Animal Models pathway

Target discovery, to identify genes or pathways with altered expression in diseased human tissues or in animal model of disease... 

Serotonin2A receptors have also been the focus of sleep enhancing agents on the basis that they promote SWS in both animal models as well as clinical trials, without the side effects associated with BzRAs. The precise interactions of these compounds within the sleep control pathway remain to be elucidated. 

The development of nucleic acid-based therapeutics is not as straightforward as researchers had initially anticipated. Stability, toxicity, specificity, and delivery of the compounds continue to be challenging issues that need further optimization. In recent years, researchers have come up with intricate solutions that have greatly improved the efficacy of potential antisense, ribozyme, as well as RNAi-based therapeutics. Clinical trials for all these types of nucleic acid-based therapeutics are underway. So far, data from several trials and studies in animal models look promising, in particular, the therapies that trigger the RNAi pathway. However, history has shown that compounds that do well in phase I or phase II clinical trials may still fail in phase III. A striking example is the nonspecific suppression of angiogenesis by siRNA via toII-Iike receptor 3 (Kleinman et al. 2008). It will become clear in the near future which compounds will make it as a new class of antiviral therapeutics. 

Inhibitors of AR have been demonstrated to prevent a wide variety of biochemical, functional and structural alterations in animal models of diabetes. Early studies demonstrated arrest of both early cataract development and nerve conduction velocity. At least 30 clinical trials of AR inhibitors have been published involving nearly 1000 patients in total. However, there is little impressive data of their efficacy up to now but, rather than undermine the hypothesis linking excess polyol pathway activity to diabetic complications, it may reflect methodological difficulties and trial design errors. 

Thrombolytics and drugs targeting several injury pathways have shown efficacy in models of hypoxia-ischemia. A number of neuroprotective strategies have been identified in animal models of ischemia, and many... 

It is now well established that a neurodegenerative pathway leading from soluble to insoluble, filamentous tau protein is central to the neurodegenerative process in the human tauopathies. The availability of animal models that exhibit the essential molecular and cellular features... 

Inhibitors of MLK (MKKK) [27], MKK4, 7 and JNK [6,28,29] have been disclosed to date. CEP-1347, a semi-synthetic analog of the natural product K252a, inhibits MLKs in the JNK pathway with K = 17 nM [30-32]. This compound has shown neuroprotective effects in cellular and animal models [33]. CEP-1347, an orally available compound that was well tolerated in the clinic, was advanced to Phase II/III trials for assessing efficacy in Parkinson s disease. However, the clinical trial was stopped due to a lack of significant efficacy [34],... 

Once in the serum, aluminium can be transported bound to transferrin, and also to albumin and low-molecular ligands such as citrate. However, the transferrrin-aluminium complex will be able to enter cells via the transferrin-transferrin-receptor pathway (see Chapter 8). Within the acidic environment of the endosome, we assume that aluminium would be released from transferrin, but how it exits from this compartment remains unknown. Once in the cytosol of the cell, aluminium is unlikely to be readily incorporated into the iron storage protein ferritin, since this requires redox cycling between Fe2+ and Fe3+ (see Chapter 19). Studies of the subcellular distribution of aluminium in various cell lines and animal models have shown that the majority accumulates in the mitochondria, where it can interfere with calcium homeostasis. Once in the circulation, there seems little doubt that aluminium can cross the blood-brain barrier. 

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