Substantial evidence indicates an association between clinical depression and altered immune function. Systemic administration of bacterial lipopolysaccharide (LPS) is commonly used to study inflammation-associated behavioral changes in rodents. In these experiments, we tested the hypothesis that peripheral immune activation leads to neuroinflammation and depressive-like behavior in mice. We report that systemic administration of LPS induced astrocyte activation in transgenic GFAP-luc mice and increased immunoreactivity against the microglial marker ionized calcium-binding adapter molecule 1 in the dentate gyrus of wild-type mice. Furthermore, LPS treatment caused a strong but transient increase in cytokine levels in the serum and brain. In addition to studying LPS-induced neuroinflammation, we tested whether sickness could be separated from depressive-like behavior by evaluating LPS-treated mice in a panel of behavioral paradigms. Our behavioral data indicate that systemic LPS administration caused sickness and mild depressive-like behavior. However, due to the overlapping time course and mild effects on depression-related behavior per se, it was not possible to separate sickness from depressive-like behavior in the present rodent model.

Taxol, a potent promoter of microtubule polymerization in vitro, induces massive assembly offree microtubules in cultured cells as visualized by immunocytochemistry and electron microscopy. The centrosomes and kinetochores largely lost their capacity to organize microtubule assembly, as became evident by the disappearance ofthe cytoplasmic microtubule complex and the mitotic spindle. The taxol-induced microtubules were partially resistant to nocodazole, an inhibitor of tubulin polymerization. Moreover, taxol induced microtubule assembly in cells pretreated with nocodazole. Increasing the ratio ofnocodazole to taxol restored the ability of the centrosomes and kdnetochores to specifically induce microtubule assembly in their immediate vicinity. The data suggest that taxol lowers the critical tubulin concentration in vivo as well as in vitro and that the organizing capacity of the microtubule-organizing centers depends on the cytoplasmic polymerization threshold.Taxol, an experimental antitumor drug (1) isolated from Taxus brevifolia, was recently shown by Schiff et aL (2, 3) to affect microtubule assembly in vitro and in living cells. It essentially eliminated the initial lag phase and decreased the critical tubulin concentration to less than 0.01 mg/ml. The rate and extent of the polymerization was increased and the microtubules were relatively resistant to depolymerization by cold and CaCl2. In living cells (3), taxol was shown to be a potent inhibitor of HeLa and mouse. fibroblast replication. The cells were blocked in the G2 and M phases of the cell cycle. It was inferred that this was due to the stabilization of cytoplasmic microtubules. Indirect immunofluorescence was used to show that taxoltreated cells displayed bundles of microtubules radiating from a common site in addition to their cytoplasmic microtubules. These microtubules were resistant to treatment with steganacin or incubation of the cells at low temperature, both of which disintegrated microtubules in control cells. Ultrastructural observations showed that the mitotic cells contained microtubule bundles but no normal spindle. It was concluded that the inability of the cells to form a mitotic spindle in the presence of taxol could be due to the fact that the cells were unable to depolymerize their microtubule cytoskeletons (3).We have investigated the effects of taxol on the cytoplasmic microtubule complex and the mitotic spindle in cultured cells. Our observations and conclusions differ partly from those published previously (3). Taxol apparently induces the assembly of free microtubules in the cytoplasm, not attached to the centrosomes or kinetochores. The preexisting microtubules, attached to the organizing centers, are not stabilized and disappear gradually.The publication costs ofthis article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. C. §1734 solely to indicate this fact. MATERIAL AND METHODSPt K2 potoroo cells, C3H mouse 3T3 cells, and human...

The dose-limiting side effect of the anti-neoplastic agent, paclitaxel, is a chronic distal symmetrical peripheral neuropathy that produces sensory dysfunction (hypoesthesia and neuropathic pain) but little or no distal motor dysfunction. Similar peripheral neuropathies are seen with chemotherapeutics in the vinca alkaloid, platinum-complex, and proteasome inhibitor classes. Studies in rats suggest that the cause is a mitotoxic effect on axonal mitochondria. If so, then the absence of motor dysfunction may be due to mitotoxicity that affects sensory axons but spares motor axons. To investigate this, paclitaxel exposure levels in the dorsal root, ventral root, dorsal root ganglion, peripheral nerve, and spinal cord were measured, and the ultrastructure and the respiratory function of mitochondria in dorsal roots and ventral roots were compared. Sensory and motor axons in the roots and nerve had comparably low exposure to paclitaxel and exposure in the spinal cord was negligible. However, sensory neurons in the dorsal root ganglion had a very high and remarkably persistent (up to10 days or more after the last injection) exposure to paclitaxel. Paclitaxel evoked a significant increase in the incidence of swollen and vacuolated mitochondria in the myelinated and unmyelinated sensory axons of the dorsal root (as seen previously in the peripheral nerve) but not in the motor axons of the ventral root. Stimulated mitochondrial respiration in the dorsal root was significantly depressed in paclitaxel-treated animals examined 2-4 weeks after the last injection, whereas respiration in the ventral root was normal. We conclude that the absence of motor dysfunction in paclitaxel-evoked peripheral neuropathy may be due to the absence of a mitotoxic effect in motor neuron axons, while the sensory dysfunction may be due to a mitotoxic effect resulting from the primary afferent neuron's cell body being exposed to high and persistent levels of paclitaxel.

Although vascular endothelial growth factor-B (VEGF-B) is a homolog of the angiogenic factor VEGF, it has only minimal angiogenic

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