Veronica Johansson

Authenticity, depression, and deep brain stimulation

In 2005 the journal Neuron published Mayberg et al.’s (2005) pioneering study on deep brain stimulation (DBS) targeting treatment-refractory major depressive disorder (MDD). Since then a handful of studies, in total encompassing little over 50 patients, have been published (Aouizerate et al., 2005; Jimenez et al., 2005; Mayberg et al., 2005; Kuhn et al., 2007; Lozano et al., 2008; Neimat et al., 2008; Schlaepfer et al., 2008; Malone et al., 2009; Bewernick et al., 2010; Sartorius et al., 2010) and larger trials are underway (Bell et al., 2009). A common ethical concern voiced when DBS is used for a psychiatric disorder such as MDD is that the stimulation specifically targets cognition, mood, and behavior; elements which are closely linked to the patients personality. Obviously, this holds true also for other antidepressants such as psychotherapy and medication. Apart from that these standard therapies have been of no avail for the patients considered for MDD DBS, one could still ask whether their potential to alter cognition, mood, and behavior, differ - with regard to ethical concerns - from that of DBS. Further, the relevant ethical concern is arguably not what functions the stimulation are intended to alter, as in psychiatric indications, but rather what functions that could be altered by DBS. Unintended alterations of cognition, mood and behaviour could occur as a consequence of both psychiatric and motoric DBS. Thus, potential alterations of personality seem, apart from the historical stigma connected with the former, to be relevant for most DBS indications. A lot of work remains to be done before a comprehensive analysis of these concerns could be presented. Our contribution is to introduce one question relevant to the intersection of DBS, MDD, and the notion(s) of authenticity.

Thinking Ahead on Deep Brain Stimulation: An Analysis of the Ethical Implications of a Developing Technology.

Deep brain stimulation (DBS) is a developing technology. New generations of DBS technology are already in the pipeline, yet this particular fact has been largely ignored among ethicists interested in DBS. Focusing only on ethical concerns raised by the current DBS technology is, albeit necessary, not sufficient. Since current bioethical concerns raised by a specific technology could be quite different from the concerns it will raise a couple of years ahead, an ethical analysis should be sensitive to such alterations, or it could end up with results that soon become dated. The goal of this analysis is to address these changing bioethical concerns, to think ahead on upcoming and future DBS concerns both in terms of a changing technology and changing moral attitudes. By employing the distinction between inherent and noninherent bioethical concerns we identify and make explicit the particular limits and potentials for change within each category, respectively, including how present and upcoming bioethical concerns regarding DBS emerge and become obsolete. Many of the currently identified ethical problems with DBS, such as stimulation-induced mania, are a result of suboptimal technology. These challenges could be addressed by technical advances, while for instance perceptions of an altered body image caused by the mere awareness of having an implant may not. Other concerns will not emerge until the technology has become sophisticated enough for new uses to be realized, such as concerns on DBS for enhancement purposes. As a part of the present analysis, concerns regarding authenticity are used as an example.

Inhibition of cell proliferation and induction of apoptosis by N(1),N(11)-diethylnorspermine-induced polyamine pool reduction.

Reduction of cellular polyamine pools results in inhibition of cell proliferation and sometimes in induction of cell death. Reduction of cellular polyamine pools can be achieved by several strategies involving all the mechanisms of polyamine homoeostasis, i.e. biosynthesis, catabolism and transport across the cell membrane. In the present paper, we concentrate on results achieved using the polyamine analogue DENSPM (N(1),N(11)-diethylnorspermine) on different cell lines. We discuss polyamine levels in DENSPM-treated cells in relation to effects on cell cycle kinetics and induction of apoptosis. To really understand the role of polyamines in cell cycle regulation and apoptosis, we believe it is now time to go through the vast polyamine literature in a meta-analysis-based manner. This short review does not claim to be such a study, but it is our hope to stimulate such studies in the polyamine field. Such work is especially important from the viewpoint of introducing drugs that affect polyamine homoeostasis in the treatment of various diseases such as cancer.

Novel anti-apoptotic effect of Bcl-2: Prevention of polyamine depletion-induced cell death

The spermine analogue N1,N11‐diethylnorspermine (DENSPM) efficiently depletes the polyamine pools in the breast cancer cell line L56Br‐C1 and induces apoptotic cell death via the mitochondrial pathway. In this study, we have over‐expressed the anti‐apoptotic protein Bcl‐2 in L56Br‐C1 cells and investigated the effect of DENSPM treatment. DENSPM‐induced cell death was significantly reduced in Bcl‐2 over‐expressing cells. Bcl‐2 over‐expression reduced DENSPM‐induced release of the pro‐apoptotic proteins AIF, cytochrome c, and Smac/DIABLO from the mitochondria. Bcl‐2 over‐expression reduced the DENSPM‐induced activation of caspase‐3. Bcl‐2 over‐expression also prevented DENSPM‐induced Bax cleavage and reduction of Bcl‐XL and survivin levels. The DENSPM‐induced activation of the polyamine catabolic enzyme spermidine/spermine N1‐acetyltransferase was reduced by Bcl‐2 over‐expression, partly preventing polyamine depletion. Thus, Bcl‐2 over‐expression prevented a number of DENSPM‐induced apoptotic effects.

Effect of polyamine deficiency on proteins involved in Okazaki fragment maturation

Polyamine depletion causes S phase prolongation, and earlier studies indicate that the elongation step of DNA replication is affected. This led us to investigate the effects of polyamine depletion on enzymes crucial for Okazaki fragment maturation in the two breast cancer cell lines MCF‐7 and L56Br‐C1. In MCF‐7 cells, treatment with N1,N11‐diethylnorspermine (DENSPM) causes S phase prolongation. In L56Br‐C1 cells the prolongation is followed by massive apoptosis. In the present study we show that L56Br‐C1 cells have substantially lower basal expressions of two Okazaki fragment maturation key proteins, DNA ligase I and FEN1, than MCF‐7 cells. Thus, these two proteins might be promising markers for prediction of polyamine depletion sensitivity, something that can be useful for cancer treatment with polyamine analogues. DENSPM treatment affects the cellular distribution of FEN1 in L56Br‐C1 cells, but not in MCF‐7 cells, implying that FEN1 is affected by or involved in DENSPM‐induced apoptosis.

Novel anti-apoptotic effect of the retinoblastoma protein: implications for polyamine analogue toxicity.

The retinoblastoma protein (pRb) pathway is frequently altered in breast cancer cells. pRb is involved in the regulation of cell proliferation and cell death. The breast cancer cell line L56Br-C1 does not express pRb and is extremely sensitive to treatment with the polyamine analogue N1,N11-diethylnorspermine (DENSPM) which causes apoptosis. Polyamines are essential for the regulation of cell proliferation, cell differentiation and cell death. DENSPM depletes cells of polyamines, e.g., by inducing the activity of the polyamine catabolic enzyme spermidine/spermine N1-acetyltransferase (SSAT). In this study, L56Br-C1 cells were transfected with human pRb–cDNA. Overexpression of pRb inhibited DENSPM-induced cell death and DENSPM-induced SSAT activity. This suggests that the pRb protein level is a promising marker for polyamine depletion sensitivity and that there is a connection between pRb and the regulation of SSAT activity. We also show that SSAT protein levels and SSAT activity do not always correlate, suggesting that there is an unknown regulation of SSAT.