Rosiglitazone

Rosiglitazone is an orally active peroxisome proliferator-activated receptor gamma (PPARγ) selective agonist that selectively activates chimeras containing the PPARγ ligand-binding domain (LBD) but not PPARα and PPARδ with an EC₅₀ of 60 nM and a K_d of 40nM^{[1, 2]}. Rosiglitazone is an activator of transient receptor potential channel 5 (TRPC5) (EC₅₀ of 30μM) and an inhibitor of transient receptor potential cation channel subfamily M member 3 (TRPM3) ^[3].

In vitro, treatment of hippocampal neurons with rosiglitazone (1 μM) for 24 or 48 h induced an increase in intracellular NF-α1 and BCL-2 protein levels ^[4]. Treatment of A2780 and SKOV3 cells with rosiglitazone (0-50 μM) for 7 days inhibited cell proliferation in a time-dependent and concentration-dependent manner ^[5].

In vivo, treatment of high-fat diet-fed obese mice with rosiglitazone (8 mg/kg) by intraperitoneal injection for 10 days reversed the abnormal molecular and cellular phenotypes of adipocytes ^[6]. Rosiglitazone (5 mg/kg) was orally administered to diabetic rats for 8 weeks and reduced the levels of IL-6, TNF-α, and VCAM-1, lipid peroxidation and nitric oxide, and increased aortic glutathionease and superoxide dismutase levels ^[7].

References:
[1] Bhagavathula N, Nerusu K C, Lal A, et al. Rosiglitazone inhibits proliferation, motility, and matrix metalloproteinase production in keratinocytes[J]. Journal of investigative dermatology, 2004, 122(1): 130-139.
[2] Lehmann J M, Moore L B, Smith-Oliver T A, et al. An antidiabetic Thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor(PPARγ)[J]. Journal of Biological Chemistry, 1995, 270(22): 12953-12956.
[3] Majeed Y, Bahnasi Y, Seymour V A L, et al. Rapid and contrasting effects of rosiglitazone on transient receptor potential TRPM3 and TRPC5 channels[J]. Molecular pharmacology, 2011, 79(6): 1023-1030.
[4] Thouennon E, Cheng Y, Falahatian V, et al. Rosiglitazone‐activated PPAR γ induces neurotrophic factor‐α1 transcription contributing to neuroprotection[J]. Journal of neurochemistry, 2015, 134(3): 463-470.
[5] Wang Z, Gao J, Ohno Y, et al. Rosiglitazone ameliorates senescence and promotes apoptosis in ovarian cancer induced by olaparib[J]. Cancer Chemotherapy and Pharmacology, 2020, 85: 273-284.
[6] Roh H C, Kumari M, Taleb S, et al. Adipocytes fail to maintain cellular identity during obesity due to reduced PPARγ activity and elevated TGFβ-SMAD signaling[J]. Molecular metabolism, 2020, 42: 101086.
[7] Ateyya H, Nader M A, El-Sherbeeny N A. Beneficial effects of rosiglitazone and losartan combination in diabetic rats[J]. Canadian Journal of Physiology and Pharmacology, 2018, 96(3): 215-220.

Rosiglitazone是一种具有口服活性的过氧化物酶体增殖物活化受体γ（PPARγ ）选择性激动剂，选择性地激活含有PPARγ配体结合域（LBD）的嵌合体，而不是PPARα和PPARδ，EC₅₀为60 nM，K_d为40 nM^{[1, 2]}。Rosiglitazone是瞬时受体电位通道5（TRPC5 ）的激活剂（EC₅₀为30 μM）和瞬时受体电位阳离子通道亚家族M成员3 （TRPM3）的抑制剂^[3]。

在体外，Rosiglitazone（1μM）处理海马神经元细胞24或48h，诱导了细胞内NF-α1和BCL-2蛋白水平升高^[4]。Rosiglitazone（0-50μM）处理A2780和SKOV3细胞7天，以时间依赖性和浓度依赖性方式抑制了细胞增殖^[5]。

在体内，Rosiglitazone（8mg/kg）通过腹膜内注射给药治疗高脂饮食的肥胖小鼠10天，可逆转脂肪细胞的异常分子和细胞表型^[6]。Rosiglitazone（5mg/kg）通过口服给药治疗糖尿病大鼠8周，降低了IL-6、TNF-α 和VCAM-1水平，降低了脂质过氧化和氮氧化物水平，增加了主动脉谷胱甘肽酶和超氧化物歧化酶水平^[7]。