the controlled proteolysis of its target proteins. Other reported roles of calpains are in cell function, helping to regulate clotting and the diameter of blood vessels, and playing a role in memory (National Stroke Association, 2002). Calpains have been implicated in apoptotic cell death, and appear to be an essential component of necrosis. In the brain, while μ-calpain is mainly located in the cell body and dendrites of neurons and to a lesser extent in axons and glial cells, m-calpain is found in glia and a small amount in axons (Lenzlinger et al, 2001). Calpain is also involved in skeletal muscle protein breakdown due to exercise and altered nutritional states (Belcastro et al, 1996).


[edit] Calpains in Pathologies
The structural and functional diversity of calpains in the cell is reflected in their involvement in the pathogenesis of a wide range of disorders. At least two well known genetic disorders and one form of cancer have been linked to tissue-specific calpains. When defective, the mammalian calpain 3 (also known as p94) is the gene product responsible for limb-girdle muscular dystrophy type 2A, calpain 10 has been identified as a susceptibility gene for type II diabetes mellitus, and calpain 9 has been identified as a tumor suppressor for gastric cancer. Moreover, the hyperactivation of calpains is implicated in a number of pathologies associated with altered calcium homeostasis such as Alzheimer’s disease, and cataract formation, as well as secondary degeneration resulting from acute cellular stress following myocardial ischemia, cerebral (neuronal) ischemia, traumatic brain injury and spinal cord injury. Excessive amounts of calpain can be activated due to Ca2+ influx after cerebrovascular accident (during the ischemic cascade) or some types of traumatic brain injury such as diffuse axonal injury). The sustained influx of calcium into the cell results in calpain hyperactivation, unregulated proteolysis of both target and non-target proteins and consequent irreversible tissue damage. Excessively active calpain breaks down molecules in the cytoskeleton such as spectrin, microtubule subunits, microtubule-associated proteins, and neurofilaments (Castillo and Babson, 1998). It may also damage ion channels, other enzymes, cell adhesion molecules, and cell surface receptors (Lenzlinger et al, 2001). This can lead to degradation of the cytoskeleton and plasma membrane. Calpain may also break down sodium channels that have been damaged due to axonal stretch injury (Iwata et al., 2004), leading to an influx of sodium into the cell. This, in turn, leads to the neuron's depolarization and the influx of more Ca2+. The exogenous regulation of calpain activity is therefore of interest for the development of therapeutics in a wide array of pathological states. As a few of the many examples supporting the therapeutic potential of calpain inhibition in ischemia, calpain inhibitor AK275 protected against focal ischemic brain damage in rats when administered after ischemia, and MDL28170 significantly reduced the size of damaged infarct tissue in a rat focal ischemia model.

In addition to damaging cell structures, calpain indirectly creates free radicals. The protease cleaves the enzyme Xanthine Dehydrogenase to Xanthine oxidase (XOA) which, in turn, creates superoxide radicals, oxygen free radicals composed of two oxygen atoms with an extra, unpaired electron (Outlinemed.com, 1998; Fouad, 2001-2003).

Calpain may be released in the brain for up to a month after a head injury, and may be responsible for a shrinkage of the brain sometimes found after such injuries (White, 1999). However, calpain may also be involved in a "resculpting" process that helps repair damage after injury (White, 1999).


[edit] Protein Structure
Calpain 1 and 2 are heterodimeric enzymes that share a common 21k regulatory subunit (encoded by the calpain 4 gene).





[edit] Cleavage Specificity
No specific amino acid sequence is uniquely recognized by calpains. Amongst protein substrates, tertiary structure elements rather than primary amino acid sequences are likely responsible for directing cleavage to a specific substrate. Amongst peptide and small-molecule substrates, the most consistently reported specificity is for small, hydrophobic amino acids (e.g. leucine, valine and isoleucine) at the P2 position, and large hydrophobic amino acids (e.g. phenylalanine and tyrosine) at the P1 position (Cuerrier, 2005). Arguably, the best currently available fluorogenic calpain substrate is (EDANS)-Glu-Pro-Leu-Phe=Ala-Glu-Arg-Lys-(DABCYL), with cleavage occurring at the Phe=Ala bond.





[edit] References
Belcastro AN, Albisser TA, Littlejohn B (1996). Role of calcium-activated neutral protease (calpain) with diet and exercise. "Can J Appl Physiol". 21(5):328-46
Büki A, Okonkwo D. O., Wang K. K. W., and Povlishock J. T. (2000). Cytochrome c Release and Caspase Activation in Traumatic Axonal Injury. The Journal of Neuroscience. 20(8): 2825-2834.
Castillo M. R. and Babson J. R. (1998). Ca2+-dependent mechanisms of cell injury in cultured cortical neurons. Neuroscience. 86(4): 1133-1144.
Cuerrier D, et al (2005). [1]
Determination of peptide substrate specificity for mu-calpain by a peptide library-based approach: the importance of primed side interactions. J Biol Chem. 280(49):40632-41

Fouad, Tamer. (2003). Free Radicals, Types, Sources and Damaging Reactions. The Doctors Lounge.
Glass J. D., Culver D.G., Levey A. I., and Nash N. R. (2002). Very early activation of m-calpain in peripheral nerve during Wallerian degeneration. Journal of the Neurological Sciences. 196(1-2): 9-20.
Iwata A., Stys P. K., Wolf J. A., Chen X. H., Taylor, A. G., Meaney D. F., and Smith D. H. (2004). Traumatic Axonal Injury Induces Proteolytic Cleavage of the Voltage-Gated Sodium Channels Modulated by Tetrodotoxin and Protease Inhibitors. The Journal of Neuroscience. 24(19): 4605-4613.
Karp G. (2005). Cell and Molecular Biology: Concepts and Experiments, Fourth ed, pp. 148, 165-170, and 624-664. John Wiley and Sons, Hoboken, NJ.
Lenzlinger PM, Saatman KE, Raghupathi R, Mcintosh TK. 2001. Overview of basic mechanisms underlying neuropathological consequences of head trauma. Chapter 1. In, Head trauma: Basic, preclinical, and clinical directions. Miller LP and Hayes RL, eds. Wiley Liss, (a John Wiley and Sons publication) New York.
National Stroke Association (NSA). (2002). Classes of Acute Treatment.
Outlinemed.com. (1998). Ischemia and Necrosis.
White V. 1999. 'Biochemical Storm' Following Brain Trauma an Important Factor in Treatment, University of Florida Researcher Finds. Available.

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John was diagnosed Jan 2005. On lipitor 20mg .On Copaxone since July 4,2005. Vitamin D3 2000iu-4000iu (depending on sunshine months)June 10 2005(RX::Dr. O'Connor) Omega 3 as well Turmeric since April 2005. Q10 60mg. 1500mg liquid Glucosamine Nov 2005.
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lynda what do you think of this???insulin lady

Postby Melody » Wed Nov 22, 2006 6:16 am

Publisher's Abstract
Nangle MR, Cotter MA, Cameron NE.

School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, Scotland, United Kingdom.

Calpains, a superfamily of Ca(2+)-activated proteases, are associated with an array of physiological and pathological events, including susceptibility to diabetes. Recently, increased calpain activity has been linked to reduced endothelium-derived nitric oxide-mediated vasodilatation in diabetes. However, a similar mechanism for neuronal-derived nitric oxide has not been examined. Thus, the aim was to investigate effects of the calpain inhibitor A-705253, N-(1-benzyl-2-carbamoyl-2-oxoethyl)-2-[E-2-(4-diethyl-aminomethylphenyl)ethen-1-yl]benzamide, on nitrergic neurovascular function in diabetic mice. Diabetes was induced by streptozotocin; duration was 6 weeks. Intervention A-705253 treatment (30 mg/kg/day) was given for 2 weeks following 4 weeks of untreated diabetes. After 6 weeks of diabetes, corpus cavernosa were isolated in organ baths for measurement of agonist- and electrical stimulation-evoked smooth muscle tensions. Adrenergic nerve- and phenylephrine-mediated contractions were not altered by diabetes or calpain inhibition. In contrast, maximum nitrergic nerve-mediated relaxation of phenylephrine-precontracted cavernosum was approximately 29% reduced by diabetes (P<0.001). This neurological deficit was 66% corrected by A-705253 treatment (P<0.05). Maximum nitric oxide-mediated endothelium-dependent relaxation to acetylcholine was attenuated approximately 39% by diabetes (P<0.01). Similarly, maximum endothelium-independent relaxation to the nitric oxide donor, sodium nitroprusside, was blunted approximately 23% by diabetes (P<0.001). A-705253 treatment partially improved endothelium-dependent relaxation to acetylcholine but had no effect on the deficit in response to nitroprusside. The data suggest that calpain contributes to the aetiology of diabetic nitrergic autonomic neuropathy and endothelial dysfunction, which may provide a novel therapeutic target for neurovascular complications.


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John was diagnosed Jan 2005. On lipitor 20mg .On Copaxone since July 4,2005. Vitamin D3 2000iu-4000iu (depending on sunshine months)June 10 2005(RX::Dr. O'Connor) Omega 3 as well Turmeric since April 2005. Q10 60mg. 1500mg liquid Glucosamine Nov 2005.
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Postby Lyon » Wed Nov 22, 2006 9:16 am

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answer to Melody re Calpain Inhibitor

Postby lyndacarol » Wed Nov 22, 2006 9:49 am

Upon first reading, the abstract seems VERY pertinent to the insulin idea. I can't say I understand it all, but I am excited that researchers are working in this area.

I need to study this more and read your posting several more times! Thank you for it!!!
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Postby CureOrBust » Thu Nov 23, 2006 1:30 am

ok, today it worked.
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