Trofinetide (NNZ-2566) is a synthetic analogue of the endogenous N-terminal tripeptide Glycine Proline-Glutamate (GPE) with neuroprotective effects [1]. Trofinetide can cross the blood-brain barrier and improve synaptic function, repair synaptic structure, reduce neuroinflammatory substances in the brain, and enhance antioxidant response[2]. Trofinetide has been widely used in Fmr1 knockout mice to correct learning and memory deficits, abnormal hyperactivity, and social interaction impairments [3].
In vitro, Trofinetide pretreatment at 1μM for 2 hours effectively reversed the cytotoxicity of Aβ42 (10µM; 24h) on BV2 cells and increased cell viability[4]. Treatment with 10μM Trofinetide for 24h reversed okadaic acid-induced cell death in isolated embryonic striatal neurons[5].
In vivo, Trofinetide treatment via continuous intravenous infusion at a rate of 3mg/kg/h for 12 hours inhibited neuroinflammation and proinflammatory cytokine expression induced by experimental penetrating ballistic-like brain injury in rats[6]. Intravenous infusion of Trofinetide (10mg/kg/h) for 4 hours significantly reduced infarct size in rats caused by middle cerebral artery occlusion (MCAO) and attenuated weight loss[7].
References:
[1] Neul J L, Percy A K, Benke T A, et al. Trofinetide for the treatment of Rett syndrome: a randomized phase 3 study[J]. Nature Medicine, 2023, 29(6): 1468-1475.
[2] Hudu S A, Elmigdadi F, Qtaitat A A, et al. Trofinetide for Rett syndrome: highlights on the development and related inventions of the first USFDA-approved treatment for rare pediatric unmet medical need[J]. Journal of Clinical Medicine, 2023, 12(15): 5114.
[3] Deacon R M J, Glass L, Snape M, et al. NNZ-2566, a novel analog of (1–3) IGF-1, as a potential therapeutic agent for fragile X syndrome[J]. Neuromolecular medicine, 2015, 17(1): 71-82.
[4] Chen M, Ning Y, Yang H, et al. Trofinetide Improves Cognitive Function in APP/PS1 Mice by Suppressing Inflammation and Apoptosis[J]. Molecular Neurobiology, 2026, 63(1): 129.
[5] Bickerdike M J, Thomas G B, Batchelor D C, et al. NNZ-2566: A Gly–Pro–Glu analogue with neuroprotective efficacy in a rat model of acute focal stroke[J]. Journal of the neurological sciences, 2009, 278(1-2): 85-90.
[6] Wei H H, Lu X C M, Shear D A, et al. NNZ-2566 treatment inhibits neuroinflammation and pro-inflammatory cytokine expression induced by experimental penetrating ballistic-like brain injury in rats[J]. Journal of neuroinflammation, 2009, 6(1): 19.
[7] Bickerdike M J, Thomas G B, Batchelor D C, et al. NNZ-2566: A Gly–Pro–Glu analogue with neuroprotective efficacy in a rat model of acute focal stroke[J]. Journal of the neurological sciences, 2009, 278(1-2): 85-90.
Trofinetide (NNZ-2566)是内源性N末端三肽甘氨酸-脯氨酸-谷氨酸（GPE）的合成类似物，具有神经保护作用[1]。Trofinetide能够穿越血脑屏障，改善突触功能，修复突触结构，降低脑内神经炎症物质，并增强抗氧化反应[2]。Trofinetide已被广泛用于Fmr1基因敲除小鼠，以纠正学习和记忆缺陷、异常多动以及社交互动障碍[3]。
在体外，使用1μM的Trofinetide预处理BV2细胞2小时，有效逆转了Aβ42（10μM；24小时）诱导的细胞毒性，并提高了细胞活力[4]。使用10μM的Trofinetide处理分离的胚胎纹状体神经元24小时，逆转了okadaic acid诱导的细胞死亡[5]。
在体内，以3mg/kg/h的速率连续静脉输注Trofinetide 12小时，抑制了实验性穿透性弹道样脑损伤诱导的大鼠神经炎症和促炎细胞因子表达[6]。静脉输注Trofinetide（10mg/kg/h）4小时，显著减小了大脑中动脉闭塞（MCAO）引起的大鼠梗死面积，并减轻了体重下降[7]。