The p75 neurotrophin receptor (p75NTR) can regulate multiple cellular functions including proliferation, survival, and apoptotic cell death. The p75NTR is widely expressed in the developing brain and is downregulated as the nervous system matures, with only a few neuronal subpopulations retaining expression into adulthood. However, p75NTR expression is induced following damage to the adult brain, including after traumatic brain injury, which is a leading cause of mortality and disability worldwide. A major consequence of traumatic brain injury is the progressive neuronal loss that continues secondary to the initial trauma, which ultimately contributes to cognitive decline. Understanding mechanisms governing this progressive neuronal death is key to developing targeted therapeutic strategies to provide neuroprotection and salvage cognitive function. In this study, we demonstrate that a cortical impact injury to the sensorimotor cortex elicits p75NTR expression in apoptotic neurons in the injury penumbra, confirming previous studies. To establish whether preventing p75NTR induction or blocking the ligands would reduce the extent of secondary neuronal cell death, we used a noninvasive intranasal strategy to deliver either siRNA to block the induction of p75NTR, or function-blocking antibodies to the ligands pro-nerve growth factor and pro-brain-derived neurotrophic factor. We demonstrate that either preventing the induction of p75NTR or blocking the proneurotrophin ligands provides neuroprotection and preserves sensorimotor function.

p75 神经营养因子受体 (p75NTR) 可以调节多种细胞功能，包括增殖、存活和凋亡细胞死亡。p75NTR 在发育中的大脑中广泛表达，随着神经系统的成熟而下调，只有少数神经元亚群在成年期仍保持表达。然而，p75NTR 表达是在成人大脑受损后诱导的，包括在创伤性脑损伤后，这是全世界死亡和残疾的主要原因。创伤性脑损伤的一个主要后果是继发于初始创伤的进行性神经元丢失，最终导致认知能力下降。了解控制这种进行性神经元死亡的机制是开发有针对性的治疗策略以提供神经保护和挽救认知功能的关键。在这项研究中，我们证明了对感觉运动皮层的皮质冲击损伤会引发损伤半影区凋亡神经元中 p75NTR 的表达，这证实了之前的研究。为了确定阻止 p75NTR 诱导或阻断配体是否会降低继发性神经元细胞死亡的程度，我们使用非侵入性鼻内策略来递送 siRNA 以阻断 p75NTR 的诱导，或针对配体促神经生长因子的功能阻断抗体和前脑源性神经营养因子。我们证明，阻止 p75NTR 的诱导或阻断前神经营养因子配体可提供神经保护并保持感觉运动功能。证实了以前的研究。为了确定阻止 p75NTR 诱导或阻断配体是否会降低继发性神经元细胞死亡的程度，我们使用非侵入性鼻内策略来递送 siRNA 以阻断 p75NTR 的诱导，或针对配体促神经生长因子的功能阻断抗体和前脑源性神经营养因子。我们证明，阻止 p75NTR 的诱导或阻断前神经营养因子配体可提供神经保护并保持感觉运动功能。证实了以前的研究。为了确定阻止 p75NTR 诱导或阻断配体是否会降低继发性神经元细胞死亡的程度，我们使用非侵入性鼻内策略来递送 siRNA 以阻断 p75NTR 的诱导，或针对配体促神经生长因子的功能阻断抗体和前脑源性神经营养因子。我们证明，阻止 p75NTR 的诱导或阻断前神经营养因子配体可提供神经保护并保持感觉运动功能。或针对配体前神经生长因子和前脑源性神经营养因子的功能阻断抗体。我们证明，阻止 p75NTR 的诱导或阻断前神经营养因子配体可提供神经保护并保持感觉运动功能。或针对配体前神经生长因子和前脑源性神经营养因子的功能阻断抗体。我们证明，阻止 p75NTR 的诱导或阻断前神经营养因子配体可提供神经保护并保持感觉运动功能。