The role of the gut microbiome in neuroinflammation and chemotherapy-induced peripheral neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most debilitating adverse effects caused by chemotherapy drugs such as paclitaxel, oxaliplatin and vincristine. It is untreatable and often leads to the discontinuation of cancer therapy and a decrease in the quality of life of cancer patients. It is well-established that neuroinflammation and the activation of immune and glial cells are among the major drivers of CIPN. However, these processes are still poorly understood, and while many chemotherapy drugs alone can drive the activation of these cells and consequent neuroinflammation, it remains elusive to what extent the gut microbiome influences these processes. In this review, we focus on the peripheral mechanisms driving CIPN, and we address the bidirectional pathways by which the gut microbiome communicates with the immune and nervous systems. Additionally, we critically evaluate literature addressing how chemotherapy-induced dysbiosis and the consequent imbalance in bacterial products may contribute to the activation of immune and glial cells, both of which drive neuroinflammation and possibly CIPN development, and how we could use this knowledge for the development of effective treatment strategies.

Macrophages Treated with VEGF and PDGF Exert Paracrine Effects on Olfactory Ensheathing Cell Function.

Glial cell transplantation using olfactory ensheathing cells (OECs) holds a promising approach for treating spinal cord injury (SCI). However, integration of OECs into the hostile acute secondary injury site requires interaction and response to macrophages. Immunomodulation of macrophages to reduce their impact on OECs may improve the functionality of OECs. Vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF), known for their immunomodulatory and neuroprotective functions, have provided improved outcomes in SCI animal models. Thus, VEGF and PDGF modulation of the SCI microenvironment may be beneficial for OEC transplantation. In this in vitro study, the effect of VEGF and PDGF on macrophages in an inflammatory condition was tested. Combined VEGF + PDGF reduced translocation nuclear factor kappa B p65 in macrophages without altering pro-inflammatory cytokines. Further, the ability of OECs to phagocytose myelin debris was assessed using macrophage-conditioned medium. Conditioned medium from macrophages incubated with PDGF and combined VEGF + PDGF in inflammatory conditions promoted phagocytosis by OECs. The growth factor treated conditioned media also modulated the expression of genes associated with nerve repair and myelin expression in OECs. Overall, these results suggest that the use of growth factors together with OEC transplantation may be beneficial in SCI therapy.

Inhibition of acid-sensing ion channels by diminazene and APETx2 evoke partial and highly variable antihyperalgesia in a rat model of inflammatory pain.

BACKGROUND AND PURPOSE: Acid-sensing ion channels (ASICs) are primary acid sensors in mammals, with the ASIC1b and ASIC3 subtypes being involved in peripheral nociception. The antiprotozoal drug diminazene is a moderately potent ASIC inhibitor, but its analgesic activity has not been assessed. EXPERIMENTAL APPROACH: We determined the ASIC subtype selectivity of diminazene and the mechanism by which it inhibits ASICs using voltage-clamp electrophysiology of Xenopus oocytes expressing ASICs 1-3. Its peripheral analgesic activity was then assessed relative to APETx2, an ASIC3 inhibitor, and morphine, in a Freund's complete adjuvant (FCA)-induced rat model of inflammatory pain. KEY RESULTS: Diminazene inhibited homomeric rat ASICs with IC50 values of ~200-800 nM, via an open channel and subtype-dependent mechanism. In rats with FCA-induced inflammatory pain in one hindpaw, diminazene and APETx2 evoked more potent peripheral antihyperalgesia than morphine, but the effect was partial for APETx2. APETx2 potentiated rat ASIC1b at concentrations 30-fold to 100-fold higher than the concentration inhibiting ASIC3, which may have implications for its use in in vivo experiments. CONCLUSIONS AND IMPLICATIONS: Diminazene and APETx2 are moderately potent ASIC inhibitors, both inducing peripheral antihyperalgesia in a rat model of chronic inflammatory pain. APETx2 has a more complex ASIC pharmacology, which must be considered when it is used as a supposedly selective ASIC3 inhibitor in vivo. Our use of outbred rats revealed responders and non-responders when ASIC inhibition was used to alleviate inflammatory pain, which is aligned with the concept of number-needed-to-treat in human clinical studies. LINKED ARTICLES: This article is part of a themed section on Recent Advances in Targeting Ion Channels to Treat Chronic Pain. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.12/issuetoc.

Increased expression of C5a receptor (CD88) mRNA in canine mammary tumors.

Mammary tumors are among the most common neoplastic conditions in dogs, and there is evidence that inflammation plays a role in the development of some tumor types in dogs. The complement system is a major participant in the inflammatory process and the complement activation component, C5a, is a potent inflammatory peptide. This study investigated the mRNA expression of the major receptor for C5a (C5aR; CD88) in histopathological samples of canine mammary tumors by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) using canine-specific primers for CD88. A total of seven canine mammary tumors (four malignant carcinomas, two benign mixed mammary tumors, and one myoepithelioma) and eight normal mammary glands were analysed. All the tumor samples expressed low levels of CD88 mRNA, while none of the normal mammary tissues showed any detectable expression. These preliminary results suggest that C5a-CD88 interaction may play a contributory role in the inflammatory response associated with mammary tumor development in dogs. Further studies investigating the mechanisms behind complement activation and C5a receptor expression in canine mammary tumors are warranted.