Modeling mitochondrial dysfunctions in the brain: from mice to men

The biologist Lewis Thomas once wrote: “my mitochondria comprise a very large proportion of me. I cannot do the calculation, but I suppose there is almost as much of them in sheer dry bulk as there is the rest of me”. As humans, or indeed as any mammal, bird, or insect, we contain a specific molecular makeup that is driven by vast numbers of these miniscule powerhouses residing in most of our cells (mature red blood cells notwithstanding), quietly replicating, living independent lives and containing their own DNA. Everything we do, from running a marathon to breathing, is driven by these small batteries, and yet there is evidence that these molecular energy sources were originally bacteria, possibly parasitic, incorporated into our cells through symbiosis. Dysfunctions in these organelles can lead to debilitating, and sometimes fatal, diseases of almost all the bodies’ major organs. Mitochondrial dysfunction has been implicated in a wide variety of human disorders either as a primary cause or as a secondary consequence. To better understand the role of mitochondrial dysfunction in human disease, a multitude of pharmacologically induced and genetically manipulated animal models have been developed showing to a greater or lesser extent the clinical symptoms observed in patients with known and unknown causes of the disease. This review will focus on diseases of the brain and spinal cord in which mitochondrial dysfunction has been proven or is suspected and on animal models that are currently used to study the etiology, pathogenesis and treatment of these diseases

Menstrual function among women exposed to polybrominated biphenyls: A follow-up prevalence study

BACKGROUND: Alteration in menstrual cycle function is suggested among rhesus monkeys and humans exposed to polybrominated biphenyls (PBBs) and structurally similar polychlorinated biphenyls (PCBs). The feedback system for menstrual cycle function potentially allows multiple pathways for disruption directly through the hypothalamic-pituitary-ovarian axis and indirectly through alternative neuroendocrine axes. METHODS: The Michigan Female Health Study was conducted during 1997–1998 among women in a cohort exposed to PBBs in 1973. This study included 337 women with self-reported menstrual cycles of 20–35 days (age range: 24–56 years). Current PBB levels were estimated by exponential decay modeling of serum PBB levels collected from 1976–1987 during enrollment in the Michigan PBB cohort. Linear regression models for menstrual cycle length and the logarithm of bleed length used estimated current PBB exposure or enrollment PBB exposure categorized in tertiles, and for the upper decile. All models were adjusted for serum PCB levels, age, body mass index, history of at least 10% weight loss in the past year, physical activity, smoking, education, and household income. RESULTS: Higher levels of physical activity were associated with shorter bleed length, and increasing age was associated with shorter cycle length. Although no overall association was found between PBB exposure and menstrual cycle characteristics, a significant interaction between PBB exposures with past year weight loss was found. Longer bleed length and shorter cycle length were associated with higher PBB exposure among women with past year weight loss. CONCLUSION: This study suggests that PBB exposure may impact ovarian function as indicated by menstrual cycle length and bleed length. However, these associations were found among the small number of women with recent weight loss suggesting either a chance finding or that mobilization of PBBs from lipid stores may be important. These results should be replicated with larger numbers of women exposed to similar lipophilic compounds

Assessment of antidepressant and anxiolytic properties of NK1 antagonists and substance P in Wistar Kyoto rats. Physiol Behav

Abstract In an attempt to explore the involvement of substance P in depression and anxiety and its' potential therapeutic effects, we measured basal plasma and hypothalamic levels of substance P in a well-studied animal model of depression -adult male Wistar Kyoto (WKY) rats and their controls, Wistar rats. We also studied the influence of a substance P receptor (NK1) antagonist (SPA) on "anxiety-like" and "depressive-like" behaviors exhibited by the WKY rats in the open field and swim test paradigms, compared to controls. WKY rats exhibited lower levels of substance P compared to controls in the hypothalamus. Though the WKY strain exhibited less rearing behavior in the open field compared to controls, SPA did not influence this pattern of behavior. In contrast, SPA had a significant effect on a depressive-like behavior exhibited by the WKY strain -it reduced significantly the immobility duration of WKY rats in the swim test. Thus it seems that depression involves alterations in levels of substance P, and that NK1 antagonists may be effective in the relief of depressive, but not anxiety symptoms. © 2006 Elsevier Inc. All rights reserved. Keywords: Substance P; Depression; Anxiety; Rat; Open field; Swim test Although the monoamine hypothesis is the most dominant attempt to unravel the biological basis of depression, this theory by itself can neither explain the entire mechanism of action of antidepressants, nor can it provide a comprehensive understanding of the pathophysiology of depression Substance P is released from neurons and preferentially interacts selectively with the neurokinin 1 (NK1) subtype of neurokinin receptor [See review at [55]]. Studies mapping the expression of substance P and NK1 receptors in neural circuits found large concentrations in the amygdala, hypothalamus and hippocampus, areas that are thought to be critical for regulating emotions [[52]; See review at In most cases, insufficient and/or contradictory evidence exists to establish particular arguments for or against the involvement of substance P in depression and/or anxiety. Several studies demonstrated the antidepressant efficacy of several NK1 receptor antagonists in patients with major depression and high anxiety On the other hand, there are several studies indicating no or even opposite effects of substance P antagonist on anxiety [[33,56,57], for review se