Shi Jian, Yang Tao, Li Yibing, Zhong Lily, Longo Frank M, Massa Stephen M
Department of Neurology, San Francisco Veterans Affairs Health Care System and University of California, San Francisco, California, USA.
Department of Neurology and Neurological Sciences, Stanford University, Stanford, California, USA.
Neurotrauma Rep. 2025 Feb 17;6(1):195-209. doi: 10.1089/neur.2024.0117. eCollection 2025.
Tropomyosin receptor-kinase B (TrkB) and TrkC neurotrophin receptors promote neuronal growth and differentiation during the development and maintenance of structural integrity and plasticity in adult animals. Here, we test the hypotheses that activation of TrkB and TrkC will mitigate neuronal damage and loss, and behavioral deficits induced by traumatic brain injury (TBI). LM22B-10 (C10), a blood-brain barrier permeant small-molecule TrkB/TrkC co-activator, significantly increased proliferation, survival, and enhanced differentiation of neuronal progenitor cells . Following controlled cortical impact injury in rats, LM22B-10 administration increased the proliferation of doublecortin-expressing (DCX) cells in the hippocampus and significantly reduced cell death in the injured cortex. Interestingly, in studies of behavior, LM22B-10 promoted anxiety-like behavior and diminished spatial memory performance in the Barnes maze in sham-TBI animals but improved both of these behaviors in injured rats, a bimodal response suggesting the possibility that excess neurotrophic activity may be detrimental in uninjured animals but compensatory after injury. Thus, TrkB/TrkC agents may constitute a new therapeutic avenue for TBI but will require further study to determine safe and effective applications.
原肌球蛋白受体激酶B（TrkB）和TrkC神经营养因子受体在成年动物结构完整性和可塑性的发育及维持过程中促进神经元生长和分化。在此，我们检验以下假设：激活TrkB和TrkC将减轻创伤性脑损伤（TBI）所致的神经元损伤和丢失以及行为缺陷。LM22B - 10（C10）是一种可透过血脑屏障的小分子TrkB/TrkC共激活剂，可显著增加神经元祖细胞的增殖、存活并增强其分化。在大鼠控制性皮质撞击损伤后，给予LM22B - 10可增加海马中双皮质素表达（DCX）细胞的增殖，并显著减少损伤皮质中的细胞死亡。有趣的是，在行为学研究中，LM22B - 10在假TBI动物中促进了焦虑样行为并降低了其在巴恩斯迷宫中的空间记忆表现，但在受伤大鼠中改善了这两种行为，这种双峰反应表明，过量的神经营养活性在未受伤动物中可能有害，但在受伤后具有代偿作用。因此，TrkB/TrkC药物可能构成TBI的一种新治疗途径，但需要进一步研究以确定安全有效的应用方法。
