Department of Pharmacology, Navsahyadri Institute of Pharmacy, Naigaon (Nasrapur), Tal. Bhor, Dist. Pune, India.
Navsahyadri Group of Institutes, Naigaon (Nasrapur), Tal. Bhor, Dist. Pune, India.
Fundam Clin Pharmacol. 2023 Apr;37(2):263-274. doi: 10.1111/fcp.12840. Epub 2022 Oct 12.
There is substantial evidence for the modulatory role of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterases (PDEs) in memory and synaptic plasticity, and an increase in intracellular cGMP facilitates these processes. The present study was aimed at the neuropharmacological investigations of tadalafil (TAD 5, 10, and 20 mg/kg, p.o.) and further involvement of nitric oxide (NO)-cGMP in its effects. The effects of tadalafil and its combination with N -nitro-L-arginine methyl ester (L-NAME) were investigated in scopolamine- and diabetes-induced cognitive dysfunction using elevated plus maze (EPM) and object recognition (ORT) tests. The results of EPM revealed that the scopolamine- and diabetes-induced learning and memory deficit was dose dependently attenuated after administration of TAD (TAD 10 and 20 mg/kg, p.o.) in both paradigms studied. Administration of L-NAME (20 mg/kg) aggravated scopolamine- and diabetes-induced learning and memory deficit. Co-administration of L-NAME (20 mg/kg) after TAD (20 mg/kg) produced significant increase in cognitive performance as compared to scopolamine- and diabetic- control group. This showed that L-NAME (20 mg/kg) aggravated scopolamine- and diabetes-induced learning and memory deficit was significantly reversed by TAD (20 mg/kg). The results of the present study revealed that tadalafil by inhibiting PDE5 possibly elevated the cGMP level that through a diversity of its substrates produced neuropharmacological effects in cognitive dysfunction.
有大量证据表明环鸟苷酸（cGMP）特异性磷酸二酯酶（PDEs）在记忆和突触可塑性中起调节作用，细胞内 cGMP 的增加有助于这些过程。本研究旨在对他达拉非（TAD 5、10 和 20mg/kg，po）的神经药理学进行研究，并进一步探讨一氧化氮（NO）-cGMP 在其作用中的参与。使用高架十字迷宫（EPM）和物体识别（ORT）测试，研究了他达拉非及其与 N-硝基-L-精氨酸甲酯（L-NAME）联合应用对东莨菪碱和糖尿病引起的认知功能障碍的影响。EPM 的结果表明，在两种研究模型中，他达拉非（TAD 10 和 20mg/kg，po）可剂量依赖性地减轻东莨菪碱和糖尿病引起的学习和记忆缺陷。给予 L-NAME（20mg/kg）加重了东莨菪碱和糖尿病引起的学习和记忆缺陷。与东莨菪碱和糖尿病对照组相比，L-NAME（20mg/kg）后给予 TAD（20mg/kg）可显著提高认知表现。这表明，L-NAME（20mg/kg）加重了东莨菪碱和糖尿病引起的学习和记忆缺陷，而 TAD（20mg/kg）可显著逆转。本研究结果表明，他达拉非通过抑制 PDE5 可能会升高 cGMP 水平，通过其多种底物产生认知功能障碍的神经药理学作用。
