Animal models stress effects

As in the case of other cardiovascular diseases, the possibility of antioxidant treatment of diabetes mellitus has been studied in both animal models and diabetic patients. The treatment of streptozotocin-induced diabetic rats with a-lipoic acid reduced superoxide production by aorta and superoxide and peroxynitrite formation by arterioles providing circulation to the region of the sciatic nerve, suppressed lipid peroxidation in serum, and improved lens glutathione level [131]. In contrast, hydroxyethyl starch desferrioxamine had no effect on the markers of oxidative stress in diabetic rats. Lipoic acid also suppressed hyperglycemia and mitochondrial superoxide generation in hearts of glucose-treated rats [132],... 

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]. 

In humans, the antidepressant activity of NMDA receptor antagonists has not been evaluated extensively (Skohiick 1999). In animal models of depression, NMDA receptor antagonists have been reported to exert positive effects in most studies (Trullas 1997). This concerns mainly the forced swim test (Maj 1992 Moryl et al. 1993 PrzegaUnski et al. 1997) and stress-induced anhe-donia (Papp and Moryl 1994). Amantadine but not memantine was effective against reserpine-induced hypothermia (Moryl et al. 1993). In the forced swim test, both amino-adamantanes produced specific antidepressive-like activity (Moryl et al. 1993). 

Interestingly, while peripheral neuroendocrine function appears normal in patients with panic disorder, decreased basal cortisol concentrations have been reported in most studies in PTSD patients. This relative hypocortisolism occurs in the context of increased feedback inhibition of the HPA axis (see Yehuda, 2000). However, a dissociation between central and adrenocortical (re)activity has been found in animal models of severe early-life stress as well as in abused children and women, suggesting that adrenal dysfunction may, at least in part, contribute to hypocortisolism in PTSD. In the face of hypocortisolism, it seems surprising that hippocampal atrophy is one of the most prominent findings in patients with PTSD, including adult survivors of childhood abuse with PTSD (see Newport and Nemeroff, 2000). While increased glucocorticoid sensitivity of hippocampal cells may play a role in the development of hippocampal atrophy, another potential mechanism may involve toxic effects of markedly increased cortisol responses to everyday stress in patients with PTSD. 

The effect of increased neurotrophins could mitigate hippocampal changes associated with exposure to stress. Although theoretical, this model of antidepressant action is supported by empirical studies of the pathophysiology of depression in patients ( 69, 70) as well as animal models (71, 72). These theories also link back to the neuroanatomical findings that began this section. 

Squalene supplementation is suggested to be accounted for tumor growth inhibition and prevention of normal cells to turn into tumor cells under oxidative stress. Although there is lack of evidence for human trials to show anticancer and antioxidant effects of squalene, animal models and in vitro experiments highlight a significant activity which urges for further exploration. 

I., Lesch, K. P., et al. (2008) Animal models of depression in dopamine, serotonin, and norepinephrine transporter knockout mice prominent effects of dopamine transporter deletions. Behav Pharmacol 19, 566-574. Luo, D. D., An, S. C. and Xhang, X. (2008) Involvement of hippocampal serotonin and neuropeptide Y in depression induced by chronic unpredicted mild stress. Brain Res Bull 77, 8-12. 

Moreover, CoQi0, menadione, ascorbate, and superoxide dismutase-mimetic manganese-5,10,15,20-tetrakis (4-benzoic acid) porphyrin (MnTBAP) have been shown to mediate their antioxidant effects on the ROS and the oxidative stress involved in neuronal death in mitochondrial diseases (S4, T6). There is increasing evidence to support the role of ROS in cell death (Rl), and antioxidants appear to have benefits in animal models of mitochondrial disease (Wl). For example, Melov et al. (M9) reported that mice lacking mitochondrial MnSOD exhibited a... 

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