Hyperglycemia aggravates brain damage after diffuse axonal injury (DAI), but the underlying mechanisms are not fully de ned. In this study, we aimed to investigate a possible role for hyperglycemia in the disruption of blood-brain barrier (BBB) integrity in a rat model of DAI and the underlying mechanisms. Accordingly, 50% glucose was intraperitoneally injected after DAI to establish the hyperglycemia model. Hyperglycemia treatment aggravated neurological impairment and axonal injury, increased cell apoptosis and glial activation, and promoted the release of in ammatory factors, including TNF-α, IL-1β, and IL-6. It also exacerbated BBB disruption and decreased the expression of tight junctionassociated proteins, including ZO-1, claudin-5, and occludin-1, whereas the PPARγ agonist rosiglitazone (RSG) had the opposite effects. An in vitro BBB model was established by a monolayer of human microvascular endothelial cells (HBMECs). Hyperglycemia induction worsened the loss of BBB integrity induced by oxygen and glucose deprivation (OGD) by increasing the release of in ammatory factors and decreasing the expression of tight junction-associated proteins. Hyperglycemia further reduced the expression of PPARγ and caveolin-1, which signi cantly decreased after DAI and OGD. Hyperglycemia also further increased the expression of toll-like receptor 4 (TLR4), which signi cantly increased after OGD. Subsequently, the PPARγ agonist RSG increased caveolin-1 expression and decreased TLR4 expression and in ammatory factor levels. In contrast, caveolin-1 siRNA abrogated the protective effects of RSG in the in vitro BBB model of hyperglycemia by increasing TLR4 and Myd88 expression and the levels of in ammatory factors, including TNF-α, IL-1β, and IL-6. Collectively, we demonstrated that hyperglycemia was involved in mediating secondary injury after DAI by disrupting BBB integrity by inducing in ammation through the PPARγ/caveolin-1/TLR4 pathway.

Paclitaxel is widely used in clinical treatment of cancer and peripheral neuropathy is a common adverse side effect of paclitaxel. Diverse mechanisms contribute to the development and maintenance of paclitaxel-induced peripheral neuropathy. However, the role of spinal notch pathway in paclitaxel-induced peripheral neuropathy is not completely understood. In this study, we established an animal model of paclitaxel-induced peripheral neuropathy using nab-paclitaxel. We found that the mechanical and thermal pain threshold of rats was decreased with treatment of nab-paclitaxel, accompanied by increased expression of Notch pathway related proteins, enhanced apoptosis, neuronal and axonal injury, and glial responses. Using DAPT, an inhibitor for notch pathway, could restore the mechanical and thermal threshold and decrease apoptosis, neuronal and axonal injury, and glial responses induced by nab-paclitaxel. DAPT relieved paclitaxel-induced peripheral neuropathy by inhibiting activation of Notch pathway related proteins, then inhibited HMGB1/TLR4 signaling pathway, reduced the expression of inflammatory factor tumor necrosis factor-α and interleukin-1β and accelerated nerve regeneration. Taking together, our study demonstrated that Notch pathway may serve as a potential target for paclitaxel-induced peripheral neuropathy intervention.

Paclitaxel is widely used in clinical treatment of cancer and peripheral neuropathy is a common adverse side effect of paclitaxel. Diverse mechanisms contribute to the development and maintenance of paclitaxel-induced peripheral neuropathy. However, the role of spinal notch pathway in paclitaxel-induced peripheral neuropathy is not completely understood. In this study, we established an animal model of paclitaxel-induced peripheral neuropathy using nab-paclitaxel. We found that the mechanical and thermal pain threshold of rats was decreased with treatment of nab-paclitaxel, accompanied by increased expression of Notch pathway related proteins, enhanced apoptosis, neuronal and axonal injury, and glial responses. Using DAPT, an inhibitor for notch pathway, could restore the mechanical and thermal threshold and decrease apoptosis, neuronal and axonal injury, and glial responses induced by nab-paclitaxel. DAPT relieved paclitaxel-induced peripheral neuropathy by inhibiting activation of Notch pathway related proteins, then inhibited HMGB1/TLR4 signaling pathway, reduced the expression of inflammatory factor tumor necrosis factor-α and interleukin-1β and accelerated nerve regeneration. Taking together, our study demonstrated that Notch pathway may serve as a potential target for paclitaxel-induced peripheral neuropathy intervention.

Objective. Paclitaxel-induced peripheral neuropathy (PIPN) is a debilitating and difficult-to-treat side effect of paclitaxel. Soluble epoxide hydrolase (sEH) can rapidly metabolize the endogenous anti-inflammatory mediators’ epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatrienoic acids. This study aimed to assess whether the sEH inhibitor N-(1-(1-oxopropy)-4-piperidinyl]-N′-(trifluoromethoxy) phenyl)-urea (TPPU) plays a critical role in PIPN of rats and provides a new target for treatment. Methods. A Sprague–Dawley male rat model of PIPN induced by nab-paclitaxel was established. Rats were randomly divided into a control group, nab-paclitaxel group, and nab-paclitaxel + TPPU (sEH inhibitor) group, with 36 rats in each group. The effects of the sEH inhibitor TPPU on behavioural assays, apoptosis, glial activation, axonal injury, microstructure, and permeability of the blood-spinal cord barrier were detected, and the underlying mechanisms were explored by examining the expression of NF-κB signalling pathways, inflammatory cytokines, and oxidative stress. Results. The results showed that the mechanical and thermal pain thresholds of rats were decreased after nab-paclitaxel treatment, accompanied by an increased expression of axonal injury-related proteins, enhanced cell apoptosis, aggravated destruction of vascular permeability, intense glial responses, and elevated inflammatory cytokines and oxidative stress in the L4-L6 spinal cord. TPPU restored the mechanical and thermal thresholds, decreased cell apoptosis, alleviated axonal injury and glial responses, and protected vascular permeability by increasing the expression of tight junction proteins. TPPU relieved PIPN by inhibiting the activation of the sEH and NF-κB signalling pathways by decreasing the levels of inflammatory cytokines and oxidative stress. Conclusion. These findings support a role for sEH in PIPN and suggest that the inhibition of sEH represents a potential new therapeutic target for PIPN.

Hyperglycemia aggravates brain damage after diffuse axonal injury (DAI), but the underlying mechanisms are not fully defined. In this study, we aimed to investigate a possible role for hyperglycemia in the disruption of blood–brain barrier (BBB) integrity in a rat model of DAI and the underlying mechanisms. Accordingly, 50% glucose was intraperitoneally injected after DAI to establish the hyperglycemia model. Hyperglycemia treatment aggravated neurological impairment and axonal injury, increased cell apoptosis and glial activation, and promoted the release of inflammatory factors, including TNF-α, IL-1β, and IL-6. It also exacerbated BBB disruption and decreased the expression of tight junction-associated proteins, including ZO-1, claudin-5, and occludin-1, whereas the PPARγ agonist rosiglitazone (RSG) had the opposite effects. An in vitro BBB model was established by a monolayer of human microvascular endothelial cells (HBMECs). Hyperglycemia induction worsened the loss of BBB integrity induced by oxygen and glucose deprivation (OGD) by increasing the release of inflammatory factors and decreasing the expression of tight junction-associated proteins. Hyperglycemia further reduced the expression of PPARγ and caveolin-1, which significantly decreased after DAI and OGD. Hyperglycemia also further increased the expression of toll-like receptor 4 (TLR4), which significantly increased after OGD. Subsequently, the PPARγ agonist RSG increased caveolin-1 expression and decreased TLR4 expression and inflammatory factor levels. In contrast, caveolin-1 siRNA abrogated the protective effects of RSG in the in vitro BBB model of hyperglycemia by increasing TLR4 and Myd88 expression and the levels of inflammatory factors, including TNF-α, IL-1β, and IL-6. Collectively, we demonstrated that hyperglycemia was involved in mediating secondary injury after DAI by disrupting BBB integrity by inducing inflammation through the PPARγ/caveolin-1/TLR4 pathway.