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Contributions of Preclinical 6OHDA Model to Understanding PD

Posted by MD Biosciences on Mar 4, 2013 10:23:00 AM

Background of the preclinical 6-OHDA model of PD 

The 6-hydroxydopamine (6-OHDA) model of Parkinson's Disease (PD) was the first model of PD generated, and has since been widely used to investigate parkinsonism in rodents. The model was originally developed following the discovery that injecting 6-OHDA into the substantia nigra pars compacta (SNpc) caused anterograde degeneration of the nigrostriatal dopaminergic system, producing a loss of dopaminergic neurons in the SNpc and loss of dopaminergic terminals in the striatum (to which the SNpc projects), similar to that observed in Parkinson’s disease. 6-OHDA is similar in structure to dopamine, but the presence of an additional hydroxyl group makes it toxic to dopaminergic neurons. Once in the cytosol, 6-OHDA auto-oxidizes to form reactive oxygen species, which are thought to cause neurodegeneration by reducing levels of anti-oxidant enzymes, elevating iron, and inhibiting mitochondrial respiration. The main features of this model that have made it popular are that it is relatively fast, inexpensive and simple to implement, and that the lesions it produces are reproducible and substantial.

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Topics: Neuro/CNS

Bioimaging in Preclinical Models of Rheumatoid Arthritis

Posted by MD Biosciences on Nov 5, 2012 11:12:00 AM

Rheumatoid arthritis is a chronic and progressive inflammatory condition estimated to affect between 0.5-1% of the world's population, with more women being affected than men. It is a systemic disease manifesting mainly as a disabiling destruction of the synovial joints of the hands and feet.

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Topics: Inflammation

Post-stroke Neuroinflammation | Astrocytes & Microglia

Posted by MD Biosciences on Jul 9, 2012 12:22:00 PM

Post-stroke neuroinflammation is a very complex phenomenon involving multiple resident and invading cell types at varying degrees of differentiation or activation - each expressing specific subsets of diffusable factors, receptors, cellular adhesion molecules and other markers - all of which is changing as time passes to create an initially neurotoxic and then finally neuroprotective environment. This inflammatory process in the penumbra offers a broad array of potential cellular and molecular targets with much wider therapeutic windows.

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Topics: Neuro/CNS

MMPs in ischemic conditions (stroke and myocardial infarct)

Posted by MD Biosciences on Jun 25, 2012 2:20:00 PM

Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that function to degrade extracellular matrix. The turnover of ECM in organs is regulated by a balance by MMPs and their inhibitors (TIMPs) and the imbalance is implicated in a variety of diseases. Here we focus on the roles of MMPs in ischemia - particularly cerebral stroke and myocardial infarct.

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Topics: Neuro/CNS, Cardiovascular

Post Myocardial Infarct (MI) Inflammatory Environment

Posted by MD Biosciences on Jun 11, 2012 2:44:00 PM

At the tissue level, inflammation ensues very rapidly after myocardial infarct (MI), initially prompted by detection of high levels of reactive oxygen species (ROS) and necrotic cellular debris by resident cells in neighboring non-infarct tissues. ROS and necrotic cell debris are also detected by peripheral leukocytes, which home to the injured tissue, exit circulation, and infiltrate infarct and non-infarct tissues. Upon entering the lesion site, these leukocytes further release ROS, proteolytic enzymes, pro-inflammatory and cytotoxic diffusible factors and participate in phagocytosis of necrotic cells and disrupted ECM. This post-MI inflammatory environment in cardiac tissues peaks at 1 to 2 weeks and generally resolves at 3 to 4 weeks after the ischemic event. While important for clearing the tissue of compromised cells and debris and preparing it for transitioning into the proliferative phase of infarct healing, inflammation that becomes excessive or chronic results in adverse remodeling, infarct expansion, and poor patient outcomes. [1-4]

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Topics: Cardiovascular

Preclinical Post-operative Pain Model Resembles Human Physiology

Posted by MD Biosciences on Apr 23, 2012 1:56:00 PM

The management of post-operative pain is a challenge for both physicians and patients. In addition to a comfortable recovery, the prevention of chronic pain and improvement of conventional outcomes are important in post-operative pain management.

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Topics: Pain

iSchemia Cerebral Models | Stroke & Neurodegeneration

Posted by MD Biosciences on Apr 19, 2012 6:45:00 AM

Preclinical stroke models are critical to our understanding of the mechanisms and neurological deficits following human stroke. While reducing infarct size is a focus of stroke therapies, much attention is also on neuroprotective properties. Adding behavioral and functional outcome measures to preclinical studies is important to evaluate the impact on impairments that occur following stroke: learning, memory, motor function and sensory. There are many behavior tests, each having different sensitivities to deficits associated with particular areas of brain damage.

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Topics: Neuro/CNS

Preclinical Human Pain Models. Translating to Clinic

Posted by MD Biosciences on Mar 30, 2012 9:16:00 AM

Management of acute pain related to surgical intervention, termed postoperative pain, continues to be a major problem facing physicians and patients today. The most common method for addressing post-operative pain is through pharmacotherapy. [1,2] Table 1 lists a selection of the most common analgesics used to treat acute surgical pain, their methods of delivery, and the mechanism by which they are thought to act. [1] Significant progress in the pain management field has been made in recent years mostly in the areas of new delivery methods and multimodal analgesia. Novel drug delivery systems for postoperative pain medications include, for example, patient-controlled analgesia, means of sustained or extended release, transdermal delivery using iontophoresis, and transmucosal and intranasal delivery systems. While a few of these methods may not yet be approved in all geographies, the majority now serve as new tools available to physicians to treat their surgical patients. [1,2] Multimodal analgesia is based on the idea that simultaneous administration of more than one pain therapy strategy offers opportunities for results that are either additive or synergistic. Although clinical data on these types of strategies are still somewhat inconsistent, some clinical trial data do demonstrate improved outcomes and reduced incidence of persistent post-operative pain. [1]

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Topics: Pain

Toll-like Receptor Family Member 4 (TLR4) in Neuropathic Pain

Posted by MD Biosciences on Mar 19, 2012 9:55:00 AM

In the context of neuropathic pain (NP), toll-like receptor member 4 (TLR4) is known to be expressed exclusively on spinal microglia and significantly up-regulated upon peripheral nerve injury. TLR4-knockout mice display reduced effects of chronic chonstriction injury (CCI) induced nerve damage. Similary, TLR4 loss-of-function mutant mice as well as TLR4 antisense oligonucleotide-treated rats both display attenuated neuropathic pain symptoms after nerve damage. Further, intrathecal administration of a TLR4 antagonist after CCI treatment results in relief of neuropathic pain symptoms. Many exogenous and endogenous ligands are known to stimulate TLR4-mediated signaling. However, both in vitro and in vivo studies involving spinal nerve ligation (SNL) treated animals implicate Fibronectin in neuropathic pain-related TLR4 signaling. Fibronectin is an extracellular matrix protein that is commonly produced in response to tissue injury. When administered intrathecally to intact rats, Fibronectin induces microglial up-regulation of the purigenic receptor, P2X4, and symptoms of neuropathic pain. This stimulation of P2X4 expression can be suppressed by interuption of Fibronectin binding the TLR4 receptor after SNL injury in rats. 

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Topics: Pain

Pain-related Characteristics | MIA-induced Preclinical OA Model

Posted by MD Biosciences on Mar 9, 2012 10:06:00 AM

Osteoarthritis (OA) is a widespread condition that affects greater than 70% of the elderly population and poses a heavy cost burden on healthcare. It is a chronic degenerative disease characterized byt the loss of articular cartilage components, which affects the entire joint structure. One of the major complaints by OA patients is the loss of joint function as well as chronic pain. Current therapies are focused on alleviating joint pain, however full pain relief is rarely experienced and significant side affects are commonly present. Research is not only focused disease pathology but also on understanding the mechanisms responsible for induction and maintenance of pain states.

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Topics: Pain