Paclitaxel alters angiogenesis in the peripheral and central nervous system of neuropathic rats

Neurotoxicity is the most debilitating non-haematological adverse effect of paclitaxel (PTX) in cancer patients that report typical symptoms of a dose cumulative sensory peripheral neuropathy with paraesthesia, disaesthesia, tingling, and numbness. Many patients develop allodynia and hyperalgesia, experiencing neuropathic pain (NP). NP can originate from a peripheral sensitization then transmitted to the central nervous system where it can determine structural and functional changes. An abundant microvascular angiogenesis was described in the primary somatosensory cortex, specifically on the hindlimb projection of rats with NP of other origin. In this work, we investigated the microstructural vascular anomalies in the central somatosensory pathway and peripheral compartments (dorsal root ganglia, DRG) in rats exposed to chronic PTX treatment. Twenty-four rats were chronically treated with PTX 10 mg/kg to induce a painful peripheral neuropathy. Animals were tested for neurophysiological abnormalities and behavioral NP and finally perfused with fixative and/or indian ink before collecting samples. Samples have been analyzed at synchrotron radiation resources by X-ray Phase-Contrast Tomography (XPCT) Imaging (Diamond, Didcot, UK and ESRF, Grenoble, France). Volume rendering allowed a detailed visualization of vasculature at the sub micrometric scale. We performed a quantitative and morphological analysis of micro-vascular structures in PNS and CSN of control and NP rats. Histochemical and histological evaluations validated the results obtained by XPCT. A significant increased number of vessels has been found in NP samples, suggesting an angiogenesis at the capillary level in NP condition. The effect was larger (about +173%) in somatosensory cortex, still relevant in lumbar spinal cord and noticeable in related DRG. Specific analyses indicated that neo-formed vessels were smaller than 15 micron. Moreover, a significant decrement of the number of capillary branch points and tortuosity was evident in NP samples, suggesting an impairment of the normal microcirculation and neuronal activity. These events have been confirmed both by tomato-lectin staining, that showed a vessel neogenesis in all peripheral and central compartments, and by histological observations at light microscopy. These results shed light on new pathogenic mechanisms and potential novel therapeutic approaches for PTX-induced painful peripheral neuropathy. References • Staff NP et al. Pathogenesis of paclitaxel-induced peripheral neuropathy: A current review of in vitro and in vivo findings using rodent and human model systems. Exp Neurol. 2020 Feb;324:113121. • Colleoni M., Sacerdote P. Murine models of human neuropathic pain. Bio-chim Biophys Acta. 2010 Oct;1802(10):924-33. • Del Grosso et al. Brain angiogenesis in chronic pain. Journal of Cerebral Blood Flow & Metabolism 37(1S). BRAIN & BRAIN PET 2017. Poster viewing session.