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Pain & Inflammation Link | Need For Relevant Preclinical Models

Posted by MD Biosciences on Sep 15, 2010 2:12:00 PM

Considering the close link between inflammation and the pain process, preclinical efficacy models that allow the evaluation of both pain and inflammation are crucial to developing new therapies.

One of the prominent features of inflammatory conditions is that normally innocuous stimuli produce pain. The pain process involves several areas which include nociception, pain perception and pain behavior. After tissue injury or nerve damage, neurons along the nociceptive pathway may display enhanced sensitivity and responsiveness. A variety of events and agents can contribute to this sensitization, including the release of inflammatory mediators (such as cytokines or prostaglandins) or the release of algesic substances from damaged cells. Cytokines and prostaglandins are important mediators of inflammation that also have an effect on pain and nociceptors. Cytokines have influence over sensory neurons and may act directly upon nociceptors or indirectly by stimulating the release of prostaglandins, which are considered sensitizing agents and in some cases directly activate nociceptors.

What would efficacy and mechanistic models that allow you to evauate the effects on pain as well as the contributing inflammatory conditions mean for your therapy?

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Topics: Pain, Inflammation

EAE Preclinical Model Associated With FDA Approved MS Drugs

Posted by MD Biosciences on Aug 24, 2010 9:54:00 AM

The Experimental Autoimmune Encephalomyelitis (EAE) model is associated with FDA Approved MS Drugs and Fingolimod

Multiple Sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) that results in motor, sensory and cognitive impairment. MS is one of the most common disabling neurological diseases in young adults and is more prevalent in Caucasians of northern European ancestry. The disease course is unpredictable and life-long, and affects women more commonly than men.  The main characteristics of this disease are focal areas of demyelination and infiltration of inflammatory cells in the CNS. Despite numerous studies and experimental trials a complete understanding of the pathogenesis still remains unclear. The etiology of the disease seems to be dependent on genetic and environmental factors, which result in substantial observed variations throughout the course of the disease. Today, new treatments and medications are advancing hope for people affected by the disease, and the experimental autoimmune encephalomyelitis (EAE) model continues to play an essential role in MS drug development.

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Topics: Inflammation, Neuro/CNS

What PD in Vivo Models Revealed About Pathogenesis & Treatment

Posted by MD Biosciences on Aug 11, 2010 8:00:00 AM

Parkinson’s Disease (PD) is typically an adult-onset progressive neurodegenerative movement disorder that affects millions of people worldwide. Pathologically, PD is characterized by the profound and specific loss of dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNpc) of the midbrain. Other areas interconnected with the SNpc, the caudate and putamen, collectively known as the striatum, also show remarkable loss of their projection fibers. In accordance with insult to brain regions involved in controlling coordinated movements, the cardinal symptoms of PD include bradykinesia, resting tremor, rigidity, and postural instability (1). To date, research into the etiology of
PD has revealed that most cases are sporadic, though some thirteen genetic loci have been identified to be disease-related (2). Examination of the biochemical properties of these mutant proteins and the pathways in which they are involved has led to the uncovering of three basic pathogenetic pathways common to both heritable and idiopathic forms of PD: (i) abnormal protein control, (ii) mitochondrial dysfunction, and (iii) altered kinase activity (2). Progress towards the identification of disease-related genes has thus led to the expansion of animal models of PD from the classic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)- and 6-hydroxydopamine (6-OHDA)-induced neurotoxin models to genetic models of the disease. Due to its complex pathology, however, no animal disease model has yet to faithfully replicate all aspects of human PD. With the evolution of such models, though, converging lines of evidence from toxin-induced and genetic models have continued to further our understanding of the pathological processes underlying PD and lend themselves as useful systems for the examination of therapeutic interventions.

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Topics: Neuro/CNS

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