Department of Pharmacology, University of Nevada, Reno School of Medicine, Reno, NV, USA.
Instituto de Ciencias Biomédicas, Universidad Autónoma de Ciudad Juárez, Ciudad Juarez, Mexico.
J Parkinsons Dis. 2022;12(3):831-850. doi: 10.3233/JPD-213016.
Parkinson's disease (PD) is a relentless, chronic neurodegenerative disease characterized by the progressive loss of substantia nigra (SN) neurons that leads to the onset of motor and non-motor symptoms. Standard of care for PD consists of replenishing the loss of dopamine through oral administration of Levodopa; however, this treatment is not disease-modifying and often induces intolerable side effects. While the etiology that contributes to PD is largely unknown, emerging evidence in animal models suggests that a significant reduction in neuroprotective Protein Kinase A (PKA) signaling in the SN contributes to PD pathogenesis, suggesting that restoring PKA signaling in the midbrain may be a new anti-PD therapeutic alternative.
We surmised that pharmacological activation of PKA via intraperitoneal administration of Forskolin exerts anti-PD effects in symptomatic PTEN-induced kinase 1 knockout (PINK1-KO), a bona fide in vivo model of PD.
By using a beam balance and a grip strength analyzer, we show that Forskolin reverses motor symptoms and loss of hindlimb strength with long-lasting therapeutic effects (> 5 weeks) following the last dose.
In comparison, intraperitoneal treatment with Levodopa temporarily (24 h) reduces motor symptoms but unable to restore hindlimb strength in PINK1-KO rats. By using immunohistochemistry and an XF24e BioAnalyzer, Forskolin treatment reverses SN neurons loss, elevates brain energy production and restores PKA activity in SN in symptomatic PINK1-KO rats.
Overall, our collective in vivo data suggest that Forskolin is a promising disease-modifying therapeutic alternative for PD and is superior to Levodopa because it confers long-lasting therapeutic effects.
帕金森病（PD）是一种进行性、慢性神经退行性疾病，其特征是黑质（SN）神经元逐渐丧失，导致运动和非运动症状的出现。PD 的标准治疗方法是通过口服左旋多巴补充多巴胺的损失；然而，这种治疗方法并不能改变疾病的进程，而且经常会引起难以忍受的副作用。虽然导致 PD 的病因在很大程度上尚不清楚，但动物模型中的新证据表明，SN 中显著减少的蛋白激酶 A（PKA）信号转导有助于 PD 的发病机制，这表明恢复中脑的 PKA 信号可能是一种新的抗 PD 治疗选择。
我们推测，通过腹腔内给予 Forskolin 来激活 PKA，可以在症状性 PTEN 诱导的激酶 1 敲除（PINK1-KO）动物模型中发挥抗 PD 作用，PINK1-KO 是 PD 的一个真正的体内模型。
通过使用平衡梁和握力分析器，我们表明 Forskolin 可以逆转运动症状和后肢力量的丧失，并具有持久的治疗效果（>5 周），直到最后一次给药后。
相比之下，腹腔内给予左旋多巴可暂时（24 小时）减轻运动症状，但不能恢复 PINK1-KO 大鼠的后肢力量。通过免疫组织化学和 XF24e BioAnalyzer，Forskolin 治疗可逆转 SN 神经元的丧失，提高大脑能量产生，并恢复 SN 中 PKA 活性在症状性 PINK1-KO 大鼠。
总的来说，我们的体内数据表明，Forskolin 是一种有前途的 PD 疾病修饰治疗选择，优于左旋多巴，因为它具有持久的治疗效果。
