Taxol (Paclitaxel) is an important natural product for the treatment of solid tumors. Despite a well documented tubulin-stabilizing effect, many side effects of taxol therapy cannot be explained by cytoskeletal mechanisms. In the present study submicromolar concentrations of taxol, mimicking concentrations found in patients, induced cytosolic calcium (Ca 2؉ ) oscillations in a human neuronal cell line. These oscillations were independent of extracellular and mitochondrial Ca 2؉ but dependent on intact signaling via the phosphoinositide signaling pathway. We identified a taxol binding protein, neuronal Ca 2؉ sensor 1 (NCS-1), a Ca 2؉ binding protein that interacts with the inositol 1,4,5-trisphosphate receptor from a human brain cDNA phage display library. Taxol increased binding of NCS-1 to the inositol 1,4,5-trisphosphate receptor. Short hairpin RNA-mediated knockdown of NCS-1 in the same cell line abrogated the response to taxol but not to other agonists stimulating the phosphoinositide signaling pathway. These findings are important for studies involving taxol as a research tool in cell biology and may help to devise new strategies for the management of side effects induced by taxol therapy.calcium imaging ͉ calcium release ͉ display cloning ͉ drug-induced side effects ͉ hypersensitivity reactions

Changes in dendritic spine turnover are a major mechanism of experience-dependent plasticity in the adult neocortex. Dendritic spine plasticity may also contribute to functional recovery after stroke, but in that setting its expression may be complicated by alterations in local tissue perfusion, especially around the infarct. Using adult Thy-1 GFP-M mice, we simultaneously recorded long-term spine dynamics in apical dendrites from layer 5 pyramidal cells and blood flow from surrounding capillaries with in vivo two-photon microscopy in peri-infarct cortex before and after unilateral middle cerebral artery occlusion. Blood flow in periinfarct cortex decreased significantly immediately after stroke and improved gradually over time, in a distance-dependent manner from the epicenter of the infarct. However, local tissue perfusion was never fully restored even after a 3 month recovery period. On average, surviving layer 5 pyramidal neurons experienced a ϳ20% decrease in spine density acutely after stroke but eventually recovered. The dynamics of this improvement were different depending on the degree of tissue perfusion acutely after arterial occlusion. Cells in ischemic areas closer to the infarct returned to normal spine density levels slowly by retaining spines, while cells in more remote regions with preserved blood flow recovered faster by adding more spines, eventually surpassing baseline spine density by 15%. Our data suggest that maintaining tissue perfusion in the area surrounding the infarct could hasten or augment synaptic plasticity and functional recovery after stroke.

Sertraline is an effective treatment for patients with generalized social phobia.

Most stroke survivors exhibit a partial recovery from their deficits. This presumably occurs because of remapping of lost capabilities to functionally related brain areas. Functional brain imaging studies suggest that remapping in the contralateral uninjured cortex might represent a transient stage of compensatory plasticity. Some postmortem studies have also shown that cortical lesions, including stroke, can trigger dendritic plasticity in the contralateral hemisphere, but the data are controversial. We used longitudinal in vivo two-photon microscopy in the contralateral homotopic cortex to record changes in dendritic spines of layer 5 pyramidal neurons in green fluorescent protein mice. We could not detect de novo growth of dendrites or changes in the density or turnover of spines for up to 4 weeks after stroke. We also used intrinsic optical signal imaging to investigate whether the forepaw (FP) sensory representation is remapped to the spared homotopic cortex after stroke. Stimulation of the contralateral FP reliably produced strong intrinsic signals in the spared hemisphere, but we could never detect a signal with ipsilateral FP stimulation after stroke. This lack of contralateral plasticity at the level of apical dendrites of layer 5 pyramidal neurons and FP sensory maps suggests that the contralesional cortex may not contribute to functional recovery after stroke and that, at least in mice, the peri-infarct cortex plays the dominant role in postischemic plasticity.

No abstract