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fasudil and aggregation

Katherine J Sellers, Christina Elliott, Joshua Jackson, Anshua Ghosh, Elena Ribe, Ana I Rojo, Heledd H Jarosz-Griffiths, Iain A Watson, Weiming Xia, Mikhail Semenov, Peter Morin, Nigel M Hooper, Rod Porter, Jane Preston, Raya Al-Shawi, George Baillie, Simon Lovestone, Antonio Cuadrado, Michael Harte, Paul Simons, Deepak P Srivastava, Richard Killick
INTRODUCTION: Synapse loss is the structural correlate of the cognitive decline indicative of dementia. In the brains of Alzheimer's disease sufferers, amyloid β (Aβ) peptides aggregate to form senile plaques but as soluble peptides are toxic to synapses. We previously demonstrated that Aβ induces Dickkopf-1 (Dkk1), which in turn activates the Wnt-planar cell polarity (Wnt-PCP) pathway to drive tau pathology and neuronal death. METHODS: We compared the effects of Aβ and of Dkk1 on synapse morphology and memory impairment while inhibiting or silencing key elements of the Wnt-PCP pathway...
March 2018: Alzheimer's & Dementia: the Journal of the Alzheimer's Association
Anju Mary Philip, Youdong Wang, Antonio Mauro, Suzan El-Rass, John C Marshall, Warren L Lee, Arthur S Slutsky, Claudia C dosSantos, Xiao-Yan Wen
Sepsis is a leading cause of death worldwide. Current treatment modalities remain largely supportive. Intervention strategies focused on inhibiting specific mediators of the inflammatory host response have been largely unsuccessful, a consequence of an inadequate understanding of the complexity and heterogeneity of the innate immune response. Moreover, the conventional drug development pipeline is time consuming and expensive and the low success rates associated with cell-based screens underline the need for whole organism screening strategies, especially for complex pathological processes...
July 2017: Molecular Medicine
Yan-Hua Li, Jing-Wen Yu, Jian-Yin Xi, Wen-Bo Yu, Jian-Chun Liu, Qing Wang, Li-Juan Song, Ling Feng, Ya-Ping Yan, Guang-Xian Zhang, Bao-Guo Xiao, Cun-Gen Ma
Bone marrow-derived neural stem cells (NSCs) are ideal cells for cellular therapy because of their therapeutic potential for repairing and regenerating damaged neurons. However, the optimization of implanted cells and the improvement of microenvironment in the central nervous system (CNS) are still two critical elements for enhancing therapeutic effect. In the current study, we observed the combined therapeutic effect of NSCs with fasudil in an 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease (PD) mouse model and explored the possible cellular and molecular mechanisms...
September 2017: Molecular Neurobiology
Lars Tatenhorst, Katrin Eckermann, Vivian Dambeck, Luis Fonseca-Ornelas, Hagen Walle, Tomás Lopes da Fonseca, Jan C Koch, Stefan Becker, Lars Tönges, Mathias Bähr, Tiago F Outeiro, Markus Zweckstetter, Paul Lingor
Parkinson's disease (PD) is the most common neurodegenerative movement disorder, yet disease-modifying treatments do not currently exist. Rho-associated protein kinase (ROCK) was recently described as a novel neuroprotective target in PD. Since alpha-synuclein (α-Syn) aggregation is a major hallmark in the pathogenesis of PD, we aimed to evaluate the anti-aggregative potential of pharmacological ROCK inhibition using the isoquinoline derivative Fasudil, a small molecule inhibitor already approved for clinical use in humans...
April 22, 2016: Acta Neuropathologica Communications
Feng-Tao Liu, Yu-Jie Yang, Jian-Jun Wu, Shan Li, Yi-Lin Tang, Jue Zhao, Zhen-Yang Liu, Bao-Guo Xiao, Ji Zuo, Wen Liu, Jian Wang
Accumulation of α-synuclein (α-syn) is pivotally implicated in the pathogenesis of Parkinson׳s disease (PD), and enhancing its clearance might be a promising strategy in PD treatment. It has recently been shown that Rho kinase (ROCK) activation is involved in many neurodegenerative diseases, and some ROCK inhibitors might promote the degradation of abnormal protein aggregates. However, it is not known if fasudil, the only ROCK inhibitor available in clinical setting, could promote the degradation of α-syn, and ameliorate the α-syn induced neurotoxicity...
February 1, 2016: Brain Research
Shunsuke Nomura, Yukiya Iwata, Motoki Baba, Akitsugu Kawashima, Hidetaka Sato, Yoshikazu Okada
Delayed traumatic intracerebral hematoma (DTICH) is a rare complication of head injury that appears suddenly after an interval of several days or months. Here, we report a case of DTICH during antiplatelet therapy for vasospasm following surgeries for a ruptured left internal carotid-posterior communicating (ICPC) aneurysm and right acute epidural hematoma (EDH). A 77-year-old man with no medical history was diagnosed with a subarachnoid hemorrhage (SAH) due to rupturing of a left ICPC aneurysm and a right linear fracture of the right parietal bone due to a head injury following the rupture...
July 2015: No Shinkei Geka. Neurological Surgery
Yuko Iida, Tomoaki Doi, Haruhiko Tokuda, Rie Matsushima-Nishiwaki, Masanori Tsujimoto, Gen Kuroyanagi, Naohiro Yamamoto, Yukiko Enomoto, Kumiko Tanabe, Takanobu Otsuka, Toru Iwama, Shinji Ogura, Osamu Kozawa, Hiroki Iida
We have previously demonstrated that ristocetin, an activator of GPIb/IX/V, induces the release of soluble CD40 ligand (sCD40L) via thromboxane A2 production in human platelets. It has been shown that thromboxane A2 induces the activation of Rho-kinase, a downstream effector of Rho, in human platelets. In the present study, we investigated the exact roles of Rho-kinase in thromboxane A2-induced platelet activation. We found that U46619, a thromboxane receptor (TP) agonist, induced the phosphorylation of cofilin, a target of Rho-kinase signaling, and that the cofilin phosphorylation by U46619 was suppressed by Y27632 or fasudil, specific inhibitors of Rho-kinase...
March 2015: Prostaglandins, Leukotrienes, and Essential Fatty Acids
Dividutta Das, Andrew Holmes, Geraldine A Murphy, Kumaril Mishra, Anke C Rosenkranz, John D Horowitz, Jennifer A Kennedy
BACKGROUND AND AIM OF THE STUDY: Aortic valve stenosis is a major cause of valve replacement, particularly in the elderly. TGF-beta1 is upregulated in stenotic valves and induces calcification and collagen synthesis in cultured valve interstitial cells. It has been shown previously that TGF-beta1 increases reactive oxygen species (ROS) in these cells in association with calcifying nodule formation, but the cellular signaling pathways responsible for these TGF-beta1-induced effects are not well defined...
September 2013: Journal of Heart Valve Disease
Akihiro Koumura, Junya Hamanaka, Koh Kawasaki, Kazuhiro Tsuruma, Masamitsu Shimazawa, Isao Hozumi, Takashi Inuzuka, Hideaki Hara
Rho kinase (ROCK), one of the serine/threonine kinases, is involved in pathologic conditions, and its activation causes neuronal cell death. Fasudil, a selective ROCK inhibitor, has been reported to cause increased cerebral blood flow (CBF) in the ischemic brain and protect against neuronal cell death by inhibiting ROCK. Ozagrel, a thromboxane A(2) synthase inhibitor, inhibits platelet aggregation and causes vasodilatation, thereby increasing CBF in cerebral thrombosis. The present study evaluates the combination therapy of fasudil and ozagrel on focal brain ischemia induced by middle cerebral artery occlusion (MCAO) in mice...
July 2011: Journal of Pharmacology and Experimental Therapeutics
Kohtaro Abe, Keiko Morikawa, Takatoshi Hizume, Toyokazu Uwatoku, Keiji Oi, Minoru Seto, Ichiro Ikegaki, Toshio Asano, Kozo Kaibuchi, Hiroaki Shimokawa
Primary pulmonary hypertension continues to be a fatal disease. We have recently demonstrated that long-term inhibition of Rho-kinase, an effector of the small GTPase Rho, is effective for the treatment of pulmonary hypertension (PH) in rats and humans. Prostacyclin has been clinically used for the treatment of PH with moderate success. However, it remains to be examined whether Rho-kinase inhibition is involved in its beneficial effects on PH. In an ELISA assay, neither prostacyclin nor its oral analogue, beraprost sodium, inhibited Rho-kinase even at higher concentrations (10(-7) to 10(-5) M, 100 to 10,000 times higher than their clinical concentrations), whereas specific Rho-kinase inhibitors, fasudil and hydroxyfasudil, markedly (approximately 95%) inhibited the Rho-kinase activity at 10(-5) M (near their clinical concentrations)...
February 2005: Journal of Cardiovascular Pharmacology
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