Istradefylline(KW-6002) is an adenosine A2A receptor antagonist. Istradefylline improves the motor dysfunction of Parkinson's disease patients by selectively antagonizing adenosine A2A receptors and regulating the indirect pathway of the basal ganglia. Istradefylline is mainly used to treat Parkinson's disease [1-4].
In B16F10 melanoma cells, as Istradefylline (20, 40, 80, 160, 320, 640, 1280, and 2560nM, 24h, 48h, and 72h) concentrations increased, there was a sharp, significant fall in the viability of B16F10 cells in culture in the three established exposure periods [5].
In heatstroke rat models, the treatment of heatstroke rats with Istradefylline (0.3mg/kg, iv, 6h) partially, but significantly, improved vascular hyporesponsiveness at 4h after heat stress [6]. In Melanoma B16F10 tumor models, the tumor volume and weight of animals treated with Istradefylline (1mg/mL, iv, 14d) were significantly reduced [7]. In PFC-lesioned rats, the decreased recognition index in PFC-lesioned rats was significantly reversed by the treatment with Istradefylline (0.1mg/kg, po, 60min) [8]. In common marmosets, Istradefylline (10mg/kg, po, 10d) is effective in improving motor function in combination with low dose dopaminergic drug treatment without provoking dyskinesia [9].
References:
[1]. Jenner P, Mori A, Aradi SD, et al. Istradefylline–a first generation adenosine A2A antagonist for the treatment of Parkinson’s disease. Expert Review of Neurotherapeutics. 2021 Mar 4; 21(3): 317-333.
[2]. Dungo R, Deeks ED. Istradefylline: first global approval. Drugs. 2013 Jun; 73: 875-882.
[3]. Ohno Y, Suzuki M, Asada H, et al. In vitro pharmacological profile of KW-6356, a novel adenosine A2A receptor antagonist/inverse agonist. Molecular Pharmacology. 2023 Jun 1; 103(6): 311-324.
[4]. Chen JF, Cunha RA. The belated US FDA approval of the adenosine A2A receptor antagonist istradefylline for treatment of Parkinson’s disease. Purinergic signalling. 2020 Jun; 16(2): 167-174.
[5]. da Silva JL, Viana AR, Passos DF, et al. Istradefylline modulates purinergic enzymes and reduces malignancy-associated factors in B16F10 melanoma cells. Purinergic Signalling. 2023 Dec; 19(4): 633-650.
[6]. Shih CC, Chen JH, Liao MH, et al. The Effect of Adenosine A2A Receptor Antagonist Istradefylline on Multiple Organ Dysfunction in Heatstroke Rats. Journal of Medical Sciences. 2020 Mar 1; 40(2): 76-82.
[7]. Gutknecht da Silva JL, Passos DF, Cabral FL, et al. Istradefylline induces A2A/P2X7 crosstalk expression inducing pro-inflammatory signal, and reduces AKT/mTOR signaling in melanoma-bearing mice. Medical Oncology. 2023 May 15; 40(6): 178.
[8]. Kadowaki Horita T, Kobayashi M, Mori A, et al. Effects of the adenosine A 2A antagonist istradefylline on cognitive performance in rats with a 6-OHDA lesion in prefrontal cortex. Psychopharmacology. 2013 Dec; 230: 345-352.
[9]. Uchida SI, Soshiroda K, Okita E, et al. The adenosine A2A receptor antagonist, istradefylline enhances the anti-parkinsonian activity of low doses of dopamine agonists in MPTP-treated common marmosets. European Journal of Pharmacology. 2015 Jan 15; 747: 160-165.
Istradefylline(KW-6002)是一种腺苷A2A受体拮抗剂。Istradefylline通过选择性拮抗腺苷A2A受体并调节基底神经节的间接通路来改善帕金森病患者的运动功能障碍。Istradefylline主要用于治疗帕金森病 [1-4]。
在B16F10黑色素瘤细胞中，随着Istradefylline（20、40、80、160、320、640、1280和2560nM，24h、48h和72h）浓度的增加，在三个既定的暴露时间段内，培养的B16F10细胞活力急剧下降 [5]。
在中暑大鼠模型中，使用Istradefylline（0.3mg/kg，ip，6h）治疗中暑大鼠，在热应激后4h，其血管低反应性得到部分显著的改善 [6]。在黑色素瘤B16F10肿瘤模型中，使用Istradefylline（1mg/mL，iv，14d）治疗的动物的肿瘤体积和重量显著减小 [7]。在PFC损伤大鼠中，使用Istradefylline（0.1mg/kg，po，60min）治疗可显著逆转PFC损伤大鼠的识别指数下降 [8]。对于普通狨猴，Istradefylline（10mg/kg，po，10d与低剂量多巴胺能药物联合治疗可有效改善运动功能，且不会引起运动障碍 [9]。