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-derived neurotrophic factor (BDNF) and ciliary neurotrophic factor (CNTF) are currently being explored as novel therapeutics in a range of neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS) and Alzheimer's disease. To this end, animal studies and clinical trials have been conducted to assess the toxic effects of recombinant NTFs. It is apparent that both NGF and BDNF induce a range of adverse effects, for example inflammation, hyperalgesia, and disturbances in CNS biogenic amine levels which variously manifest as weight loss/gain, changes in feeding behaviour and general malaise. It has been demonstrated that NGF induces release of biologically active mediators, such as histamine, from rat peritoneal mast cells (RPMC). However, whether other NTFs do likewise or indeed are able to induce secretion from other mast cells types had not been explored. We have developed a novel protocol 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 concentration dependent manner in response to NTFs, with a rank order of BDNF > CNTF > NGF; in contrast RPMC were refractory to the effects of BDNF and CNTF. The ability of NTFs to induce release of histamine (a neurotransmitter and neuromodulator in the CNS) from RBMC may go some way to explain some of the adverse effects apparent in vivo upon dosing with NTFs. Mast cells in vitro, and brain mast cells in particular, offer the potential to screen novel NTFs for their neuroimmunotoxic potential relevant to detecting likely clinical adverse effects in humans.
Purcell
W M
WM
Cellular Toxicology Unit, University of Hertfordshire, Herts, U.K.
Westgate
C
C
Atterwill
C K
CK
D000818:Animals; D001921:Brain / Q000187:drug effects*; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D020934:Ciliary Neurotrophic Factor; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D008297:Male; D008407:Mast Cells / Q000187:drug effects*; D009414:Nerve Growth Factors / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
D019208:Brain-Derived Neurotrophic Factor; D020934:Ciliary Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins