Purcell W M, Westgate C, Atterwill C K
Cellular Toxicology Unit, University of Hertfordshire, Herts, U.K.
Neurotoxicology. 1996 Fall-Winter;17(3-4):845-50.
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.
神经营养因子（NTFs），如神经生长因子（NGF）、脑源性神经营养因子（BDNF）和睫状神经营养因子（CNTF），目前正作为新型疗法在一系列神经退行性疾病中进行探索，如肌萎缩侧索硬化症（ALS）和阿尔茨海默病。为此，已经开展了动物研究和临床试验来评估重组NTFs的毒性作用。显然，NGF和BDNF都会引发一系列不良反应，例如炎症、痛觉过敏以及中枢神经系统生物胺水平紊乱，这些反应分别表现为体重减轻/增加、进食行为改变和全身不适。已经证明，NGF能诱导大鼠腹膜肥大细胞（RPMC）释放生物活性介质，如组胺。然而，其他NTFs是否也有同样作用，或者是否能够诱导其他类型肥大细胞分泌，尚未得到研究。我们开发了一种从大鼠脑组织中分离肥大细胞的新方法，特别是从丘脑分离，丘脑在成年大鼠中含有数量最多的肥大细胞。大鼠脑肥大细胞（RBMC）对NTFs以浓度依赖方式释放组胺，其顺序为BDNF > CNTF > NGF；相比之下，RPMC对BDNF和CNTF的作用不敏感。NTFs从RBMC诱导释放组胺（一种中枢神经系统中的神经递质和神经调节剂）的能力，可能在一定程度上解释了NTFs给药后在体内出现的一些不良反应。体外的肥大细胞，特别是脑肥大细胞，为筛选新型NTFs的神经免疫毒性潜力提供了可能，这与检测人类可能的临床不良反应相关。
