Transient ischemia models

OA were aborted in 2003 due to the development of mild to moderate liver fibrosis in dogs treated for 9 months with high doses of pralnacasan. This was in spite of recent evidence demonstrating the effectiveness of pralnacasan treatment in the acute dextran sulfate sodium (DSS)-induced colitis model, which resembles Crohn s disease (CD) characteristics, and in transient ischemia induced brain damage. 

A group from La Jolla Pharmaceuticals has released data on their novel hydrazines in recent scientific [20,59,60] and patent literature [61,62], A series of arylallyl hydrazines (e.g., 8 and 9) were shown to be potent, irreversible inhibitors of rat and human SSAO/VAP-1 [59]. LJP-1207 (8, IC50 = 2nM, human) was evaluated in a series of in vivo inflammation models. Significant efficacy was observed in a mouse ulcerative colitis, mouse LPS-induced septic shock, and the rat carrageenan foot models [20], in a mouse model that resembles human multiple sclerosis [63], and in a transient forebrain ischemia model in estrogen-treated ovariectomized female rats [60]. 

A number of animal models have been developed to mimic cerebral ischemia experimentally. They can be roughly categorized into global (bilateral arterial occlusion) and focal (unilateral arterial occlusion) cerebral ischemia models. Probably the widest applied method is the middle cerebral artery occlusion (MCAO), performed by transiently blocking the arterial blood flow with a removable thread or... 

Similarly, Schmid-Elsaesser et al. (7) reported a synergistic effect of hypothermia when added to therapy with either tirilizad or magnesium (Mg). In this study, rats were subjected to transient ischemia of 90 min duration using a suture occlusion model. Hypothermia was administered intraischemically and animals were rewarmed simultaneous with reperfusion. Subjects were treated with various combinations of the three agents, in a systematic fashion. A stepwise increase in the reduction in infarct volume was observed between Tirilizad + Mg, hypothermia alone, and hypothermia + tirilizad + Mg in combination. 

Interestingly, the pro-apoptotic effects of Bad are blocked by the immunosuppressants cyclosporin (CsA) and FK506. In a model of transient ischemia/reperfusion following middle cerebral artery occlusion, both compounds reduced cerebral infarct volume to 30% of control (49). Blockade of calcineurin-mediated dephosphorylation of Bad is a potential mechanism for this effect. Thus phosphorylated, Bad remains sequestered in the cytoplasm and is unable to bind to Bcl-2 (or Bcl-XL), thereby allowing Bcl-2 to exert its protective effect. Regulating expression of specific members of the Bcl-2 family by targeted gene expression is another potential therapeutic tool. This approach is covered in Chapter 11. 

Yin W, Badr AE, Mychaskiw G, Zhang JH. Down regulation of cox-2 is involved in hyperbaric oxygen treatment in a rat transient focal cerebral ischemia model. Brain Res. 2002 926 165-171... 

AIF may contribute to acute neuronal injury induced by trauma, hypoglycemia or transient ischemia as well as in chronic neurodegeneradve diseases (Table 3). The translocadon of AIF has been observed in different experimental models of neurotoxicity including death of photoreceptors induced by rednal detachment, neuronal cell death induct in vivo by brain trauma and cerebral ischemia and death of cortical neurons induced in vitro by exposure to... 

P743 was tested on a validated multiple-insult rat model [35] involving transient renal ischemia, dehydration, uninephrectomy and selective injection of a high dose (about 1.8 gl kg ) into the single remaining kidney and was found to have only minimal effects on GFR (evaluated by the endogenous creatinine clearance) and induced moderate enzymuria (NAG release into the final urine) or proteinuria. The effects observed were lower than those of the HOCA diatri-zoate [25]. 

An early in vivo study in the model of global forebrain ischemia in the gerbil showed that a selective agonist of A3AR, IB-MECA, acutely administered 15 min prior to ischemia, impaired post-ischemic blood flow, increased mortality and exacerbated the loss of hippocampal neurons (von Lubitz et al. 1994). IB-MECA administration 20 min prior to transient middle cerebral ischemia also resulted in a significant increase in infarct size(von Lubitz et al. 2001). 

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