Other Animal Models

This methodology provides resolution of approximately 1 mm. Thus, not only in vitro but in vivo data from genetic knockouts and other animal models can be obtained with PET and more recently SPECT imaging [65]. 

Data suggesting that other animal models are the most sensitive species . 

Norepinephrine may also play a role in the induction of immediate early genes in response to pup exposure (Thomas and Palmiter, 1997). Norepinephrine has been linked to maternal behavior in certain other animal models, such as sheep and rats. It may also play a role in olfactory recognition and memory in rats. Intraventricular administration of 6-OHDA prior to birth has been noted to impair postpartum maternal behavior administration after birth had no such effect. 

Fertility assessment in test animals has limited sensitivity as a measure of reproductive injury, because, unlike humans, males of most test species produce sperm in excess of the minimum requirements for fertility. In addition, test animals can undergo multiple matings (Amann, 1981 Working, 1988 Chapin Heindel, 1993). In some strains of rats and mice, production of sperm can be reduced by 90% or more without compromising fertility (Aafjes et al., 1980 Meistrich, 1982 Working, 1988) in human males, less severe reduction in sperm production can cause reduced fertility. Thus, measurement of change in sperm count or fertility in laboratory rodents may be insufficient to assess reproductive health risk in humans. Other animal models may be more suitable for assessing fertility (Chapin et al., 1998). However, it should not be assumed that a reduction in sperm count (i.e., <90%) will have no effect on fertility in rodents (Wine et al., 1997). 

These problems were circumvented in most of the studies on knockout and drug-treated mice described above, as well as several on rats and other animal models, by using the alternative method(s) for measuring cholesterol absorption described in detail in this chapter. This method was first pioneered and validated by Quintao et al. (33) and remains widely used today because it is simple, accurate, noninvasive, reproducible, inexpensive, and does not require sophisticated equipment or specialized technical or surgical skills. 

TFPI, when administered to rabbits, has been shown to have an antithrombotic effect when thromboplastin was used as a thrombogenic challenge (I 10). TFPI was also shown to be an effective inhibitor when thrombosis was induced in rabbit jugular veins by endothelial destruction and restricted blood flow. The antithrombotic and antiprotease actions of TFPI have been tested in several other animal models. Warn-Cramer et al. investigated the effect of immunodepletion of TFPI in factor Vila and Xa induced coagulation in rabbits (III). These rabbits were observed to be sensitized to the procoagulant effects of factor Vila, but not factor Xa in the absence of factor Vila. Two studies have indicated that TFPI administration reduces the lethal effects of . coli administration in a septic shock model in baboons (I 12). These studies also indicated that TFPI may have an anti-inflammatory effect, as an attenuation of the IL-6 response was also observed. Administration of TFPI has been observed to prevent... 

Time-course analysis in a rabbit iliac artery model disclosed <20% stent re-endothelialization at four days, <40% at seven days, and near-complete endothelialization at 28 days following stent implantation (18). The re-endothelialization process has been studied in several other animal models using different types of injuries with very controversial results, suggesting, in part, a diversity in the response and capacity of vascular healing. 

Although it is essential to test promising compounds in mice and other animal models prior to human trials, it is economically, ethically and often scientifically preferable to use cell-based and in vitro approaches to eliminate inactive compounds before commencing animal trials. Clearly, animal models are not an appropriate screen for combinatorial libraries of platinum complexes they should be used to study further the promising leads identified by high-throughput methods. 

Numerous other animal models of psychosis have been proposed, but few others have been used routinely for drug screening. The model called the conditioned avoidance response is considered important, however. Smith and colleagues describe the test as follows ... 

Recently, a family of monocationic complexes of the type [M(N)(P-N-P)-(S2CNR1R2)]+, which exhibit high myocardial uptake in rats, was also described [51,52]. Some of these complexes possess superior biological properties, compared with Sestamibi and Tetrafosmin. However, because of the possibility of species-dependent effects, further studies of these agents in other animal models are underway, in order to assess their utility as heart perfusion agents [52]. 

ILAR. Nonhuman primate and other animal models of women s health. Inst Lab Animal Res. 2004 45 83-219. 

Today, the overwhelming majority of animal ocular toxicity studies are performed in the rabbit model, and the study of SM is no exception. New Zealand white rabbits have been used extensively with both liquid SM and vapor exposures (Amir et al, 2000, 2003 Bossone et al, 2002 Vidan et al, 2002 Babin et al, 2004). Other animal models have been employed, including those using bovine and rat corneas. Many articles appear on these in the Bulletin of Johns Hopkins Hospital, Vol. 82, 1948. Individual articles from this volume are cited in the mechanism of action section. 

Evidence for neuroinflammation has also been found in other animal models of motor neuron degeneration. Eor example, microglial activation was observed in the Wobbler mouse, a finding that has been confirmed by several groups (Rathke-Hartlieb et al., 1999 Boillee et al., 2001). Elevated TNE- a levels were found in the brain and spinal cord of the mnd mouse (Ghezzi et al., 1998). It appears that these other murine models of motor neuron degeneration share some neu-roinflammatory features with the mSODl model. 

Whether or not Hb accentuates lethal effects of endotoxin is also not resolved. When inoculation with living E. coli or endotoxin has been used to induce sepsis in mice, some Hb preparations have been found to demonstrate deleterious effects. " In contrast, other studies using better characterized, modified Hb solutions have failed to confirm these findings, both in mice and in other animal models. ... 

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. 

In a similar logic, the multi-hit hypothesis can be applied to rodent or other animal models with precompromised host liver functions, either by genetic knockout, knock-in, RNAi knockdown, high-fat diet, alcohol pretreatment, or... 

After the introduction of the first neuroleptic drugs, many animal models were developed to screen new compounds for potential antipsychotic activity. These models predict both antipsychotic efficacy and side effect liability in humans (104-106). Other animal models at-... 

The aerosol toxicity of ricin has been documented in several laboratory animals, including rhesus (Wilhelmsen and Pitt, 1996) and African green monkeys, but it remains unclear which, if any, of these effectively model the human response to ricin. Is it necessary to conduct animal trials with medical countermeasures for ricin in an NHP aerosol model, or will other animal models suffice to predict the human response The unexpected appearance of VLS in human clinical trials underscores the difficulty in extrapolating from animal models. Data addressing these questions will be critical in devising practical and effective strategies for coping with ricin as a toxin weapon. 

Other animal models not addressed here, but which have been used to model symptoms of PTSD, include predator stress models. In addition, models of early stress, such as effects of maternal separation on endocrine function, in particular the HPA axis (reviewed in Meaney, 2001), may have implications for the development of stress disorders. Other studies (Cohen et al., 2006) evaluated stress response in juvenile rats as a precursor to adult stress responses. These animal models may help understand the biology of stress, stress vulnerability, and stress resistance and may be useful to identify appropriate therapeutic targets to reduce stress pathology. 

A study found that hypericin inhibits bovine choroidal endothelial cell proliferation in vitro (Kimura et al., 1997). The effect was found to be dose dependent. Further studies in other animal models are needed to investigate this potential effect. 

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