Controlling neuropathic pain is an unmet medical need and we set out to identify new therapeutic candidates. AV411 (ibudilast) is a relatively nonselective phosphodiesterase inhibitor that also suppresses glial-cell activation and can partition into the CNS. Recent data strongly implicate activated glial cells in the spinal cord in the development and maintenance of neuropathic pain. We hypothesized that AV411 might be effective in the treatment of neuropathic pain and, hence, tested whether it attenuates the mechanical allodynia induced in rats by chronic constriction injury (CCI) of the sciatic nerve, spinal nerve ligation (SNL) and the chemotherapeutic paclitaxel (Taxol). Twice-daily systemic administration of AV411 for multiple days resulted in a sustained attenuation of CCI-induced allodynia. Reversal of allodynia was of similar magnitude to that observed with gabapentin and enhanced efficacy was observed in combination. We further show that multi-day AV411 reduces SNL-induced allodynia, and reverses and prevents paclitaxel-induced allodynia. Also, AV411 cotreatment attenuates tolerance to morphine in nerve-injured rats. Safety pharmacology, pharmacokinetic and initial mechanistic analyses were also performed. Overall, the results indicate that AV411 is effective in diverse models of neuropathic pain and support further exploration of its potential as a therapeutic agent for the treatment of neuropathic pain.

Chromium(VI) promotes pulmonary fibrosis and is a human carcinogen. Cr(VI) affects expression of various genes, including catalase, heme oxygenase, 5-aminolevulinate synthase, and urokinase plasminogen activator receptor (1-3). These chromium-mediated changes in gene expression are attributed to the generation of reactive chromium and oxygen species, DNA damage, or alterations in mRNA stability. This study examined whether Cr(VI) has additional effects on gene expression at the level of transcription factor activation or transcriptional competence. This type of epigenetic interference with the transcriptional machinery would have profound effects by shifting the patterns of genes expressed without causing molecular damage.Nuclear factor-B (NF-B) 1 is a mammalian transcription activator protein involved in regulating expression of immune and inflammatory response genes. It occurs in both homo-and heterodimeric forms. The most common transcriptionally competent form is composed of a p50 DNA-binding subunit attached to a p65 transactivation subunit. In nonstimulated cells, NF-B is localized in the cytoplasm bound to its inhibitor, IB, and to the catalytic subunit of protein kinase A (PKAc) (4). Upon cellular activation by cytokines, viral infection, lipopolysaccharide, and reactive oxygen species, IB is phosphorylated and degraded. This degradation unmasks the ATP-binding site on PKAc, resulting in activation and NF-B p65 phosphorylation (4). Furthermore, loss of IB exposes the NF-B nuclear localization sequence, allowing NF-B to translocate to the nucleus and to bind to its consensus sequence within the promoter region of genes.Studies have shown that, in addition to DNA binding, the interaction of p65 with CREB-binding protein (CBP) is essential for NF-B-enhanced transcriptional activity (5, 6). CBP is a coactivator molecule that links enhancer-bound transcription factors (transcription factor IIB and TATA-binding protein) to the basal transcriptional machinery. Interaction of CBP with p65 occurs at two sites. PKAc-induced phosphorylation of p65 on serine 276 mediates the phosphorylation-dependent interaction of p65 with the KIX region of CBP (amino acids 452-661). Alternatively, the C-terminal portion of p65 interacts with CBP in a phosphorylation-independent manner (5). In addition to p65, CBP interacts with various other transcription factors, including CREB, c-Jun, c-Fos, p53, glucocorticoid receptor, and retinoid X receptor (7-11). Thus, differences in the interaction of p65 with CBP may occur as a result of decreases in p65 phosphorylation or competition between transcription factors for limiting quantities of CBP.In this study, the complex multistep pathway for NF-B-dependent gene expression was chosen to examine how nontoxic concentrations of Cr(VI) produce epigenetic effects on cell phenotype. The effects of Cr(VI) on both basal and TNF-␣-stimulated gene expression were investigated in A549 human lung carcinoma cells. Cr(VI) inhibited both basal and stimulated expression of an NF-B-driven luciferase repo...

No abstract

Diabetes can induce a bewildering list of sensory changes, including alteration in pain sensitivity. Painful diabetic neuropathy is refractory to most common analgesics. This study examined the effect of a p38alpha MAPK inhibitor, SD-282, on mechanical allodynia, thermal hyperalgesia, and formalin-evoked nociception in streptozotocin-induced diabetic rats. Four-week diabetic rats exhibited mechanical allodynia, decreased mechanical thresholds, and C- and Adelta-fiber mediated thermal hyperalgesia. Mechanical and thermal responses were measured in diabetic rats following acute and repeated intraperitoneal administration of vehicle, 15 or 45 mg/kg SD-282. Mechanical allodynia was reversed by acute and repeated administration of 15 and 45 mg/kg SD-282. Repeated administration of 15 or 45 mg/kg SD-282 prevented the exacerbation of C-, but not Adelta-fiber, mediated thermal hyperalgesia. Repeated administration of 45 mg/kg SD-282 attenuated flinching behaviors during the quiescent period and the second phase of the formalin response in diabetic rats. Acute and repeated administration of 15 or 45 mg/kg SD-282 had no effect on mechanical, thermal or formalin responses in age-matched control rats. These results indicate a potential therapeutic value of p38alpha MAPK inhibitors in the treatment of aberrant pain sensitivity produced by diabetes.