RAT-BRAIN MAST-CELLS - AN IN-VITRO PARADIGM FOR ASSESSING THE TOXIC EFFECTS OF NEUROTROPIC THERAPEUTICS

Neurotrophic factors (NTFs) such as nerve growth factor (NGF), brain-d erived neurotrophic factor (BDNF) and ciliary neurotrophic factor (CNT F) are currently being explored as novel therapeutics in a range of ne urodegenerative disorders such as amyotrophic lateral sclerosis (ALS) and Alzheimer's disease. To this end, animal studies and clinical tria ls have been conducted to assess the toxic effects of recombinant NTFs . It is apparent that both NGF and BDNF induce a range of adverse effe cts, for example inflammation, hyperalgesia, and disturbances in CNS b iogenic amine levels which variously manifest as weight loss/gain, cha nges in feeding behaviour and general malaise. It has been demonstrate d that NGF induces release of biologically active mediators, such as h istamine, from rat peritoneal mast cells (RPMC). However, whether othe r NTFs do likewise or indeed are able to induce secretion from other m ast cells types had not been explored. We have developed a novel proto col for dispersing mast cells from rat brain tissue, in particular the thalamus which contains the highest number of mast cells in the adult rat. Rat brain mast cells (RBMC) released histamine in a concentratio n dependent manner in response to NTFs, with a rank order of BDNF > CN TF > NGF; in contrast RPMC were refractory to the effects of BDNF and CNTF. The ability of NTFs to induce release of histamine (a neurotrans mitter and neuromodulator in the CNS) from RBMC may go some way to exp lain some of the adverse effects apparent in vivo upon dosing with NTF s. Mast cells in vitro, and brain mast cells in particular, offer the potential to screen novel NTFs for their neuroimmunotoxic potential re levant to detecting likely clinical adverse effects in humans. (C) 199 6 Intox Press, Inc.