Department of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research (STAR), University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Department of Pain and Translational Symptom Science, University of Maryland School of Nursing, Baltimore, MD 21201, USA.
Cells. 2020 May 11;9(5):1194. doi: 10.3390/cells9051194.
Brain-derived neurotrophic factor (BDNF), a major focus for regenerative therapeutics, has been lauded for its pro-survival characteristics and involvement in both development and recovery of function within the central nervous system (CNS). However, studies of tyrosine receptor kinase B (TrkB), a major receptor for BDNF, indicate that certain effects of the TrkB receptor in response to disease or injury may be maladaptive. More specifically, imbalance among TrkB receptor isoforms appears to contribute to aberrant signaling and hyperpathic pain. A truncated isoform of the receptor, TrkB.T1, lacks the intracellular kinase domain of the full length receptor and is up-regulated in multiple CNS injury models. Such up-regulation is associated with hyperpathic pain, and TrkB.T1 inhibition reduces neuropathic pain in various experimental paradigms. Deletion of TrkB.T1 also limits astrocyte changes in vitro, including proliferation, migration, and activation. Mechanistically, TrkB.T1 is believed to act through release of intracellular calcium in astrocytes, as well as through interactions with neurotrophins, leading to cell cycle activation. Together, these studies support a potential role for astrocytic TrkB.T1 in hyperpathic pain and suggest that targeted strategies directed at this receptor may have therapeutic potential.
脑源性神经营养因子（BDNF）是再生治疗的主要焦点，因其具有促生存特性，并参与中枢神经系统（CNS）的发育和功能恢复而受到赞誉。然而，对酪氨酸受体激酶 B（TrkB）的研究表明，该受体对疾病或损伤的某些反应可能是适应不良的。更具体地说，TrkB 受体亚型之间的失衡似乎导致异常信号和痛觉过敏。受体的截短亚型 TrkB.T1 缺乏全长受体的细胞内激酶结构域，在多种中枢神经系统损伤模型中上调。这种上调与痛觉过敏有关，并且 TrkB.T1 抑制可减少各种实验模型中的神经病理性疼痛。TrkB.T1 的缺失也限制了体外星形胶质细胞的变化，包括增殖、迁移和激活。从机制上讲，TrkB.T1 被认为通过星形胶质细胞内钙离子的释放以及与神经营养因子的相互作用来发挥作用，从而导致细胞周期激活。这些研究共同支持星形胶质细胞 TrkB.T1 在痛觉过敏中的潜在作用，并表明针对该受体的靶向策略可能具有治疗潜力。
