Knockout animal studies

Knockout animal studies, in contrast to the above methods, are dependent upon phenotype observation. The approach entails the generation and study of mice in which a specific gene has been deleted. Phenotypic studies can sometimes yield clues as to the function of the gene knocked out. 

The best evidences are studies from preclinical animal models [86, 87, 105], or knockout animals lacking appropriate anti-oxidative pathways [106]. For example, Balb/c mice administered a variety of anti-oxidants in their chow were protected from acetaminophen hepatotoxicity [107]. Rats fed with the anti-oxidant melatonin were protected from cholesterol mediated oxidative liver damage [108]. The best clinical evidence that oxidative stress is a key player in a variety of liver injury diseases is the beneficial application of silymarin in these disease indications [109]. Silymarin is a polyphenolic plant fiavonoid (a mixture of flavonoid isomers such as silibinin, isosilibinin, silidianin and silichristin) derived from Silymarin maria-num that has antioxidative, antilipid peroxidative, antifibrotic and anti-inflammatory effects [109, 110]. 

Redrobe JP, Dumont Y, Fournier A, Quirion R (2002a) The neuropeptide Y (NPY) Y1 receptor subtype mediates NPY-induced antidepressant-like activity in the mouse forced swimming test. Neiuopsychopharmacology 26 615-624 Redrobe JP, Dmnont Y, Quirion R (2002b) Neiuopeptide Y (NPY) and depression From animal studies to the hmnan condition. Life Sci 71 2921-2937 Redrobe JP, Dmnont Y, Herzog H, Quirion R (2003) Neiuopeptide Y (NPY) Y2 receptors mediate behaviour in two animal models of anxiety evidence from Y 2 receptor knockout mice. Behav Brain Res 141 251-255... 

Much evidence supports the neurotrophic hypothesis of depression, but not all evidence is consistent with this concept. Animal studies in BDNF knockout mice have not always suggested an increase in depressive or anxious behaviors that would be expected with a deficiency of BDNF. In addition, some animal studies have found an increase in BDNF levels after some types of social stress and an increase rather than a decrease in depressive behaviors with lateral ventricle injections of BDNF. 

The results of knockout mouse studies indicate that caspase function can be divided into two broad phenotypic classes, those that have primary crucial effect on animal development (proapoptotic caspases, i.e., caspase-3, -7, -8, and -9) and those that mediate immune system functions (proinflammatory caspases, i.e., caspase-1 and -11) [64, 73]. 

Animal studies, especially rodent studies, significantly contributed to the current knowledge on how genes, the environment, and their interaction may produce anxiety. As people with a high level of neuroticism respond more poorly to stress, certain inbred, selectively bred (28, 29), and knockout rodent strains (see below) have increased emotional reactions to stress... 

Rosenberg MP, Bortner D. Why transgenic and knockout animal models should be used (for drug efficacy studies in cancer). Cancer Metastasis Rev 1998 17 295-9. 

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