1. Drug Discovery and Development, Italian Institute of Technology, , Genoa, Italy;2. Division of Neurosurgery, Galliera Hospital, , Genoa, Italy;3. Department of Pharmacy, Pharmacology and Toxicology Section, University of Genoa, , Genoa, Italy;4. Center of Excellence for Biomedical Research, University of Genoa, , Genoa, Italy
Abstract:
Our study was aimed at investigating whether complement, a complex of soluble and membrane‐associated serum proteins, could, in addition to its well‐documented post‐synaptic activity, also pre‐synaptically affect the release of classic neurotransmitters in central nervous system (CNS). Complement (dilution 1 : 10 to 1 : 10000) elicited the release of preloaded 3H]‐d ‐aspartate (3H]d ‐ASP) and endogenous glutamate from mouse cortical synaptosomes in a dilution‐dependent manner. It also evoked 3H]d ‐ASP release from mouse hippocampal, cerebellar, and spinal cord synaptosomes, as well as from rat and human cortical nerve endings, but left unaltered the release of GABA, 3H]noradrenaline or 3H]acetylcholine. Lowering external Na+ (from 140 to 40 mM) or Ca2+ (from 1.2 to 0.1 mM) ions prevented the 1 : 300 complement‐evoked 3H]d ‐ASP release from mouse cortical synaptosomes. Complement‐induced releasing effect was unaltered in synaptosomes entrapped with the Ca2+ ions chelator 1,2‐bis‐(2‐aminophenoxy) ethane‐N,N,N’,N’, tetra‐acetic acid or with pertussis toxin. Nifedipine,/ω‐conotoxin GVIA/ω‐conotoxin MVIIC mixture as well as the vesicular ATPase blocker bafilomycin A1 were also inefficacious. The excitatory amino acid transporter blocker DL‐threo‐ß‐benzyloxyaspartic acid, on the contrary, reduced the complement‐evoked releasing effect in a concentration‐dependent manner. We concluded that complement‐induced releasing activity is restricted to glutamatergic nerve endings, where it was accounted for by carrier‐mediated release. Our observations afford new insights into the molecular events accounting for immune and CNS crosstalk.
