The present study was conducted to develop a new animal model of neuropathic pain employing injury to the distal sciatic nerve branches. Under halothane anesthesia, the tibial, sural, and/or common peroneal nerves were injured and neuropathic pain behaviors were compared among different groups of rats. Different types of injury produced different levels of neuropathic pain. Rats with injury to the tibial and sural nerves showed the most vigorous mechanical allodynia, cold allodynia, and spontaneous pain. These neuropathic pain behaviors were not relieved by functional sympathectomy using guanethidine.The results suggested that injury to the tibial and sural nerves, while leaving the common peroneal nerve intact, can be used as a new animal model of neuropathic pain and that this model represents sympathetically independent pain (SIP). The present animal model is very simple to produce injury and can produce profound and reliable pain behaviors. These features enable the new animal model to be a useful tool in elucidating the mechanisms of neuropathic pain, especially SIP. NeuroReport

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Prolonged stress results in elevation of glucocorticoid (GC) hormones, which can have deleterious effects in the brain. The hippocampus, which has a high concentration of glucocorticoid receptors, is especially vulnerable to increasing levels of GCs. GCs have been suggested to endanger hippocampal neurons by exacerbating the excitotoxic glutamate-calcium-reactive oxygen species (ROS) cascade. In an effort to reveal the mechanisms underlying GC-mediated hippocampal neurotoxicity, we aimed to clarify the molecular pathway of GC-induced ROS increase by using organotypic hippocampal slice cultures. Assays for ROS, using 2',7'-dichlorodihydrofluorescein diacetate fluorescence, showed that treatment of synthetic GC, dexamethasone (DEX) significantly enhanced ROS levels. Time course and dose response analyses indicated that peak amount of ROS was generated at 4 h after treatment with 50 micromol/L DEX. By contrast, other steroid hormones, progesterone and estradiol did not influence ROS production. N-acetyl-L-cysteine completely suppressed ROS produced by DEX. Propidium iodide staining exhibited prominent cell death in the hippocampal layer after 96 h of DEX treatment. RU486, a GC receptor antagonist, almost completely blocked the effect of DEX on ROS production and cell death, indicating that DEX-induced ROS overproduction and hippocampal death are mediated via GC receptors. Real-time reverse transcriptase PCR analysis demonstrated that after DEX treatment the level of glutathione peroxidase mRNA was decreased whereas that of NADPH oxidase mRNA was significantly enhanced. These findings suggest that excess GCs cause hippocampal damage by regulating genes involved in ROS generation.

Ascorbic acid (AA) is a well-known antioxidant. It also has pro-oxidant effects, however, in the presence of free transition metals. Because of the pro-oxidant effects of AA, dehydroascorbic acid (DHA), an oxidized form of AA, has been used as a substitute for AA. DHA has been shown recently to have a protective effect in an experimental stroke model. This study was carried out to determine if DHA has different effects from AA on hydrogen peroxide (H 2 O 2 )-induced oxidative cell death in primary astrocytes. DHA was found to prevent cell death and reverse mitochondrial dysfunction after exposure to H 2 O 2 . DHA significantly increased the glutathione peroxidase (GPx) and glutathione reductase (GR) activities 1 hr after H 2 O 2 exposure. Moreover, DHA not only reversed the decrease in the glutathione (GSH) levels, but also significantly enhanced it by stimulating the pentose phosphate pathway (PPP) 15 hr after H 2 O 2 exposure. DHA also reduced production of reactive oxygen species (ROS) after H 2 O 2 exposure. In contrast, AA accelerated H 2 O 2 -induced cell death. To determine if the pro-oxidant effect of AA is related to iron, the effect of AA on cell death was examined using an iron chelator, desferrioxamine. Even though co-pretreatment with AA and desferrioxamine could abrogate the aggravating effects of AA on H 2 O 2 -induced cell death at early stages, it could not prevent H 2 O 2 -induced cell death over a 24-hr period. These results suggest that DHA has distinct effects from AA and prevent H 2 O 2 -induced cell death by increasing the GSH levels mediated by the GPx and GR activities and PPP.