ROCK and PDE-5 Inhibitors for the Treatment of Dementia: Literature Review and Meta-Analysis

Abstract

Dementia is a disease in which memory, thought, and behavior-related disorders progress gradually due to brain damage caused by injury or disease. It is mainly caused by Alzheimer's disease or vascular dementia and several other risk factors, including genetic factors. It is difficult to treat as its incidence continues to increase worldwide. Many studies have been performed concerning the treatment of this condition. Rho-associated kinase (ROCK) and phosphodiesterase-5 (PDE-5) are attracting attention as pharmacological treatments to improve the symptoms. This review discusses how ROCK and PDE-5 affect Alzheimer's disease, vascular restructuring, and exacerbation of neuroinflammation, and how their inhibition helps improve cognitive function. In addition, the results of the animal behavior analysis experiments utilizing the Morris water maze were compared through meta-analysis to analyze the effects of ROCK inhibitors and PDE-5 inhibitors on cognitive function. According to the selection criteria, 997 publications on ROCK and 1772 publications on PDE-5 were screened, and conclusions were drawn through meta-analysis. Both inhibitors showed good improvement in cognitive function tests, and what is expected of the synergy effect of the two drugs was confirmed in this review.

Keywords: Alzheimer’s disease; ERM; LIMK; MLC; Morris water maze; PDE-5 inhibitor; ROCK inhibitor; cGMP; meta-analysis; vascular dementia.

Figure 1

The RhoA/ROCK pathway and PDE-5 pathway contribute to smooth muscle contraction. ROCK prevents dephosphorylation of phosphorylated MLC and contributes to smooth muscle contraction by activating the LIMK2/cofilin pathway and the ERM pathway. PDE-5 decomposes increased cGMP from eNOS/NO, contributing to the contraction of VSMC. cGMP: cyclic Guanosine monophosphate; eNOS: endothelial nitric oxide synthase; ERM: ezrin/radixin/moesin; GTP: guanosine triphosphate; LIMK: Lin11-Isl1-Mec3 kinase; MLC: myosin light chain; NO: nitric oxide; PDE-5: phosphodiesterase-5; ROCK: rho-associated protein kinase.

Figure 2

Improvement of the inflammatory response and recruitment of inflammatory cells due to various factors in the ROCK and PDE family. CyPA: cyclophilin A; ICAM-1: intercellular adhesion molecule 1; MCP-1: monocyte chemoattractant protein 1; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; NO: nitric oxide; PDE-5: phosphodiesterase-5; PKA: protein kinase A; ROCK: rho-associated protein kinase; ROS: reactive oxygen species; VCAM-1: vascular cell adhesion molecule 1.

Figure 3

The ROCK inhibitor study was conducted independently by two reviewers according to the screening criteria. The studies were selected in the following order: (1) Duplicate articles were excluded. (2) Those with unrelated titles were excluded. Subsequently, (3) those with unrelated abstracts were excluded, and the exclusion considerations for the abstracts were as follows: only traditional medicine, herb extracts, alkaloids, and flavonoids. No dementia model animal or patient. No cognition assessment. No ROCK inhibitors. No clinical trials. (4) The following text was checked to exclude articles that did not study the effect of ROCK inhibitors on behavioral experiments. (5) Studies included in the quantitative synthesis. (6) Finally, only studies using the Morris water maze were left.

Figure 4

The phosphodiesterase-5 inhibitor study was performed independently along with the flow chart by two reviewers: (1) Duplicate articles were excluded. (2) Publications with unrelated titles and abstracts were excluded. (3) According to the eligibility, publications that had no therapeutic effect in the behavioral experiment were excluded. (4) Full-text articles that were not available for meta-analysis, that had no animal, cognition, or Morris water maze test, were excluded.

Figure 5

This forest plot shows an analysis of the difference between the experimental group and the control group of each subgroup by standardized mean difference (SMD). Because of the high heterogeneity, each group was analyzed by dividing it into subgroups. SD: standard deviation.

Figure 6

In the forest plot, the difference between the control group and the experimental group of each subgroup was analyzed by mean difference (MD). Each subgroup is located at the top and bottom with PDE-5 inhibitors and ROCK inhibitors. Because of the high heterogeneity, each group was analyzed by dividing it into subgroups.