Butylphthalide (3-n-Butylphthalide) is a natural compound with a wide range of pharmacological activities, primarily used for the treatment of acute ischemic stroke[1]. The mechanisms of action of Butylphthalide include antioxidant effects and mitochondrial protection[2]. Butylphthalide can also improve symptoms of myocardial infarction[3]. In addition, Butylphthalide has the potential to treat tissue damage induced by ischemia-reperfusion[4].
In vitro, pretreatment of SV40-transformed rat aortic endothelial cells with Butylphthalide (1μM) for 6 hours, followed by oxygen-glucose deprivation (OGD) for 6 hours, significantly enhances PGC-1α expression and protects cells from OGD-induced damage, increasing cell viability[5]. Pretreatment of SH-SY5Y cells with Butylphthalide (5μM) for 6 hours, followed by stimulation with 6-OHDA (100μM) for 24 hours, significantly increases cell viability, reduces cell apoptosis and ROS production, inhibits NLRP3 inflammasome activation and related inflammatory factor expression, alleviates mitochondrial damage, and decreases abnormal aggregation of α-synuclein (α-Syn)[6].
In vivo, Butylphthalide (200mg/kg) is administered intraperitoneally once daily to C57BL/6 mice starting at 8 weeks of age until the 10th week. Butylphthalide significantly alleviates behavioral deficits induced by Rotenone, reduces the loss of dopaminergic neurons, and inhibits microglial activation[7]. Butylphthalide (4mg/kg) is administered intraperitoneally as a single dose to rats with middle cerebral artery occlusion/reperfusion (MCAO/R) model. Butylphthalide significantly alleviates behavioral deficits induced by MCAO/R, reduces brain infarct volume, inhibits microglial activation, suppresses ferroptosis by activating the Nrf2/HO-1 signaling pathway, and alleviates lipid peroxidation, iron accumulation, and mitochondrial damage induced by ischemia-reperfusion[8].
References:
[1] Chen XQ, Qiu K, Liu H, et al. Application and prospects of butylphthalide for the treatment of neurologic diseases. Chin Med J (Engl). 2019 Jun 20;132(12):1467-1477.
[2] Zhu T, Wang L, Feng Y, et al. Classical Active Ingredients and Extracts of Chinese Herbal Medicines: Pharmacokinetics, Pharmacodynamics, and Molecular Mechanisms for Ischemic Stroke. Oxid Med Cell Longev. 2021 Mar 13;2021:8868941.
[3] Bai M, Pan CL, Jiang GX, et al. Effects of butylphthalide on oxidative stress and inflammatory response in rats with myocardial infarction through Akt/Nrf2 signaling pathway. Eur Rev Med Pharmacol Sci. 2019 Nov;23(21):9642-9650.
[4] Lu P, Li WP, Zhou BJ, et al. N-butylphthalide (NBP) ameliorated ischemia/reperfusion-induced skeletal muscle injury in male mice via activating Sirt1/Nrf2 signaling pathway. Physiol Rep. 2024 Dec;12(23):e70149.
[5] Wei H, Zhan LP, Zhang B, et al. dl-3n-butylphthalide reduces oxygen-glucose deprivation-induced endothelial cell damage by increasing PGC-1α. Eur Rev Med Pharmacol Sci. 2019 May;23(10):4481-4490.
[6] Que R, Zheng J, Chang Z, et al. Dl-3-n-Butylphthalide Rescues Dopaminergic Neurons in Parkinson's Disease Models by Inhibiting the NLRP3 Inflammasome and Ameliorating Mitochondrial Impairment. Front Immunol. 2021 Dec 1;12:794770.
[7] Liu Y, Duan R, Li P, et al. 3-N-butylphthalide attenuates neuroinflammation in rotenone-induced Parkinson's disease models via the cGAS-STING pathway. Int J Immunopathol Pharmacol. 2024 Jan-Dec;38:3946320241229041.
[8] Sun M, Chen J, Liu F, et al. Butylphthalide inhibits ferroptosis and ameliorates cerebral Ischaemia-Reperfusion injury in rats by activating the Nrf2/HO-1 signalling pathway. Neurotherapeutics. 2024 Sep;21(5):e00444.