Oxaliplatin induces pH acidification in dorsal root ganglia neurons

Abstract

Oxaliplatin induced peripheral neurotoxicity is characterized by an acute cold-induced syndrome characterized by cramps, paresthesias/dysesthesias in the distal limbs and perioral region, that develops rapidly and lasts up to one week affecting nearly all the patients as well as by long-lasting symptoms. It has been previously shown that pharmacological or genetic ablation of TRPA1 responses reduces oxaliplatin-induced peripheral neurotoxicity in mouse models. In the present report, we show that treatment with concentrations of oxaliplatin similar to those found in plasma of treated patients leads to an acidification of the cytosol of mouse dorsal root ganglia neurons in culture and this in turn is responsible for sensitization of TRPA1 channels, thereby providing a mechanistic explanation to toxicity of oxaliplatin. Reversal of the acidification indeed leads to a significantly reduced activity of TRPA1 channels. Last, acidification occurs also in vivo after a single injection of therapeutically-relevant doses of oxaliplatin.

Early Stimulation of TREK Channel Transcription and Activity Induced by Oxaliplatin-Dependent Cytosolic Acidification

“…As shown in Figure 1 A, TREK channels underwent a transient upregulation following OHP treatment. Furthermore, we also studied the effect of OHP on TRPV1 expression after 6 h of treatment and did not find any significant change (log 2 FC = 0.57 ± 0.23 relative to the untreated control, p -value = 0.19, Student’s t -test), as already reported for OHP-treated neurons after 48 h from plating [ 13 ]. These data indicate a relative specificity of action for OHP in gene expression modulation.…”

“…Figure 3 A shows the single-channel currents recorded at a holding potential of 40 mV in an OHP-treated neuron before and during the perfusion of the high potassium solution containing 10 μM nigericin at pH 7.4. In these ionic conditions, nigericin was generated in neurons with an acidic pH i , a net efflux of H + that set its value near 7.4 [ 13 ]. Following the perfusion with nigericin, the patch activity NP o decreased from 0.57 ± 0.19 to 0.08 ± 0.11 ( N being the number of channels in the patch and P o the channel open-state probability), in agreement with a high sensitivity of these channels to acidic intracellular pH.…”

“…Interestingly, recent reports have shown that therapeutically-relevant OHP concentrations induce cytosolic acidification in cultured dorsal root ganglion (DRG) neurons as well as in DRG cells from treated animals [ 13 ]. In in vitro experiments, acidification occurs after 30 min from OHP application [ 14 ] and produces a reversible hypersensitization of TRPA1 channels [ 13 ].…”

“…Interestingly, recent reports have shown that therapeutically-relevant OHP concentrations induce cytosolic acidification in cultured dorsal root ganglion (DRG) neurons as well as in DRG cells from treated animals [ 13 ]. In in vitro experiments, acidification occurs after 30 min from OHP application [ 14 ] and produces a reversible hypersensitization of TRPA1 channels [ 13 ]. In the present study, we have investigated the early involvement of K2P channels, TREK-1 and TREK-2, in this context since these channels, among other stimuli, also respond to intracellular pH changes (pH i ) [ 15 , 16 , 17 ].…”

Amorphous Fe‐Based Nanoagents for Self‐Enhanced Chemodynamic Therapy by Re‐Establishing Tumor Acidosis

“…Confocal laser scanning microscopy (CLSM) showed that the FITC‐decorated AFeNPs@CAI nanoparticles could be engulfed by MB231 cells after coculturing for 4 h with strong green fluorescence (Figure S6, Supporting Information). Then we used BCECF‐AM, a pH‐sensitive probe, which decreases its fluorescence emission intensity with decreasing pH to show the change of pH intracellular . As shown in Figure d, MB231 cells in the control group displayed the strongest green fluorescence compared with AFeNPs@PA and AFeNPs@CAI group within 2 h both hypoxia and normoxia.…”