Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy.
Department of Neurology, The Evelyn McKnight Brain Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
Int J Mol Sci. 2019 Jul 19;20(14):3544. doi: 10.3390/ijms20143544.
Neurodegenerative diseases are among the leading causes of mortality and disability worldwide. However, current therapeutic approaches have failed to reach significant results in their prevention and cure. Protein Kinase Cs (PKCs) are kinases involved in the pathophysiology of neurodegenerative diseases, such as Alzheimer's Disease (AD) and cerebral ischemia. Specifically ε, δ, and γPKC are associated with the endogenous mechanism of protection referred to as ischemic preconditioning (IPC). Existing modulators of PKCs, in particular of εPKC, such as ψεReceptor for Activated C-Kinase (ψεRACK) and Resveratrol, have been proposed as a potential therapeutic strategy for cerebrovascular and cognitive diseases. PKCs change in expression during aging, which likely suggests their association with IPC-induced reduction against ischemia and increase of neuronal loss occurring in senescent brain. This review describes the link between PKCs and cerebrovascular and cognitive disorders, and proposes PKCs modulators as innovative candidates for their treatment. We report original data showing εPKC reduction in levels and activity in the hippocampus of old compared to young rats and a reduction in the levels of δPKC and γPKC in old hippocampus, without a change in their activity. These data, integrated with other findings discussed in this review, demonstrate that PKCs modulators may have potential to restore age-related reduction of endogenous mechanisms of protection against neurodegeneration.
神经退行性疾病是全球范围内导致死亡和残疾的主要原因之一。然而，目前的治疗方法在预防和治疗方面都没有取得显著的效果。蛋白激酶 C（PKCs）是参与神经退行性疾病病理生理学的激酶，如阿尔茨海默病（AD）和脑缺血。特别是 ε、δ 和 γPKC 与被称为缺血预处理（IPC）的内源性保护机制有关。PKCs 的现有调节剂，特别是 εPKC 的调节剂，如 ψεRACK 和白藜芦醇，已被提议作为治疗脑血管和认知疾病的潜在治疗策略。PKCs 在衰老过程中的表达发生变化，这可能表明它们与 IPC 诱导的对缺血的减少以及衰老大脑中神经元丢失的增加有关。本综述描述了 PKCs 与脑血管和认知障碍之间的联系，并提出了 PKC 调节剂作为其治疗的创新候选物。我们报告了原始数据，显示与年轻大鼠相比，老年大鼠海马体中的 εPKC 水平和活性降低，δPKC 和 γPKC 水平降低，但活性没有变化。这些数据与本综述中讨论的其他发现相结合，表明 PKC 调节剂可能有潜力恢复与年龄相关的内源性神经退行性保护机制的减少。
