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Part 2 | Cutting Edge Rheumatoid Arthritis Model Readouts

Posted by MD Biosciences on Aug 10, 2010 7:54:00 AM

Continuing the discussion of imaging technologies, this week we will cover biofluorescence and bioluminescence as readouts for RA models.

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Topics: Inflammation

Cutting Edge Rheumatoid Arthritis Models

Posted by MD Biosciences on Jul 5, 2010 10:10:00 AM

Rheumatoid arthritis is a chronic and progressive inflammatory condition estimated to affect between 0.5% and 1% of the world’s population, with more women being affected than men. RA is a systemic disease manifesting mainly as a disabling destruction of the synovial joints of the hands and feet.  In addition to the disability and decreased quality of life caused by RA, patients are at increased risk of developing cardiovascular disease. Joint destruction is induced by dysregulated immune activation of both the innate and adaptive immune responses resulting in alterations in the synovium, cartilage and bone.  The normal joint has a thin synovial lining (intimal lining layer), 1-3 cells thick. Beneath this is a sub-lining layer of connective tissue scattered with immune cells, blood vessels and nerve cells.  Together these layers form the synovium, which produces the synovial fluid that serves to lubricate the joint. Disease initiation results in profound changes in the structure and composition of the synovium and synovial fluid; with the infiltration of inflammatory cells, synovial cell hyperplasia, increased angiogenesis, fibroblast proliferation and extracellular matrix production. This increase in synovial cell proliferation can result in the lining increasing up to five times its original size and can result in pannus formation. The culmination of these events is bone and cartilage erosion and loss of joint function.

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Topics: Inflammation

Occlusion-induced ischemia Reperfusion Injury Model

Posted by MD Biosciences on Jun 16, 2010 10:35:00 AM

The preclinical occlusion-induced myocardial infarct model is a well-known technique for investigating the cardio-protection of a drug therapy in the event of ischemia/reperfusion injury. The advantage of the model is the ability to study the functional relevance of a drug treatment on the heart following direct coronary flow and the mechanisms by which the drug promotes myocardial protection.

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Topics: Cardiovascular

Screening Assays | Targeting Fibroblast-like Synovioctyes

Posted by MD Biosciences on May 13, 2010 8:39:00 AM

Rheumatoid arthritis (RA) is a chronic autoimmune joint disease characterized by inflammation of the synovium and destruction of cartilage and bone. During synovial inflammation, inflammatory cells (macrophages, mast cells, dentritic cells and lymphocytes) are recruited while resident cells (fibroblast synoviocytes, chondrocytes, osteoclasts, and osteoblasts) are altered to support the inflammatory process.  Together, these events create a pathological tissue response.
The synovium consists of two layers, the sublining and intimal lining.  In RA, the sublining becomes infiltrated with mononuclear cells, B lymphocytes produce autoantibodies, blood vessels proliferate, lymphoid aggregates form and the intimal lining shows increased cellularity.  Macrophages in the synovium produce pro-inflammatory cytokines, chemokines and growth factors which in turn activate fibroblast-like synoviocytes (FLS) to produce their own array of mediators (e.g. proteolytic enzymes, chemokines and cytokines).  This produces a paracrine/autocrine network that leads to synovitis, the recruitment of new cells and the destruction of the extracellular matrix.  Fibroblast-like synoviocytes have emerged as key pro-inflammatory cells promoting the disease, largely due to their ability to produce massive amounts of degradative enzymes.
The availability of biological therapies has improved clinical outcomes by decreasing inflammation and joint destruction, however only about half of the patients exhibit substantial efficacy. Targeting FLS may further improve clinical outcomes without suppressing systemic immunity.  In vitro FLS assays can be used to evaluate effective therapies for arthritis. Using FLS obtained from normal, RA and OA patients, we can evaluate a compound's effect on the production of pro-inflammatory mediators in a preclinical in vitro model. 

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Topics: Inflammation

Efficacy of anti-CD20 Therapy in Rhuematoid Arthritis

Posted by MD Biosciences on May 11, 2010 11:46:00 AM

We read an interesting article published this week in Journal of Immunology (v184 Bottaro & co.) on the efficacy of anti-CD20 therapy in RA. The article highlights the continuing uncertaintity over the mode of action of B-cell directed therapy in Rheumatoid Arthritis (RA) [review of the differing theories is presented in Clin Exp Immunol. 2009 Aug;157(2):191-7].

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Topics: Inflammation

Determine Immunomodulatory Mechanism of Action for Compounds

Posted by MD Biosciences on May 5, 2010 9:42:00 AM

Determine immunomodulatory mechanism of action for compounds in indication discovery or respositioning of approved therapies.

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Topics: Inflammation

MS Whitepaper: EAE Models | Evaluating Neuroprotective Treatment

Posted by MD Biosciences on Apr 20, 2010 9:12:00 AM

Cognitive impairment is common in multiple sclerosis (MS), occuring at all stages of disease. It is a main source of disability, social impairment and has a great impact on an individuals quality of life. In the clinic, factors that can affect MS-related cognitive impairment are disease course, fatigue, and affective disturbance.  While the neurochemical basis underlying motor and cognitive defects in patients with MS is unclear, it appears that a balance of tissue destruction, tissue repair and adaptive function reorganization are related to the degree of impairment.

Its most commonly believed that MS is an autoimmune disease in which the body's own immune system recognizes myelin proteins or myelin related proteins as foreign and marks them for destruction. In the body's periphery, major histocompatibility complex (MHC) Class II proteins expressed on the surface of antigen presenting cells (APC) mistakenly bind to these proteins. This causes a naive-T (Th0) to bind to the antige and undergo activation and differentiation. Adhesion molecules and matrix metalloproteinases (MMPs) help T-helper 1 (TH1) cells stick and penetrate the blood brain barrier (BBB) into the CNS, they engage antigen-MHC complexes and produce pro-inflammatory cytokines leading to damage in the CNS. 

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Topics: Inflammation, Neuro/CNS

Why Post-operative Pain Is Under-Treated

Posted by MD Biosciences on Mar 23, 2010 9:22:00 AM

Adequate pain relief following surgical procedures is well-documented to improve the degree and time course of patient recovery. Nontheless, post-operative pain remains grossly under treated, with up to 70% of patients reporting moderate to severe pain following surgery (1). Perhaps the biggest underlying contributor to the under treatment of post-operative pain is simply a lack of information, both on the part of basic scientists as well as clinicians. Scientists are in the relatively early stages of investigation into the specific mechanisms contributing to the development of incisional pain, which may differ from those mediating acute pain induced by chemical or inflammatory algesic agents. Currently, clinicians essentially rely on treatments that have been developed for other painful conditions, most notably opioids, the side effects of which can hinder rehabilitation and recovery. 

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Topics: Pain

Pain Processing: Cation Channel Blockers. Choosing Pain Models

Posted by MD Biosciences on Jan 11, 2010 11:54:00 AM

Sodium and calcium cation channel blockers.

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Topics: Pain

Cannabinoid System | A Target For Pain Relief.

Posted by MD Biosciences on Nov 17, 2009 2:00:00 PM

The body's cannabinoid system consists of two cannabinoid receptors, CB1 and CB2, their endogenous ligands, which include 2-arachidonoyl glycerol (2-AG) and anandamide (AEA), and the enzymes that regulate the synthesis and degradation of these ligands. While the endogenous cannabinoid system serves naturally to modulate pain transmission, it can be exploited to provide more robust relief, either through administration of agonists at CB1 or CB2 receptors or through inhibition of degrading enzymes to increase endogenous cannabinoid levels.

CB1 receptors are expressed in neurons throughout the central and peripheral nervous system, including in the DRG, where noiciceptor cell bodies reside, the dorsal horn of the spinal cord, and the PAG, all of which are important sites for modulation of pain transmission. CB2 receptors, on the other hand, are not found in the CNS under normal conditions (although they may be upregulated in nociceptive neurons after injury) and are instead expressed in a variety immune cells and microglia. Although activation of either receptor can promote pain relief, CB1 receptors are responsible for the centrally-mediated psychomimetic side effects that sometimes accompany administration of cannabinoid receptor agonists such as tetrahydrocannabinol (THC).

Both CB1 and CB2 are GPCRs that signal predominantly through Gi/o to decrease VGCC conductance and activate GIRKs to hyperpolarize cells. Therefore, ligand binding to cannabinoid receptors results in decreased release of excitatory neurotransmitters from nociceptive neurons and post-synaptic cells exhibiting decreased excitability for signals they do receive. Activation of cannabinoid receptors on immune cells can similarly inhibit their function and thereby indirectly modulate pain processing. Since CB2 receptors are found primarily on immune cells and microglia, this indirect, anti-inflammatory effect is the primary mechanism by which CB2-selective agonists modulate pain responses.

Cannabinoid agonists have shown efficacy in acute models such as tail flick and capsaicin injection, as well as carrageenan and CFA inflammatory pain models. Translation from animal models to the human condition has been documented for a variety of neuropathic conditions as well as for post-operative pain relief; therefore, both neuropathic and post-operative pain models would be appropriate for testing novel compounds designed to target the cannabinoid system as well.
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Topics: Pain