Department of Clinical Psychology, Psychobiology and Methodology, Area of Psycobiology, University of La Laguna, Tenerife, Spain.
Fundación Investigación Hospital Clínico, Instituto de Investigación Sanitaria (INCLIVA), Valencia, Spain; Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Valencia, Spain.
Vitam Horm. 2022;118:247-288. doi: 10.1016/bs.vh.2021.11.006. Epub 2022 Jan 5.
Cyclic Guanosine-Monophosphate (cGMP) is implicated as second messenger in a plethora of pathways and its effects are executed mainly by cGMP-dependent protein kinases (PKG). It is involved in both peripheral (cardiovascular regulation, intestinal secretion, phototransduction, etc.) and brain (hippocampal synaptic plasticity, neuroinflammation, cognitive function, etc.) processes. Stimulation of hippocampal cGMP signaling have been proved to be beneficial in animal models of aging, Alzheimer's disease or hepatic encephalopathy, restoring different cognitive functions such as passive avoidance, object recognition or spatial memory. However, even when some inhibitors of cGMP-degrading enzymes (PDEs) are already used against peripheral pathologies, their utility as neurological treatments is still under clinical investigation. Additionally, it has been demonstrated a list of cGMP roles as not second but first messenger. The role of extracellular cGMP has been specially studied in hippocampal function and cognitive impairment in animal models and it has emerged as an important modulator of neuroinflammation-mediated cognitive alterations and hippocampal synaptic plasticity malfunction. Specifically, it has been demonstrated that extracellular cGMP decreases hippocampal IL-1β levels restoring membrane expression of glutamate receptors in the hippocampus and cognitive function in hyperammonemic rats. The mechanisms implicated are still unclear and might involve complex interactions between hippocampal neurons, astrocytes and microglia. Membrane targets for extracellular cGMP are still poorly understood and must be addressed in future studies.
环磷酸鸟苷（cGMP）作为第二信使参与了众多途径，其作用主要通过 cGMP 依赖性蛋白激酶（PKG）执行。它参与外周（心血管调节、肠道分泌、光转导等）和大脑（海马突触可塑性、神经炎症、认知功能等）过程。刺激海马 cGMP 信号转导已被证明在衰老、阿尔茨海默病或肝性脑病的动物模型中是有益的，可恢复不同的认知功能，如被动回避、物体识别或空间记忆。然而，即使已经有一些 cGMP 降解酶（PDEs）抑制剂用于治疗外周疾病，它们作为神经治疗的用途仍在临床研究中。此外，已经证明 cGMP 作为第二信使的作用，还存在一些非传统角色。细胞外 cGMP 在海马功能和认知障碍的动物模型中的作用已经得到了特别研究，它已成为神经炎症介导的认知改变和海马突触可塑性功能障碍的重要调节因子。具体来说，已经证明细胞外 cGMP 降低海马 IL-1β 水平，恢复海马中谷氨酸受体的膜表达和高氨血症大鼠的认知功能。所涉及的机制尚不清楚，可能涉及海马神经元、星形胶质细胞和小胶质细胞之间的复杂相互作用。细胞外 cGMP 的膜靶标仍知之甚少，必须在未来的研究中解决。
