MD Biosciences Blog

First let's start by talking about what makes a good preclinical model of psoriasis?

A good pre-clinical psoriasis model should obviously re-capitulate the key features of the clinical disease in humans. Therefore, a plausible model will exhibit the following criteria:

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.

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]

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.

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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