Oxaliplatin neurotoxicity – no general ion channel surface-charge effect

<p>Abstract</p> <p>Background</p> <p>Oxaliplatin is a platinum-based chemotherapeutic drug. Neurotoxicity is the dose-limiting side effect. Previous investigations have reported that acute neurotoxicity could be mediated via voltage-gated ion channels. A possible mechanism for some of the effects is a modification of surface charges around the ion channel, either because of chelation of extracellular Ca²⁺, or because of binding of a charged biotransformation product of oxaliplatin to the channel. To elucidate the molecular mechanism, we investigated the effects of oxaliplatin and its chloride complex [Pt(dach)oxCl]^-on the voltage-gated Shaker K channel expressed in <it>Xenopus </it>oocytes. The recordings were made with the two-electrode and the cut-open oocyte voltage clamp techniques.</p> <p>Conclusion</p> <p>To our surprise, we did not see any effects on the current amplitudes, on the current time courses, or on the voltage dependence of the Shaker wild-type channel. Oxaliplatin is expected to bind to cysteines. Therefore, we explored if there could be a specific effect on single (E418C) and double-cysteine (R362C/F416C) mutated Shaker channels previously shown to be sensitive to cysteine-specific reagents. Neither of these channels were affected by oxaliplatin. The clear lack of effect on the Shaker K channel suggests that oxaliplatin or its monochloro complex has no general surface-charge effect on the channels, as has been suggested before, but rather a specific effect to the channels previously shown to be affected.</p

Non-Invasive In Vivo Imaging of Calcium Signaling in Mice

Rapid and transient elevations of Ca2+ within cellular microdomains play a critical role in the regulation of many signal transduction pathways. Described here is a genetic approach for non-invasive detection of localized Ca2+ concentration ([Ca2+]) rises in live animals using bioluminescence imaging (BLI). Transgenic mice conditionally expressing the Ca2+-sensitive bioluminescent reporter GFP-aequorin targeted to the mitochondrial matrix were studied in several experimental paradigms. Rapid [Ca2+] rises inside the mitochondrial matrix could be readily detected during single-twitch muscle contractions. Whole body patterns of [Ca2+] were monitored in freely moving mice and during epileptic seizures. Furthermore, variations in mitochondrial [Ca2+] correlated to behavioral components of the sleep/wake cycle were observed during prolonged whole body recordings of newborn mice. This non-invasive imaging technique opens new avenues for the analysis of Ca2+ signaling whenever whole body information in freely moving animals is desired, in particular during behavioral and developmental studies

Synthesis and solution properties of a temperature-responsive PNIPAM–b-PDMS–b-PNIPAM triblock copolymer

In this paper, we report the synthesis and self-assembly of a novel thermoresponsive PNIPAM60–b-PDMS70–b-PNIPAM60 triblock copolymer in aqueous solution. The copolymer used a commercially available precursor modified with an atom transfer radical polymerization (ATRP) initiator to produce an ABA triblock copolymer via ATRP. Small-angle neutron scattering (SANS) was used to shed light on the structures of nanoparticles formed in aqueous solutions of this copolymer at two temperatures, 25 and 40 °C. The poly(dimethylsiloxane) block is very hydrophobic and poly(N-isopropylacrylamide) (PNIPAM) is thermoresponsive. SANS data at 25 °C indicates that the solutions of PNIPAM–b-PDMS–b-PNIPAM copolymers form well-defined aggregates with presumably core–shell structures below cloud point temperature. The scattering curves originating from nanoparticles formed at 40 °C in 100% D2O or 100% H2O were successfully fitted with the Beaucage model describing aggregates with hierarchical structure

Dose Effects of Oxaliplatin on Persistent and Transient Na+ Conductances and the Development of Neurotoxicity

BACKGROUND: Oxaliplatin, a platinum-based chemotherapy utilised in the treatment of colorectal cancer, produces two forms of neurotoxicity--acute sensorimotor neuropathic symptoms and a dose-limiting chronic sensory neuropathy. Given that a Na(+) channelopathy has been proposed as the mechanism underlying acute oxaliplatin-induced neuropathy, the present study aimed to determine specific mechanisms of Na(+) channel dysfunction. METHODOLOGY/PRINCIPAL FINDINGS: Specifically the function of transient and persistent Na(+) currents were followed during treatment and were investigated in relation to oxaliplatin dose level. Eighteen patients were assessed before and after a single oxaliplatin infusion with motor and sensory axonal excitability studies performed on the median nerve at the wrist. While refractoriness (associated with Na(+) channel inactivation) was significantly altered post-oxaliplatin infusion in both motor (Pre: 31.7±6.4%; Post: 68.8±14.5%; P≤.001) and sensory axons (Pre: 31.4±5.4%; Post: 21.4±5.5%; P<.05), strength-duration time constant (marker of persistent Na(+) conductances) was not significantly altered post-infusion (Motor Pre: 0.395±0.01 ms; Post: 0.394±0.02 ms; NS; Sensory Pre:0.544±0.03 ms; Post: 0.535±0.05 ms; NS). However, changes in strength-duration time constant were significantly correlated with changes in refractoriness in motor and sensory axons (Motor correlation coefficient = -.65; P<.05; Sensory correlation coefficient = .67; P<.05). CONCLUSIONS/SIGNIFICANCE: It is concluded that the predominant effect of acute oxaliplatin exposure in human motor and sensory axons is mediated through changes in transient rather than persistent Na(+) conductances. These findings are likely to have implications for the design and trial of neuroprotective strategies