The Therapeutic Potential of Rho Kinase Inhibitor Fasudil Derivative FaD-1 in Experimental Autoimmune Encephalomyelitis

Abstract

Although therapeutic potential of fasudil in EAE is promising, action mechanism and clinical limitations are still not fully understood and resolved. In this study, we observed the therapeutic potential of a novel Rho kinase (ROCK) inhibitor FaD-1, a fasudil derivative, and explored possible mechanism in MOG 35-55 -induced EAE. Experimental autoimmune encephalomyelitis (EAE) was induced by myelin oligodendrocyte glycoprotein (MOG 35-55 ) immunization. The pathology of spinal cord was measured by immunohistochemistry and neurological impairment was evaluated using clinical scores. FaD-1, as a novel ROCK inhibitor, inhibited the expression of ROCK II that is mainly expressed in the CNS. We show here that FaD-1 ameliorates the neurological defects and the severity of MOG-induced EAE in mice, accompanied by the protection of demyelination and the inhibition of neuroinflammation in spinal cord of EAE. In addition, FaD-1 dampened TLR2 and TLR4 signaling as well as Th1 (IFN-γ) and Th17 (IL-17) responses in spinal cord of EAE. FaD-1 also prevented the expression of iNOS and production of inflammatory cytokine IL-1β, IL-6, and TNF-α which are specific markers for M1 inflammatory microglia/macrophages. This study highlights the therapeutic potential of FaD-1 as a ROCK inhibitor for the treatment of human autoimmune diseases with both inflammatory and autoimmune components.

Matrine Treatment Blocks NogoA-Induced Neural Inhibitory Signaling Pathway in Ongoing Experimental Autoimmune Encephalomyelitis

“…***p < 0.001, comparison between naïve groups and vehicletreated EAE group. ##p < 0.01, comparison between vehicle-and MAT-treated EAE groups inhibitor fasudil ameliorated clinical severity of EAE at various EAE models and at different stages [13][14][15]. Consistent with the previous observations, we detected reduced RhoA expression and the ratio of ROCK/p-ROCK in brain lesions of MAT-treated rats, which is in line with the increase in Gap43.…”

“…These inhibitors bind their receptor complex, including NgR1, the p75 neurotrophin receptor (p75NTR), and LINGO-1 [8], and downstream signaling leads to failure of remyelination and arrest of neurite/axon growth [9]. An important downstream pathway of these myelin-associated inhibitors (MAIs) is Rho molecules, especially RhoA, and their kinases (Rho kinases (ROCKs)), whose activities are considerably increased in several neurological disorders such as stroke, MS, Alzheimer's disease (AD), and Parkinson's disease (PD) [10,11], while the blockade of Rho/ROCK is thought to inhibit inflammation, to reduce infarct size [12], and to suppress EAE [13][14][15]. On the other hand, adenosine 3′,5′-cyclic monophosphate (cAMP) plays an important role in neuronal survival and modulation of growth cone and enhancement of neurite outgrowth [16].…”

Therapeutic Potential of Targeting the Th17/Treg Axis in Autoimmune Disorders

“…As reported by Biswas et al [ 187 ] ROCK inhibition diminished production of IL-17 and IL-21 and ameliorated disease signs in Def6 trap/trap DO11.10 mice, a murine model of RA-like arthritis. Fasudil derivative FaD-1, a ROCK inhibitor, was reported to ameliorate neurological defects and disease severity in EAE mice, in part via downregulation of the Th17-response in the spinal cord [ 192 ]. WAR-5, another ROCK inhibitor described to selectively inhibit ROCK2 led to the attenuation of myelin damage, reduction of CNS inflammation and alleviation of clinical symptoms in EAE mice [ 193 ].…”

TLR4-RelA-miR-30a signal pathway regulates Th17 differentiation during experimental autoimmune encephalomyelitis development

“…Currently, several available immune inhibitor therapies for MS have achieved satisfactory effects [59, 60], but it is still difficult to fundamentally protect patients from relapsing MS. Thus, searching for more effective and more feasible therapies is the top priority for MS treatment.…”