Preventative and therapeutic effects of a GABA transporter 1 inhibitor administered systemically in a mouse model of paclitaxel-induced neuropathic pain

ABSTRACT Background. There is a dearth of drugs to manage a dose-limiting painful peripheral neuropathy induced by paclitaxel in some patients during the treatment of cancer. Gamma-aminobutyric acid transporter-1 (GAT-1) whose expression is increased in the brain and spinal cord during paclitaxel-induced neuropathic pain (PINP) might be a potential therapeutic target for managing PINP. Thus, our aim was to evaluate if systemic administration of a GAT-1 inhibitor ameliorates PINP. Methods. The reaction latency to thermal stimuli (hot plate test; at 55 • C) and cold stimuli (cold plate test; at 4 • C) of female BALB/c mice was recorded before and after intraperitoneal treatment with paclitaxel, its vehicle, and/or a selective GAT-1 inhibitor NO-711. The effects of NO-711 on motor coordination were evaluated using the rotarod test at a constant speed of 4 rpm or accelerating mode from 4 rpm to 40 rpm over 5 min. Results. The coadministration of paclitaxel with NO-711 3 mg/kg prevented the development of paclitaxel-induced thermal hyperalgesia and cold allodynia at day 7 after drug treatment. NO-711 at 3 mg/kg produced antihyperalgesic activity up to 1 h and antiallodynic activity up to 2 h in mice with established paclitaxel-induced thermal hyperalgesia and cold allodynia. No motor deficits were observed with NO-711 at a dose of 3 mg/kg, whereas a higher dose 5 mg/kg caused motor impairment and reduced mean time spent on the rotarod at a constant speed of 4 rpm. However, at a rotarod accelerating mode from 4 rpm to 40 rpm over 5 min, NO-711 3 mg/kg caused motor impairment up to 1 h, but had recovered by 2 h. Conclusions. These results show that systemic administration of the GAT-1 inhibitor NO-711 has preventative and therapeutic activity against paclitaxel-induced thermal hyperalgesia and cold allodynia. NO-711's antiallodynic effects, but not antihyperalgesic effects, were independent of its motor impairment/sedation properties. Thus, low doses of GAT-1 inhibitors could be useful for the prevention and treatment of PINP with proper dose titration to reduce motor impairment/sedation side effects

Preventative and therapeutic effects of a GABA transporter 1 inhibitor administered systemically in a mouse model of paclitaxel-induced neuropathic pain

Background There is a dearth of drugs to manage a dose-limiting painful peripheral neuropathy induced by paclitaxel in some patients during the treatment of cancer. Gamma-aminobutyric acid transporter-1 (GAT-1) whose expression is increased in the brain and spinal cord during paclitaxel-induced neuropathic pain (PINP) might be a potential therapeutic target for managing PINP. Thus, our aim was to evaluate if systemic administration of a GAT-1 inhibitor ameliorates PINP. Methods The reaction latency to thermal stimuli (hot plate test; at 55 °C) and cold stimuli (cold plate test; at 4 °C) of female BALB/c mice was recorded before and after intraperitoneal treatment with paclitaxel, its vehicle, and/or a selective GAT-1 inhibitor NO-711. The effects of NO-711 on motor coordination were evaluated using the rotarod test at a constant speed of 4 rpm or accelerating mode from 4 rpm to 40 rpm over 5 min. Results The coadministration of paclitaxel with NO-711 3 mg/kg prevented the development of paclitaxel-induced thermal hyperalgesia and cold allodynia at day 7 after drug treatment. NO-711 at 3 mg/kg produced antihyperalgesic activity up to 1 h and antiallodynic activity up to 2 h in mice with established paclitaxel-induced thermal hyperalgesia and cold allodynia. No motor deficits were observed with NO-711 at a dose of 3 mg/kg, whereas a higher dose 5 mg/kg caused motor impairment and reduced mean time spent on the rotarod at a constant speed of 4 rpm. However, at a rotarod accelerating mode from 4 rpm to 40 rpm over 5 min, NO-711 3 mg/kg caused motor impairment up to 1 h, but had recovered by 2 h. Conclusions These results show that systemic administration of the GAT-1 inhibitor NO-711 has preventative and therapeutic activity against paclitaxel-induced thermal hyperalgesia and cold allodynia. NO-711’s antiallodynic effects, but not antihyperalgesic effects, were independent of its motor impairment/sedation properties. Thus, low doses of GAT-1 inhibitors could be useful for the prevention and treatment of PINP with proper dose titration to reduce motor impairment/sedation side effects

Optimal Dispatch Strategy of Virtual Power Plant for Day-Ahead Market Framework

Renewable energy sources prevail as a clean energy source and their penetration in the power sector is increasing day by day due to the growing concern for climate action. However, the intermittent nature of the renewable energy based-power generation questions the grid security, especially when the utilized source is solar radiation or wind flow. The intermittency of the renewable generation can be met by the integration of distributed energy resources. The virtual power plant (VPP) is a new concept which aggregates the capacities of various distributed energy resources, handles controllable and uncontrollable loads, integrates storage devices and empowers participation as an individual power plant in the electricity market. The VPP as an energy management system (EMS) should optimally dispatch the power to its consumers. This research work is proposed to analyze the optimal scheduling of generation in VPP for the day-ahead market framework using the beetle antenna search (BAS) algorithm under various scenarios. A case study is considered for this analysis in which the constituting energy resources include a photovoltaic solar panel (PV), micro-turbine (MT), wind turbine (WT), fuel cell (FC), battery energy storage system (BESS) and controllable loads. The real-time hourly load curves are considered in this work. Three different scenarios are considered for the optimal dispatch of generation in the VPP to analyze the performance of the proposed technique. The uncertainties of the solar irradiation and the wind speed are modeled using the beta distribution method and Weibull distribution method, respectively. The performance of the proposed method is compared with other evolutionary algorithms such as particle swarm optimization (PSO) and the genetic algorithm (GA). Among these above-mentioned algorithms, the proposed BAS algorithm shows the best scheduling with the minimum operating cost of generation