Neuroprotective effects of bcl‐2 overexpression in hippocampal cultures: interactions with pathways of oxidative damage

Abstract

Overexpression of bcl-2 protects neurons from numerous necrotic insults, both in vitro and in vivo. While the bulk of such protection is thought to arise from Bcl-2 blocking cytochrome c release from mitochondria, thereby blocking apoptosis, the protein can target other steps in apoptosis, and can protect against necrotic cell death as well. There is evidence that these additional actions may be antioxidant in nature, in that Bcl-2 has been reported to protect against generators of reactive oxygen species (ROS), to increase antioxidant defenses and to decrease levels of ROS and of oxidative damage. Despite this, there are also reports arguing against either the occurrence, or the importance of these antioxidant actions. We have examined these issues in neuron-enriched primary hippocampal cultures, with overexpression of bcl-2 driven by a herpes simplex virus amplicon: (i) Bcl-2 protected strongly against glutamate, whose toxicity is at least partially ROS-dependent. Such protection involved reduction in mitochondrially derived superoxide. Despite that, Bcl-2 had no effect on levels of lipid peroxidation, which is thought to be the primary locus of glutamate-induced oxidative damage; (ii) Bcl-2 was also mildly protective against the pro-oxidant adriamycin. However, it did so without reducing levels of superoxide, hydrogen peroxide or lipid peroxidation; (iii) Bcl-2 protected against permanent anoxia, an insult likely to involve little to no ROS generation. These findings suggest that Bcl-2 can have antioxidant actions that may nonetheless not be central to its protective effects, can protect against an ROS generator without targeting steps specific to oxidative biochemistry, and can protect in the absence of ROS generation. Thus, the antioxidant actions of Bcl-2 are neither necessary nor sufficient to explain its protective actions against these insults in hippocampal neurons.

Acetaminophen Attenuates Obesity-Related Renal Injury Through ER-Mediated Stress Mechanisms

“…Indeed, it is thought that excess intracellular non-esterified free fatty acid is a contributor to the progression of the renal disease oftentimes associated with obesity [26,27]. Moreover, FFA overload can also stimulate the synthesis of triglycerides (TGs), very low density lipoprotein (VLDL), and low density lipoprotein (LDL), which may be lipotoxic, especially if the LDL becomes oxidized LDL [2].…”

Absence of cellular stress in brain after hypoxia induced by arousal from hibernation in Arctic ground squirrels

“…This oxidative stress results in oxidative damage, including lipid peroxidation, protein oxidation, and DNA damage, which can lead to cell death (62). Multiple lines of evidence demonstrate that reactive oxygen species are generated during reperfusion, hypoxia, and reoxygenation and cause oxidative damage to important cellular components that contributes to cell death (2,3,22,53,57). We therefore examined brain tissues from euthermic, hibernating, and late-arousal AGS for cellular damage and oxidative modification.…”

The Bile Acid Tauroursodeoxycholic Acid Modulates Phosphorylation and Translocation of Bad via Phosphatidylinositol 3-Kinase in Glutamate-Induced Apoptosis of Rat Cortical Neurons

“…were rapidly down-regulated after glutamate incubation. In this regard, Bcl-2 overexpression in the central nervous system has been shown to protect cells from glutamate toxicity (Behl et al, 1993;Lawrence et al, 1996;Howard et al, 2002).…”