c-Jun N-terminal kinases trigger both degeneration and neurite outgrowth in primary hippocampal and cortical neurons.

We provide a comprehensive analysis on c-Jun N-terminal kinase (JNK) actions leading to death or differentiation in postnatal hippocampal and cortical neurons. Stimulation with glutamate or 6-hydroxy-dopamine caused activation of caspase-3 and apoptotic neuronal death which were both attenuated by JNK-inhibition. In cortical neurons, stress-induced nuclear JNK distribution was rather complex. We observed a decrease of activated and total JNK in the nucleus after stimulation, but an increase of the phosphorylated transcription factor c-Jun. Isoform-analysis revealed a nuclear translocation of JNK2, while nuclear protein levels of JNK1 decreased. This activation pattern differed from neurite formation. In hippocampal and cortical neurons, JNK activity continuously increased during neuritogenesis, whereas levels of phosphorylated c-Jun gradually declined. Despite these similarities, JNK inhibition by SP600125 only affected neurite outgrowth in hippocampal cells. Furthermore, experiments in JNK-deficient mice demonstrated that all JNK isoforms contributed to neuritogenesis. Summarizing, JNKs are involved in both neuritogenesis and death of primary neurons with differentially regulated nuclear translocation of specific isoforms after degenerative stress, while neuritogenesis is supported by all JNK isoforms.

Combined use of tertiary amine parasympathomimetics with a quaternary amine parasympatholitic--a new perspective to use parasympathomimetic drugs for systemic analgesia.

The interactions on antinociception between a muscarinic agonist arecoline (arec), an anticholinesterase physostigmine (physo) which both cross CNS, and a peripherally acting antimuscarinic hyoscine-N-butyl bromide (hyo), were assessed by tail flick test in mice. All drugs were administered intraperitoneally (i.p.). While hyoscine-N-butyl bromide (0.15 and 4.00 mg/kg, i.p.) did not produce antinociception, physostigmine salicylate (0.3 mg/kg, i.p.) and arecoline hydrobromide (8.00 mg/kg, i.p.) exerted significant antinociceptive effect. In combined applications, physo + hyo (0.075 + 0.15; 0.15 + 0.30; 0.30 + 0.60 mg/kg) and arec + hyo (1.00 + 0.50; 2.00 + 1.00; 4.00 + 2.00; 8.00 + 4.00 mg/kg), respectively, produced significant antinociception and the tail flick latencies produced by physo 0.30 + hyo 0.60 mg/kg and arec 8.00 + hyo 4.00 mg/kg were not significantly different from those of physo 0.30 mg/kg and arec 8.00 mg/kg, respectively, showing that hyo did not antagonise the antinociceptive effects of physo and arec. We believe that combining an centrally acting cholinergic drug applied systemically with a peripherally acting (quaternary amine) antimuscarinic compound might be used as an effective analgesic in clinical practice.