phenanthrenes and Peripheral-Nerve-Injuries

Recently, accumulating data have demonstrated that triptolide exhibits neurotrophic and neuroprotective properties. However, the role of triptolide in repair and regeneration of peripheral nerve injury (PNI) has rarely been performed. The current study was designed to observe the possible beneficial effect of triptolide on promoting peripheral nerve regeneration in rats. Rats with sciatic nerve crush injury were administered daily with triptolide for 7 days. Axonal regeneration was evaluated by morphometric analysis and Fluoro-gold retrograde tracing. Motor functional recovery was evaluated by walking track analysis, electrophysiological assessment and histological appearance of target muscles. Levels of pro-inflammatory cytokines within injured nerves were also determined. The results demonstrated that triptolide was capable of promoting peripheral nerve regeneration. Additionally, triptolide significantly decreased the levels of pro-inflammatory cytokines within injured nerves. These findings indicate the possibility of developing triptolide as a therapeutic agent for PNI. The neuroprotective effects of triptolide might be associated with its anti-inflammatory properties.

Topics: Animals; Diterpenes; Epoxy Compounds; Interleukin-1beta; Interleukin-6; Nerve Crush; Nerve Regeneration; Neuroprotective Agents; Peripheral Nerve Injuries; Phenanthrenes; Rats, Sprague-Dawley; Sciatic Nerve; Tumor Necrosis Factor-alpha

Competitive N-methyl-d-aspartate receptor (NMDAR) antagonists bind to the GluN2 subunit, of which there are four types (GluN2A-D). We report that some N(1)-substituted derivatives of cis-piperazine-2,3-dicarboxylic acid display improved relative affinity for GluN2C and GluN2D versus GluN2A and GluN2B. These derivatives also display subtype selectivity among the more distantly related kainate receptor family. Compounds 18i and (-)-4 were the most potent kainate receptor antagonists, and 18i was selective for GluK1 versus GluK2, GluK3 and AMPA receptors. Modeling studies revealed structural features required for activity at GluK1 subunits and suggested that S674 was vital for antagonist activity. Consistent with this hypothesis, replacing the equivalent residue in GluK3 (alanine) with a serine imparts 18i antagonist activity. Antagonists with dual GluN2D and GluK1 antagonist activity may have beneficial effects in various neurological disorders. Consistent with this idea, antagonist 18i (30 mg/kg ip) showed antinociceptive effects in an animal model of mild nerve injury.

Topics: Analgesics; Animals; Binding Sites; Excitatory Postsynaptic Potentials; Female; HEK293 Cells; Hippocampus; Humans; In Vitro Techniques; Male; Models, Molecular; Neuralgia; Oocytes; Patch-Clamp Techniques; Peripheral Nerve Injuries; Phenanthrenes; Piperazines; Point Mutation; Protein Subunits; Rats; Rats, Wistar; Receptors, Kainic Acid; Receptors, N-Methyl-D-Aspartate; Recombinant Proteins; Stereoisomerism; Structure-Activity Relationship; Xenopus