Moreover emerging evidence suggests that BDNF plays different and perhaps

Moreover emerging evidence suggests that bdnf plays

This preview shows page 14 - 15 out of 25 pages.

Moreover, emerging evidence suggests that BDNF plays different and perhaps opposing roles in the brain stress system including the hippocampus and hypothalamus– pituitary–adrenocortical axis, and the brain reward system including the nucleus accumbens and the ventral tegmental area (Berton et al , 2006; Eisch et al , 2003). It is clear that specific circuits and brain regions are undoubtedly involved in the pathophysiology of mood disorders; defining the effects of altering-specific signaling pathways, in specific brain regions of rodents, will allow for translational studies of similar brain regions/functions in humans (ie studies of human endophenotypes). Bcl-2 is a Therapeutic Target for the Actions of Lithium and VPA One of the major downstream targets of the ERK MAPK cascades is arguably one of the most important neuropro- tective proteins, bcl-2. Bcl-2 is expressed in the rodent and mammalian nervous system and is localized to the outer mitochondrial membrane, endoplasmic reticulum, and nuclear membrane. It is now clear that bcl-2 is a protein that inhibits both apoptotic and necrotic cell death induced by diverse stimuli (Adams and Cory, 1998; Bruckheimer et al , 1998; Merry and Korsmeyer, 1997, and references therein). Several cellular mechanisms are likely involved in mediating bcl-2’s protective effects, including sequestering the proforms of caspases, inhibiting the effects of caspase activation, antioxidant effects, enhancing mitochondrial calcium uptake, and attenuating the release of calcium and cytochrome c from mitochondria (reviewed in Adams and Cory, 1998; Bruckheimer et al , 1998; Li and Yuan, 1999; Sadoul, 1998). The role for bcl-2 in protecting neurons from cell death is now supported by abundant evidence; bcl-2 has been shown to protect neurons from a variety of insults in vitro including growth factor deprivation, glucocorticoids, ionizing radiation, and oxidant stressors such as hydrogen peroxide, tert -butylhydroperoxide, reactive oxygen species, and buthionine sulfoxamine (Adams and Cory, 1998; Bruckheimer et al , 1998). In addition to these potent in vitro effects, bcl-2 also prevents cell death in numerous studies in vivo . In the absence of pharmacological means of increasing CNS bcl-2 expression (until recently), all the studies have hitherto utilized transgenic mouse models or viral vector- mediated delivery of the bcl-2 gene into the CNS. In these models, bcl-2 overexpression has been shown to prevent motor neuron death induced by facial nerve axotomy and sciatic nerve axotomy, to save retinal ganglion cells from axotomy-induced death, to protect cells from the deleter- ious effects of MPTP or focal ischemia, and to protect photoreceptor cells from two forms of inherited retinal degeneration; interestingly, neurons that survive ischemic lesions or traumatic brain injury in vivo show upregulation of bcl-2 (Bonfanti et al , 1996; Chen et al , 1997; Lawrence et al , 1996; Merry and Korsmeyer, 1997; Raghupathi et al , 1998; Sadoul, 1998; Yang et al , 1998, and references therein).
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