Adrian Pini

During development of the nervous system, distinct populations of nerve cells extend specialized processes, axons and dendrites, over considerable distances to locate their targets. There is strong evidence for two general mechanisms by which these connections are made. The first involves attractive and repulsive interactions, both between cells and between them and their extracellular matrix. The second depends on the release of diffusible chemoattractants by target structures. Evidence is now provided for a mechanism of axon guidance in which diffusible chemorepulsive factors create exclusion zones for developing axons, causing them to turn away from inappropriate territory.

In neurodegenerative conditions and following brain trauma it is not understood why neurons die while astrocytes and microglia survive and adopt pro-inflammatory phenotypes. We show here that the damaged adult brain releases diffusible factors that can kill cortical neurons and we have identified histone H1 as a major extracellular candidate that causes neurotoxicity and activation of the innate immune system. Extracellular core histones H2A, H2B H3 and H4 were not neurotoxic. Innate immunity in the central nervous system is mediated through microglial cells and we show here for the first time that histone H1 promotes their survival, up-regulates MHC class II antigen expression and is a powerful microglial chemoattractant. We propose that when the central nervous system is degenerating, histone H1 drives a positive feedback loop that drives further degeneration and activation of immune defences which can themselves be damaging. We suggest that histone H1 acts as an antimicrobial peptide and kills neurons through mitochondrial damage and apoptosis.

By examination of compound action potentials in the saphenous nerve of the anaesthetized rat it has been shown that capsaicin causes a rapid, dose-dependent, failure of conduction in many C-fibres when applied directly to the nerve. A large reduction in C-fibre conduction occurs with concentrations as low as 110 microM. After a 15-30 min exposure to capsaicin, only partial recovery occurs in 1 h. Similar block of C-fibre conduction occurs in the ferret. However, only smaller, reversible, reductions in C-fibre conduction were seen in the guinea-pig and rabbit, even at the highest concentration of capsaicin used (33 mM). A small reduction in the A delta component of the compound action potential occurred in all four species. In the rat and ferret the effects were much less than those on C-fibres. At high doses, small reversible effects were also seen on the fastest conducting A alpha beta component of the compound action potential in the rat, rabbit and guinea-pig; no effects were seen on the A alpha beta fibres in the ferret. Decreases in amplitude of the compound action potential were accompanied by some slowing of conduction in most cases. The slowing was less than 5% except for the rat A alpha beta and C-fibres and the ferret C-fibres where 9-15% changes occurred at the highest doses of capsaicin. Opening the connective tissue sheath of the nerve did not significantly increase the effectiveness of capsaicin.