With this: (plays a pivotal role in regulating
the damage, survival, axon guidance, and regeneration of neurons) our stroke researchers should immediately figure out how to use this to get survivors recovered. But since we have NO STROKE STRATEGY to update and NO STROKE LEADERSHIP to contact, nothing will happen, and trillions of neurons will continue dying each day.
Advantages of Rho-associated kinases and their inhibitor fasudil for the treatment of neurodegenerative diseases
- Open
Abstract
Ras homolog (Rho)-associated kinases (ROCKs) belong to the serine-threonine kinase family, which plays a pivotal role in regulating the damage, survival, axon guidance, and regeneration of neurons. ROCKs are also involved in the biological effects of immune cells and glial cells, as well as the development of neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis. Previous studies by us and others confirmed that ROCKs inhibitors attenuated the symptoms and progression of experimental models of the above mentioned neurodegenerative diseases by inhibiting neuroinflammation, regulating immune imbalance, repairing the blood-brain barrier, and promoting nerve repair and myelin regeneration. Fasudil, the first ROCKs inhibitor to be used clinically, has a good therapeutic effect on neurodegenerative diseases. Fasudil increases the activity of neural stem cells and mesenchymal stem cells, thus optimizing cell therapy. This review will systematically describe, for the first time, the effects of abnormal activation of ROCKs on T cells, B cells, microglia, astrocytes, oligodendrocytes, and pericytes in neurodegenerative diseases of the central nervous system, summarize the therapeutic potential of fasudil in several experimental models of neurodegenerative diseases, and clarify the possible cellular and molecular mechanisms of ROCKs inhibition. This review also proposes that fasudil is a novel potential treatment, especially in combination with cell-based therapy. Findings from this review add support for further investigation of ROCKs and its inhibitor fasudil for the treatment of neurodegenerative diseases.
Introduction
The Ras homolog (Rho) protein family is a member of the Ras protein superfamily, which is present in many tissue types and includes more than 20 intracellular signaling proteins, such as Ras homolog family member A (RhoA), Rac, and cell division control protein 42. The Rho family consists of small guanosine triphosphate (GTP)-binding proteins that are widely expressed in eukaryotes and have GTPase activity. Therefore, they are also known as Rho GTPases. The Rho GTPases play an important role in the construction of the cytoskeleton, as they can anchor to the cell membrane after lipid modification. Rho proteins act as a molecular switch as they can change between the active state of GTP binding and the inactive state of guanosine diphosphate (GDP) binding under the regulation of Rho guanine nucleotide exchange factors, Rho GTPase-activating proteins, and Rho guanine nucleotide dissociation inhibitors. The regulation of Rho proteins is complex. For instance, guanine nucleotide exchange factors promote the conversion of GDP to GTP and thus promote the activation of Rho GTPase, whereas guanine nucleotide dissociation inhibitors inhibit the catalytic effect of guanine nucleotide exchange factors, which prevents the dissociation of GDP from Rho GTPase and keeps Rho GTPase in an inactive state. GTPase-activating proteins, however, can activate endogenous GTP hydrolase, which induces the hydrolysis of GTP and causes Rho GTPase to lose its activity (Kobayashi et al., 2016; Shimokawa et al., 2016; Narumiya and Thumkeo, 2018).
Rho-associated kinases (ROCKs), important downstream effectors of Rho GTPase, play important roles in many cellular functions, including contraction, motility, proliferation, and apoptosis. Therefore, ROCKs regulate the damage, survival, axon guidance, and regeneration of neurons and are involved in the activation, migration, and proliferation of immune cells and glial cells. ROCKs exist as two isoforms, ROCK1 and ROCK2, which were initially reported to be ubiquitously expressed during embryogenesis and in adult tissues. Specifically, analysis of the distribution of ROCK1 and ROCK2 expressed sequence tags using the Tissue-Specific Gene Expression and Regulation database (Liu et al., 2008) revealed that their distribution patterns are similar and there are few specific organs and tissues with dramatically higher expression levels (Lu et al., 2020b). Both ROCK1 and ROCK2 activities are enhanced by binding to active GTP-bound RhoA. Many ROCK1 and ROCK2 substrates have been identified, including myosin light chain (MLC), myosin phosphatase target subunit 1, the ezrin/radixin/moesin family, adducin, phosphatase and tensin homolog (PTEN), endothelial nitric oxide synthase, tau, and LIM kinase. MLC is crucial for contraction of vascular smooth muscle cells and is phosphorylated by Ca2+/calmodulin-activated dependent MLC kinase and is dephosphorylated by MLC phosphatase (Figure 1) (Kobayashi et al., 2016; Shimokawa et al., 2016; Narumiya and Thumkeo, 2018). We have reviewed the recent advances in the investigation of ROCKs for the treatment of central nervous system (CNS) diseases and the development of fasudil, a ROCKs inhibitor.
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