Complement control protein (VCP), a potent inhibitor of alternative and classical > test(사용X)

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Complement control protein (VCP), a potent inhibitor of alternative and classical pathway C3 convertases [69,72]. In these studies, the intracranial administration of VCP mediated neuroprotective effects related to posttraumatic preservation PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/14960617 of spatial memory, as compared to vehicle-injected controls [69,72].Further therapeutic approaches were designed to more specifically target "key" effector components of complement activation, such as the anaphylatoxin C5a and its receptor (C5aR, CD88) [29,67,73,74]. In addition, more attention was recently devoted to target specific pathways of complement activation exclusively, in order to overcome the potentially deleterious effects of a complete "shut-down" of complement activation at the central C3 level. This notion is based on the fact that complement also mediates neuroprotective effects in the injured brain, as e.g. shown by a dose-dependent protection of glutamate-induced excitotoxicity against neurons by the C3derived proteolytic fragment, anaphylatoxin C3a [75], and by C3a-mediated induction of nerve growth factor (NGF) by microglia [76]. Based on the recent concept of a "dual role" for complement in the pathophysiology of brain injury, by promoting both early neurotoxic and late neuroreparative mechanisms after TBI [12,77,78], the exclusive targeting of selected complement pathways was given more consideration, as opposed to the "pan" inhibition at the C3 convertase level [79-82]. Among these, the targeted inhibition of the alternative pathway has drawn particular attention in recent years [79,80,83]. Factor B, the "key" component of the alternative pathway, was previously reported to be significantly elevated in the intrathecal compartment of patients with severe TBI [65]. Experimental studies on factor B-deficient mice (fB-/-), which are devoid of a functional alternative pathway, revealed significant neuroprotection after closed head injury, in conjunction with a decreased extent of posttraumatic complement activation [79]. These positive findings derived from studies in gene knockout mice were extrapolated into a pharmacological approach, using a neutralizing monoclonal anti-factor B antibody (mAb1379) in the same model system [80]. The postinjury injection of mAb1379 led to significantly attenuated extent of complement activation and anaphylatoxin C5a generation, and was associated with an improved neurological recovery and reduced neuronal cell death after experimental closed head injury [80]. These data imply an important role of the alternative complement pathway in contributing to the delayed neuropathology after TBI, and provide strategic opportunities for therapeutic targeting 2-Chloro-3-methoxyaniline of alternative pathway molecules as a potential future pharmacological strategy. An additional avenue of research has been focusing on the terminal complement pathway, or "membrane attack" pathway, which results in PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/3971254 cellular lysis by the MAC/C5b-9 [51,84,85]. In clinical studies, elevated levels of activated soluble MAC/C5b-9 were detected in the CSF of severely 2,2,3,3-Tetrafluoropropyl N,N'-diethylcarbamimidothioate trifluoromethanesulfonate head-injured patients [62]. Moreover, the extent of intrathecal complement activation was associated with secondary cerebral insults in TBI patients, including post-injury BBB dysfunctionNeher et al. Journal of Biomedical Science 2011, 18:90 http://www.jbiomedsci.com/content/18/1/Page 6 of[10,62,64]. Experimental studies have revealed that the intracerebroventricular injection of MAC induced a marked upregulation of adhesion molecule expression a.