Department of Pharmacology, All India Institute of Medical Sciences (AIIMS), New Delhi 110029, India.
RBMCH, ICMR-Head Quarter's Ansari Nagar, New Delhi-110029, India.
Curr Drug Metab. 2022;23(7):571-583. doi: 10.2174/1389200223666220810152633.
Diabetic peripheral neuropathy is the most common complication of diabetes mellitus. Epalrestat, an aldose reductase inhibitor, has been approved for clinical therapy for diabetic peripheral neuropathic pain. In the present study, solid lipid-based nanoparticles are used for oral administration of epalrestat (E-SLN) and evaluated against diabetic neuropathic pain in a rat model.
Experimental diabetes in rats was induced by a single dose of streptozotocin (STZ) administration. The therapeutic efficiency of Epalrestat nanoparticles (0.25, 0.50, 1, and 5 mg/kg) in diabetic rats was studied. STZinduced diabetic rats were treated with different doses of E-SLN for 8 weeks. The nanoparticles were orally administered at a single dose in rats, and the various parameters related to peripheral neuropathy were evaluated and compared with the bare drug. The blood glucose level was estimated by standard glucometer, HbA1c, triglycerides, total cholesterol, and liver function test (ALT and AST) were analyzed by blood samples collected from retro-orbital plexus. Oxidative stress markers and Na+K+ATPase, TNF-α, and IL-1β levels were measured in the homogenate of sciatic nerves. Behavioral tests were also performed by the hot plate method and tail-flick method.
E-SLN synthesized by the micro-emulsification method was 281 ± 60 nm in size, and encapsulation efficacy was found to be 88 ± 2%. Optimized E-SLN were characterized and found to be optimum in size, spherical shape, decent encapsulation efficiency, stable at acidic gastric pH, and suitable for oral delivery. E-SLNs did not significantly reverse the STZ-induced elevated blood glucose level (FBS and PPBS), HbA1c, triglycerides, and total cholesterol but significantly improved TNF-α, IL-1β, and increased Na+K+ATPase levels, oxidative stress marker and ALT, AST in the treated rat group as compared with the diabetic group. Doses of E-SLN, i.e. 0.5, 1.0, 2.5, and 5 mg/kg, significantly increased the tail-flick latency time and hot plate response time in a dose-dependent manner compared with the diabetic group.
Thus, it is suggested that E-SLN were equally effective and less hepatotoxic compared with the standard treatment of epalrestat. To the best of our knowledge, we, for the first time, propose the orally deliverable E-SLN that ameliorates STZ-induced diabetes neuropathic pain effectively as compared with conventional epalrestat.
糖尿病周围神经病变是糖尿病最常见的并发症。醛糖还原酶抑制剂依帕司他已被批准用于治疗糖尿病周围神经病理性疼痛的临床治疗。本研究中，采用固体脂质纳米粒（E-SLN）进行依帕司他的口服给药，并在大鼠模型中针对糖尿病神经病理性疼痛进行评估。
通过单次给予链脲佐菌素（STZ）诱导大鼠实验性糖尿病。研究了依帕司他纳米粒（0.25、0.50、1 和 5mg/kg）在糖尿病大鼠中的治疗效果。用不同剂量的 E-SLN 治疗 STZ 诱导的糖尿病大鼠 8 周。将纳米粒单次口服给予大鼠，并评估与裸药相比与周围神经病变相关的各种参数。通过从眶后丛采集的血液样本来估计血糖水平，通过血液样本分析 HbA1c、甘油三酯、总胆固醇和肝功能测试（ALT 和 AST）。在坐骨神经匀浆中测量氧化应激标志物和 Na + K + ATPase、TNF-α 和 IL-1β 水平。还通过热板法和尾巴闪烁法进行行为测试。
通过微乳液法合成的 E-SLN 粒径为 281±60nm，包封效率为 88±2%。对优化的 E-SLN 进行了表征，发现其粒径、球形、包封效率均为最佳，在酸性胃 pH 值下稳定，适合口服给药。E-SLNs 并未显著逆转 STZ 诱导的血糖升高（FBS 和 PPBS）、HbA1c、甘油三酯和总胆固醇，但与糖尿病组相比，E-SLN 显著提高了 TNF-α、IL-1β 和增加的 Na + K + ATPase 水平、氧化应激标志物和 ALT、AST。E-SLN 剂量（0.5、1.0、2.5 和 5mg/kg）与糖尿病组相比，以剂量依赖性方式显著增加了尾巴闪烁潜伏期和热板反应时间。
因此，与依帕司他的标准治疗相比，E-SLN 同样有效且肝毒性较小。据我们所知，我们首次提出了可口服的 E-SLN，与常规依帕司他相比，可有效改善 STZ 诱导的糖尿病神经病理性疼痛。
