Pathological Stimuli (pathological + stimulus)

Distribution by Scientific Domains

Selected Abstracts

Rapid loss of motor nerve terminals following hypoxia,reperfusion injury occurs via mechanisms distinct from classic Wallerian degeneration

Becki Baxter
Abstract Motor nerve terminals are known to be vulnerable to a wide range of pathological stimuli. To further characterize this vulnerability, we have developed a novel model system to examine the response of mouse motor nerve terminals in ex vivo nerve/muscle preparations to 2 h hypoxia followed by 2 h reperfusion. This insult induced a rapid loss of neurofilament and synaptic vesicle protein immunoreactivity at pre-synaptic motor nerve terminals but did not appear to affect post-synaptic endplates or muscle fibres. The severity of nerve terminal loss was dependent on the age of the mouse and muscle type: in 8,12-week-old mice the predominantly fast-twitch lumbrical muscles showed an 82.5% loss, whereas the predominantly slow-twitch muscles transversus abdominis and triangularis sterni showed a 57.8% and 27.2% loss, respectively. This was contrasted with a > 97% loss in the predominantly slow-twitch muscles from 5,6-week-old mice. We have also demonstrated that nerve terminal loss occurs by a mechanism distinct from Wallerian degeneration, as the slow Wallerian degeneration (Wlds) gene did not modify the extent of nerve terminal pathology. Together, these data show that our new model of hypoxia,reperfusion injury is robust and repeatable, that it induces rapid, quantitative changes in motor nerve terminals and that it can be used to further examine the mechanisms regulating nerve terminal vulnerability in response to hypoxia,reperfusion injury. [source]

Sequence-selective DNA binding drugs mithramycin A and chromomycin A3 are potent inhibitors of neuronal apoptosis induced by oxidative stress and DNA damage in cortical neurons

Sukalyan Chatterjee PhD
Global inhibitors of RNA or protein synthesis such as actinomycin D or cycloheximide abrogate neuronal apoptosis induced by numerous pathological stimuli in vitro and in vivo. The clinical application of actinomycin D or cycloheximide to human neurological disease has been limited by the toxicities of these agents. To overcome these toxicities, strategies must be developed to inhibit selectively the expression of deleterious proapoptotic proteins, while leaving the expression of antiapoptotic, proregeneration, and other critical homeostatic proteins unperturbed. Mithramycin A (trade name Plicamycin) is an aureolic acid antibiotic that has been used in humans to treat hypercalcemia and several types of cancers. This class of agents is believed to act, in part, by selectively inhibiting gene expression by displacing transcriptional activators that bind to G-C-rich regions of promoters. Here we demonstrate that mithramycin A and its structural analog chromomycin A3 are potent inhibitors of neuronal apoptosis induced by glutathione depletion-induced oxidative stress or the DNA-damaging agent camptothecin. We correlate the protective effects of mithramycin A with its ability to inhibit enhanced DNA binding of the transcription factors Sp1 and Sp3 to their cognate "G-C" box induced by oxidative stress or DNA damage. The protective effects of mithramycin A cannot be attributed to global inhibition of protein synthesis. Together, these results suggest that mithramycin A and its structural analogs may be effective agents for the treatment of neurological diseases associated with aberrant activation of apoptosis and highlight the potential use of sequence-selective DNA-binding drugs as neurological therapeutics. Ann Neurol 2001;49:345,354 [source]

The effect of ageing on macrophage Toll-like receptor-mediated responses in the fight against pathogens

C. R. Dunston
Summary The cellular changes during ageing are incompletely understood yet immune system dysfunction is implicated in the age-related decline in health. The acquired immune system shows a functional decline in ability to respond to new pathogens whereas serum levels of cytokines are elevated with age. Despite these age-associated increases in circulating cytokines, the function of aged macrophages is decreased. Pathogen-associated molecular pattern receptors such as Toll-like receptors (TLRs) are vital in the response of macrophages to pathological stimuli. Here we review the evidence for defective TLR signalling in normal ageing. Gene transcription, protein expression and cell surface expression of members of the TLR family of receptors and co-effector molecules do not show a consistent age-dependent change across model systems. However, there is evidence for impaired downstream signalling events, including inhibition of positive and activation of negative modulators of TLR induced signalling events. In this paper we hypothesize that despite a poor inflammatory response via TLR activation, the ineffective clearance of pathogens by macrophages increases the duration of their activation and contributes to perpetuation of inflammatory responses and ageing. [source]

Adaptative or maladaptative hypertrophy, different spatial distribution of myocardial contraction

Francesco Cappelli
Summary Background:, Left ventricular hypertrophy (LVH) may be an adaptative remodelling process induced by physical training, or result from pathological stimuli. We hypothesized that different LVH aetiology could lead to dissimilar spatial distribution left ventricular (LV) contraction, and compared different components of LV contraction using 2-dimensional (2-D) speckle tracking derived strain in subjects with adaptative hypertrophy (endurance athletes), maladaptative hypertrophy (hypertensive patients) and healthy controls. Method:, We enrolled 22 patients with essential hypertension, 50 endurance athletes and 24 healthy controls. All subjects underwent traditional echocardiography and 2-D strain evaluation of LV longitudinal, circumferential and radial function. LV basal and apical rotation and their net difference, defined as LV torsion, were evaluated. Results:, LV wall thicknesses, LV mass and left atrium diameter were comparable between hypertensive group and athletes. LV longitudinal strain was reduced only in hypertensive patients (P < 005). LV apex circumferential strain was higher in hypertensive patients than in other groups (P < 0001), LV basal circumferential strain, although slightly increased, did not reach significant difference. Hypertensive patients showed significantly increased rotation and torsion (P < 0001), while no differences were observed between athletes and control. Conclusion:, In patients with pathological LVH, LV longitudinal strain was reduced, while circumferential deformation and torsion were increased. No differences were observed in LV contractile function between subjects with adaptative LVH and controls. In pathological LVH, increasing torsion could be considered a compensatory mechanism to counterbalance contraction and relaxation abnormalities to maintain a normal LV output. [source]