Also, a reminder that we differ from the animals in experiments:

Recent clinical failures in Parkinson's disease with apoptosis inhibitors underline the need for a paradigm shift in drug discovery for neurodegenerative diseases

Understanding the mechanisms of neuronal death in concert with the identification of drugable molecular targets key to this process has held great promise for the development of novel chemical entities (NCEs) to halt neurodegenerative disease progression. Two key targets involved in the apoptotic process identified over the past decade include the mixed lineage kinase (MLK) family and glyceraldehyde phosphate dehydrogenase (GAPDH). Two NCEs, CEP-1347 and TCH346, directed against these respective targets have progressed to the clinic. For each, robust neuroprotective activity was demonstrated in multiple in vitro and in vivo models of neuronal cell death, but neither NCE proved effective Parkinson's disease (PD) patients. These recent clinical failures require a reassessment of both the relevance of apoptosis to neurodegenerative disease etiology and the available animal models used to prioritize NCEs for advancement to the clinic in this area.

ANOTHER ARTICLE:

http://www.sciencedirect.com/science...06a473ba#SECX1

"Cytoplasmic hybrid cells (cybrids) from patients with sporadic PD have revealed that expression of PD mitochondrial genes generates multiple detrimental consequences for cell survival and these correlate with changes in PD brain. The consequences include decreased complex I activity (Dawson and Dawson, 2003, Schapira et al., 1998 and Swerdlow et al., 1996), increased production of ROS (Swerdlow et al., 1996), altered intracellular calcium homeostasis (Sheehan et al., 1997), increased levels of antioxidant enzymes (Cassarino and Bennett, 1999), nuclear translocation and increased levels of the transcription factor NF-κB (Cassarino et al., 2000), increased levels of survival-promoting Bcl-2 and Bcl-XL proteins (Veech et al., 2000), increased numbers of morphologically abnormal mitochondria (Trimmer et al., 2000) as well as spontaneous production of true Lewy body inclusions (Trimmer et al., 2004). These multiple changes demonstrate both the pervasive cellular consequence of expressing PD mitochondrial genes and the dualistic responses (pro-apoptotic and pro-survival) they induce.".....

....."The anti-oxidant N-acetylcysteine (NAC) has been reported to promote cell survival through a number of mechanisms (Cotgreave, 1997) including enhancement of intracellular glutathione levels, anti-oxidant activity (Aruoma et al., 1989), and regulation of transcription (Fujisawa et al., 1996 and Keogh et al., 1998). Although the precise mechanism by which NAC protects neurons from cell death is unknown, it is widely assumed to be due to its anti-oxidant properties and its ability to elevate glutathione.

In the present study, we sought to systematically investigate the relative contributions of ERK, JNK, p38, and NF-κB to cell survival in PD cybrids under basal conditions and after treatment with NAC. We found that under basal replicating conditions, PD cybrids have increased JNK and p38 activity that leads to increased caspase-mediated processing and decreased survival. This increased vulnerability to cell death is eliminated by incubating the cells in NAC. Thus, expression of PD mitochondrial genes in PD cybrids results in the activation of signal transduction pathways leading to apoptotic death, an effect attenuated by pharmacologically reducing intracellular oxidative stress."....

....."The antioxidant NAC decreased JNK activity and increased NF-κB activity downstream of the ERK and PI3-K pathways, thus eliminating caspase-mediated PARP cleavage. Using specific inhibitors, we found that blocking the PI3K pathway significantly decreased viability, whereas inhibition of either JNK or p38 activity significantly enhanced survival. Taken together, our findings support the concept that PD mitochondrial gene expression drives oxidative stress-mediated changes in intracellular signaling that promote caspase-requiring apoptosis."...

....."These results reflect a complex interplay of pro- and anti-apoptotic pathways elicited by the amplification of PD mitochondrial genes in cybrid cells (Fig. 9). It is likely that the dynamic balance among forces promoting cell death and forces promoting cell survival determines the ultimate fate of the cell. This study has outlined a few of what may turn out to be multiple signaling pathways mediating cell survival/death in this cellular model. These fundamental regulatory pathways are influenced by PD mitochondria, apparently due to increased oxidative stress. It seems likely that in the more complex whole brain, additional inputs from external and internal events would also contribute to the balance between survival and cell death. A primary goal of future study will be to identify critical points which tip the balance toward survival and normal function"