Animal models ischemic injury

Fig. 10.1 Chemical structures of NMDA and AMPA antagonists used for the treatment of ischemic injury in animal models. PCP (a) MK-801 (b) Dextrorphan (c) and Dextromethorphan (d)...

PCP inhibits brain nitric oxide synthase irreversibly (Osawa and Davila, 1993 Jewett et al., 1996 Klamer et al., 2005). Depending upon its levels, nitric oxide acts as a neuroprotective or neurodestructive molecule (Lipton, 1993 Lipton et al., 1998). NMDA receptor antagonists that have treated ischemic injury of the brain in animal models with some benefit are presented in Tables 10.1 and 10.2. All studies on their use in humans have been unsuccessful because they not only block normal neuronal function, but also produce serious side effects such as headache, anxiety, agitation, nausea, vomiting, hallucinations, dizziness, and coma (Schehr, 1996 Koroshetz and Moskowitz, 1996 Ratan et al., 1994). Clinical trials of NMDA antagonists for stroke and traumatic brain injury have been abandoned (Kemp and McKeman, 2002 Lees et al., 2000 Sacco et al., 2001). 

Two types of circulatory perturbations contribute to different types of ischemic injury to the brain (reviewed by Lipton 1999) (1) stroke (a complete occlusion of a cerebral artery) irreversibly kills the neurons in its core region and severely damages others in the penumbral region and (2) reversible circulatory arrest, with a transient total stop of cerebral blood flow, selectively kills vulnerable cell populations. These clinical conditions can be studied in animals, with focal ischemic models replicating stroke and global ischemic models replicating cardiac arrest. 

While all of the above-mentioned studies were performed using adult models, the effects of focal ischemia on SVZ or SGZ precursor cells were also investigated in neonatal animals. Unilateral hypoxic-ischemic injury elicited an increase of BrdU+ cells in ipsilateral hippocampus, mainly DG, and the number of BrdU+ neuronal cells was also increased in DG, while the number of oligodendrocytes decreased (Bartley et al. 2005). Ischemia also upregulated progenitor cell proliferation in neonatal SVZ, peri-infarct striatum (Plane et al. 2004), and cortex (Fagel et al. 

Earliest proof of an ischemic situation on MRI can be obtained within seconds after stroke onset by perfusion imaging (PI), depicting the area of reduced cerebral blood flow (Fig. 8.2 see also Chap. 6). This is followed within minutes by a rapid delineation of the early ischemic injury (cytotoxic edema) on DWI. Focus of this chapter will be on data acquired in animal ischemia models, using PD-w, Tl-w, and T2-w MRI, and their correlation with histopathology. 

Studies in various animal models and in human hearts suggest that apoptosis does occur in ischemia/reperfusion injury of the heart, though the relative contribution of apoptosis in comparison with necrosis to cell loss in ischemia/ reperfusion injury is still controversial. Cardiomyocyte apoptosis was first reported by Gottlieb et al. [107], who studied the ischemia/reperfusion in rabbit hearts and found the hallmark of apoptosis in ischemic/reperfused hearts but not in the normal or ischemic-only rabbit hearts. Identification of apoptosis was based on the presence of fragmented DNA in electrophoretic gels, on in situ nick end-labeling assays, and on electron microscopy. They concluded that apoptosis may be a specific feature of reperfusion injury in cardiac myocytes. Subsequent studies have shown that apoptosis probably occurs both in ischemia and reperfusion [108], It appears that apoptosis is more prominent after ischemia followed by reperfusion than after ischemia alone [109, 110],... 

The neuroprotective properties of mild hypothermia have been demonstrated in numerous experimental animal models. Research in this area has been conducted for many years, yet the mechanisms of cerebral protection by mild hypothermia remain unclear and continue to be the subject of intense investigation. The neuroprotective effects of mild hypothermia have been attributed to alterations in metabolic rate (24), neurotransmitter release (25-27), activity of protein kinases (28), resynthesis of cellular repair proteins (29), cerebral blood flow (30), preservation of the blood-brain barrier (BBB) (31), attenuation of inflammatory processes (32,33), and decreases in free radical production (34). Although these may all be components of a complex cascade leading to neurologic injury, it has become increasingly clear that the primary mechanism of action of hypothermia may be different at various temperatures as well as under different ischemic and traumatic conditions. 

There is also evidence from animal models that brimonidine may provide neuroprotective properties that could spare retinal ganglion cells and the optic nerve. Using different models to achieve neuronal insult, including mechanical and acute retinal ischemic/reperfu-sion injury, brimonidine appears to protect the optic nerve and retinal ganglion cells from further degeneration. 

Various animal models have been used to study the pathogenesis of acute kidney injury (AKl) and develop therapeutic interventions that prevent or amehorate the severity of tubular injury following an acute ischemic or toxic renal insult. Utilization of animal models has advantages over other in mtro models such as isolated perfused kidneys, isolated proximal tubules, or tubular cell culture. It reproduces the complex interactions of hemodynamics and local tubular factors seen in the whole animal with AKl. 

Ischemic, nephrotoxic, and septic rodent models of acute renal injury were developed to study mechanisms of acute kidney injury. Decreasing renal blood flow is critical in the pathophysiology of AKI in humans. Ischemic and other animal models are used to reproduce the morphological features of human disease. 

Two waves of apoptosis during the reperfusion phase after ischemic AKl have been described. The first coincides with a maximum proliferative activity that is at 2-3 days post-injury. The second occurs on day 7-8 following injury [53]. Other investigators have demonstrated that apoptosis peaks between 4 and 14 days of post-ischemia [10]. The discrepancy may be due to different methods used to detect and quantify apoptosis or different animal models of ischemic AKI. 

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