Increased expression and colocalization of GAP43 and CASP3 after brain ischemic lesion in mouse.

GAP43 is a protein involved in neurite outgrowth during development and axon regeneration reflecting its presynaptic localization in developing neurons. Recently, it has been demonstrated that GAP43 is a ligand of CASP3 involved in receptor endocytosis and is also localized post-synaptically. In this study, by using a transgenic mouse strain carrying a bioluminescent reporter for GAP43 combined with an in vivo bioluminescence assay for CASP3, we demonstrated that one day after brain ischemic lesion and, even more pronounced, four days after stroke, expression of both CASP3 and Gap43 in neurons increased more than 40 times. The in vivo approach of CASP3 and GAP43 colocalization imaging was further validated and quantified by immunofluorescence. Importantly, in 82% of GAP43 positive cells, colocalization with CASP3 was present. These findings suggested that one and four days after stroke CASP3 expression, not necessarily associated with neuronal death, increased and suggested that CASP3 and GAP43 might be part of a common molecular pathway involved in early response to ischemic events occurring after onset of stroke.

Changes in vagal reactivity to the sympathicotonia during the progression of heart failure: from self-suppression to counteraction.

Activities of both autonomic nervous system divisions, sympathetic and parasympathetic, are dual--continuous, tonic and changing, modulating. Tonic activity domination accompanies stationary (patho)physiological conditions, while modulating activity occurs with the change of stimuli. The intensity of the two activities is inversely proportional. In patients with heart failure, spectral analysis of heart rate variability displays reduced sympathetic modulation activity during illness, as a logical consequence of an increased sympathetic tone. On the other hand, vagal modulation activity slightly decreases or does not change at the very early stage of disease, soon afterwards it increases, and after a certain period of time, with the progression of the disease, vagal modulation decreases, and finally disappears. These changes reveal sequential response of vagal tone to the progression of heart failure and consequent sympathicotonia; slight initial oscillation or unresponsiveness, soon followed by self-suppression, and then, in an advanced heart failure, by counteraction to the sympathicotonia. This model of polyphasic reaction of vagal system, dependent on the stage of heart failure, challenges traditional concept of sympathovagal interaction. By this hypothesis, the self-suppression of vagal tone occurs in order to enable full sympathetic activation of compensatory mechanisms which aim to correct hemodynamic deterioration. Once the sympathicotonia becomes inefficient and even harmful, counter-regulatory increase in vagal tone develops, in order to decrease oxygen consumption and preserve or possibly enhance residual systolic and diastolic cardiac function. Decreased vagal tonic activity is probably mediated centrally. Later increase of vagal tone is probably triggered by an increased concentration of natriuretic peptides. The existence of predominantly adrenergic IL, Ca and predominantly cholinergic IK, Ach currents and of a common If current in sinoatrial nodal cells enables such dual--synergistic and antagonistic--sympatho-vagal relationship. In conclusion, a complex, polyphasic vagal reaction to the sympathicotonia and heart failure progression is suggested by the hypothesis. Clinical and experimental studies based on this hypothesis will probably allow better insight into autonomic functions.