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{{Short description|Chemical compound}}
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| ChemSpiderID = 3426
| ChemSpiderID = 3426
| ChEBI = 43871
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'''Fasudil''' ([[International Nonproprietary Name|INN]]) is a potent [[Rho-associated protein kinase|Rho-kinase]] inhibitor and [[vasodilator]].<ref>{{Cite news |title= Drug Found That Could Reduce Risk Of Alzheimer's | url = https://www.sciencedaily.com/releases/2009/02/090202102932.htm |work= [[Science Daily]]}}</ref> Since it was discovered, it has been used for the treatment of [[cerebral vasospasm]], which is often due to [[subarachnoid hemorrhage]],<ref name="pmid8217408">{{cite journal |vauthors= Shibuya M, Suzuki Y |title= [Treatment of cerebral vasospasm by a protein kinase inhibitor AT 877] |language= ja |journal= Nō to Shinkei - Brain and Nerve |volume= 45 |issue=9 |pages= 819–24 |date= Sep 1993 |pmid= 8217408 }}</ref> as well as to improve the cognitive decline seen in [[stroke]] patients. It has been found to be effective for the treatment of [[pulmonary hypertension]].<ref name="Doggrell2005">{{cite journal |vauthors= Doggrell SA |title= Rho-kinase inhibitors show promise in pulmonary hypertension |journal= Expert Opinion on Investigational Drugs |volume= 14 |issue=9 |pages= 1157–9 |date= Sep 2005 |pmid= 16144499 |doi= 10.1517/13543784.14.9.1157 }}</ref> It has been demonstrated that fasudil could improve [[memory]] in normal mice, identifying the drug as a possible [[Investigational New Drug |treatment]] for [[Age-related memory loss|age-related]] or [[Neurodegeneration|neurodegenerative]] memory loss.<ref name=Huentelman2009>{{cite journal |vauthors= Huentelman MJ, Stephan DA, Talboom J, Corneveaux JJ, Reiman DM, Gerber JD, Barnes CA, Alexander GE, Reiman EM, Bimonte-Nelson HA |title= Peripheral delivery of a ROCK inhibitor improves learning and working memory |journal= Behavioral Neuroscience |volume= 123 |issue= 1 |pages= 218–23 |date= Feb 2009 |pmid= 19170447 |pmc= 2701389 |doi= 10.1037/a0014260 | postscript = <!--None--> }}</ref><ref>Kumar M, Bansal N. Fasudil hydrochloride ameliorates memory deficits in rat model of streptozotocin-induced Alzheimer's disease: Involvement of PI3-kinase, eNOS and NFκB. ''Behav Brain Res''. 2018 Oct 1;351:4-16. {{doi|10.1016/j.bbr.2018.05.024}} {{pmid|29807069}}</ref><ref>Song X, He R, Han W, Li T, Xie L, Cheng L, Chen H, Xie M, Jiang L. Protective effects of the ROCK inhibitor fasudil against cognitive dysfunction following status epilepticus in male rats. ''J Neurosci Res''. 2019 Apr;97(4):506-519. {{doi|10.1002/jnr.24355}} {{pmid|30421453}}</ref>
'''Fasudil''' ([[International Nonproprietary Name|INN]]) is a potent [[Rho-associated protein kinase|Rho-kinase]] inhibitor and [[vasodilator]].<ref>{{Cite news |title= Drug Found That Could Reduce Risk Of Alzheimer's | url = https://www.sciencedaily.com/releases/2009/02/090202102932.htm |work= [[Science Daily]]}}</ref> Since it was discovered, it has been used for the treatment of [[cerebral vasospasm]], which is often due to [[subarachnoid hemorrhage]],<ref name="pmid8217408">{{cite journal |vauthors= Shibuya M, Suzuki Y |title= [Treatment of cerebral vasospasm by a protein kinase inhibitor AT 877] |language= ja |journal= Nō to Shinkei - Brain and Nerve |volume= 45 |issue=9 |pages= 819–24 |date= Sep 1993 |pmid= 8217408 }}</ref> as well as to improve the cognitive decline seen in [[stroke]] patients. It has been found to be effective for the treatment of [[pulmonary hypertension]].<ref name="Doggrell2005">{{cite journal |vauthors= Doggrell SA |title= Rho-kinase inhibitors show promise in pulmonary hypertension |journal= Expert Opinion on Investigational Drugs |volume= 14 |issue=9 |pages= 1157–9 |date= Sep 2005 |pmid= 16144499 |doi= 10.1517/13543784.14.9.1157 |s2cid= 35237787 }}</ref> It has been demonstrated that fasudil could improve [[memory]] in normal mice, identifying the drug as a possible [[Investigational New Drug|treatment]] for [[Age-related memory loss|age-related]] or [[Neurodegeneration|neurodegenerative]] memory loss.<ref name=Huentelman2009>{{cite journal |vauthors= Huentelman MJ, Stephan DA, Talboom J, Corneveaux JJ, Reiman DM, Gerber JD, Barnes CA, Alexander GE, Reiman EM, Bimonte-Nelson HA |title= Peripheral delivery of a ROCK inhibitor improves learning and working memory |journal= Behavioral Neuroscience |volume= 123 |issue= 1 |pages= 218–23 |date= Feb 2009 |pmid= 19170447 |pmc= 2701389 |doi= 10.1037/a0014260 }}</ref><ref>{{cite journal | vauthors = Kumar M, Bansal N | title = Fasudil hydrochloride ameliorates memory deficits in rat model of streptozotocin-induced Alzheimer's disease: Involvement of PI3-kinase, eNOS and NFκB | journal = Behavioural Brain Research | volume = 351 | pages = 4–16 | date = October 2018 | pmid = 29807069 | doi = 10.1016/j.bbr.2018.05.024 | s2cid = 44121036 }}</ref><ref>{{cite journal | vauthors = Song X, He R, Han W, Li T, Xie L, Cheng L, Chen H, Xie M, Jiang L | display-authors = 6 | title = Protective effects of the ROCK inhibitor fasudil against cognitive dysfunction following status epilepticus in male rats | journal = Journal of Neuroscience Research | volume = 97 | issue = 4 | pages = 506–519 | date = April 2019 | pmid = 30421453 | doi = 10.1002/jnr.24355 | s2cid = 53289377 }}</ref>


It has been approved for use in Japan and China since 1995,<ref>Zhao J, Zhou D, Guo J, Ren Z, Zhou L, Wang S, Xu B, Wang R. Effect of fasudil hydrochloride, a protein kinase inhibitor, on cerebral vasospasm and delayed cerebral ischemic symptoms after aneurysmal subarachnoid hemorrhage. ''Neurol Med Chir (Tokyo)''. 2006 Sep;46(9):421-8. {{doi|10.2176/nmc.46.421}} {{pmid|16998274}}</ref> but has not been approved by the [[United States Food and Drug Administration]] or by the [[European Medicines Agency]].
It has been approved for use in Japan and China since 1995,<ref>{{cite journal | vauthors = Zhao J, Zhou D, Guo J, Ren Z, Zhou L, Wang S, Xu B, Wang R | display-authors = 6 | title = Effect of fasudil hydrochloride, a protein kinase inhibitor, on cerebral vasospasm and delayed cerebral ischemic symptoms after aneurysmal subarachnoid hemorrhage | journal = Neurologia Medico-Chirurgica | volume = 46 | issue = 9 | pages = 421–8 | date = September 2006 | pmid = 16998274 | doi = 10.2176/nmc.46.421 | doi-access = free }}</ref> but has not been approved by the [[United States Food and Drug Administration]] or by the [[European Medicines Agency]]. Woolsey Pharmaceuticals is developing BRAVYL (oral fasudil) for various neurodegenerative diseases.<ref name="jacobson">{{cite web |url=https://www.businesswire.com/news/home/20210218005184/en/ |title=Woolsey Pharmaceuticals Emerges from Stealth Mode to Announce Patients Enrolled in Two New CNS Studies |last=Jacobson |first=Sven |date=February 18, 2021 |website=Businesswire}}</ref>


== Molecular mechanism ==
== Molecular mechanism ==
Fasudil (HA-1077) is a selective RhoA/[[Rho-associated protein kinase|Rho kinase]] (ROCK) inhibitor.<ref name="Nagumo_2000">{{cite journal |vauthors= Nagumo H, Sasaki Y, Ono Y, Okamoto H, Seto M, Takuwa Y |title= Rho kinase inhibitor HA-1077 prevents Rho-mediated myosin phosphatase inhibition in smooth muscle cells |journal= American Journal of Physiology. Cell Physiology |volume= 278 |issue=1 |pages= C57–65 |date= Jan 2000 |pmid= 10644512 |doi= 10.1152/ajpcell.2000.278.1.c57}}</ref> ROCK is an enzyme that plays an important role in mediating vasoconstriction and vascular remodeling in the pathogenesis of pulmonary hypertension. ROCK induces vasoconstriction by phosphorylating the myosin-binding subunit of myosin light chain (MLC) phosphatase, thus decreasing MLC phosphatase activity and enhancing vascular smooth muscle contraction.<ref name="Nagumo_2000"/>
Fasudil (HA-1077) is a selective RhoA/[[Rho-associated protein kinase|Rho kinase]] (ROCK) inhibitor.<ref name="Nagumo_2000">{{cite journal |vauthors= Nagumo H, Sasaki Y, Ono Y, Okamoto H, Seto M, Takuwa Y |title= Rho kinase inhibitor HA-1077 prevents Rho-mediated myosin phosphatase inhibition in smooth muscle cells |journal= American Journal of Physiology. Cell Physiology |volume= 278 |issue=1 |pages= C57–65 |date= Jan 2000 |pmid= 10644512 |doi= 10.1152/ajpcell.2000.278.1.c57|s2cid= 1158687 |doi-access= free }}</ref> ROCK is an enzyme that plays an important role in mediating vasoconstriction and vascular remodeling in the pathogenesis of pulmonary hypertension. ROCK induces vasoconstriction by phosphorylating the myosin-binding subunit of myosin light chain (MLC) phosphatase, thus decreasing MLC phosphatase activity and enhancing vascular smooth muscle contraction.<ref name="Nagumo_2000"/>


=== ACE expression ===
=== ACE expression ===
[[Angiotensin-converting enzyme]] (ACE) is an enzyme that catalyzes the conversion of [[Angiotensin#Angiotensin_I|angiotensin-I]] (Ang-I) to [[Angiotensin#Angiotensin_II|angiotensin-II]] (Ang-II). Ang-II is a peptide hormone which increases blood pressure by initiating [[vasoconstriction]] and [[aldosterone]] secretion. ROCK increases ACE expression and activity in pulmonary hypertension. By inhibiting ROCK with fasudil, circulating ACE and Ang-II are reduced, leading to a decrease in pulmonary vascular pressure.<ref>{{cite journal | vauthors = Ocaranza MP, Rivera P, Novoa U, Pinto M, González L, Chiong M, Lavandero S, Jalil JE | title = Rho kinase inhibition activates the homologous angiotensin-converting enzyme-angiotensin-(1-9) axis in experimental hypertension | journal = Journal of Hypertension | volume = 29 | issue = 4 | pages = 706–15 | date = Apr 2011 | pmid = 21330937 | doi = 10.1097/HJH.0b013e3283440665 }}</ref>
[[Angiotensin-converting enzyme]] (ACE) is an enzyme that catalyzes the conversion of [[Angiotensin#Angiotensin I|angiotensin-I]] (Ang-I) to [[Angiotensin#Angiotensin II|angiotensin-II]] (Ang-II). Ang-II is a peptide hormone which increases blood pressure by initiating [[vasoconstriction]] and [[aldosterone]] secretion. ROCK increases ACE expression and activity in pulmonary hypertension. By inhibiting ROCK with fasudil, circulating ACE and Ang-II are reduced, leading to a decrease in pulmonary vascular pressure.<ref>{{cite journal | vauthors = Ocaranza MP, Rivera P, Novoa U, Pinto M, González L, Chiong M, Lavandero S, Jalil JE | title = Rho kinase inhibition activates the homologous angiotensin-converting enzyme-angiotensin-(1-9) axis in experimental hypertension | journal = Journal of Hypertension | volume = 29 | issue = 4 | pages = 706–15 | date = Apr 2011 | pmid = 21330937 | doi = 10.1097/HJH.0b013e3283440665 | hdl = 10533/134321 | s2cid = 205630605 | hdl-access = free }}</ref>


=== eNOS expression ===
=== eNOS expression ===
Line 73: Line 76:
=== ERK activation ===
=== ERK activation ===
The proliferative effects of ROCK on vascular endothelial cells is due to the activation of [[extracellular signal-regulated kinase]] (ERK).<ref name="Liu_2011">{{cite journal | vauthors = Liu AJ, Ling F, Wang D, Wang Q, Lü XD, Liu YL | title = Fasudil inhibits platelet-derived growth factor-induced human pulmonary artery smooth muscle cell proliferation by up-regulation of p27kip¹ via the ERK signal pathway | journal = Chinese Medical Journal | volume = 124 | issue = 19 | pages = 3098–104 | date = Oct 2011 | pmid = 22040563 }}</ref> ERK mediates cell proliferation via the phosphorylation of p27Kip1, thus accelerating the degradation rate of [[CDKN1B|p27Kip1]].<ref>{{cite journal | vauthors = Delmas C, Manenti S, Boudjelal A, Peyssonnaux C, Eychène A, Darbon JM | title = The p42/p44 mitogen-activated protein kinase activation triggers p27Kip1 degradation independently of CDK2/cyclin E in NIH 3T3 cells | journal = The Journal of Biological Chemistry | volume = 276 | issue = 37 | pages = 34958–65 | date = Sep 2001 | pmid = 11418594 | doi = 10.1074/jbc.m101714200 | doi-access = free }}</ref> p27Kip1 is a cyclin-dependent kinase (CDK) inhibitor which down-regulates cell cycle by binding cyclin-CDK complex.<ref>{{cite journal | vauthors = Fouty BW, Rodman DM | title = Mevastatin can cause G1 arrest and induce apoptosis in pulmonary artery smooth muscle cells through a p27Kip1-independent pathway | journal = Circulation Research | volume = 92 | issue = 5 | pages = 501–9 | date = Mar 2003 | pmid = 12600884 | doi = 10.1161/01.RES.0000061180.03813.0F | doi-access = free }}</ref> Human pulmonary arterial smooth muscle cells treated with fasudil showed a decrease in cell proliferation in a dose-dependent manner. Fasudil also decreases ERK activities, as well as increases level of p27Kip1. This suggested that the anti-proliferative effects of fasudil is due to the decrease of ERK activities via the inhibition of ROCK.<ref name="Liu_2011"/>
The proliferative effects of ROCK on vascular endothelial cells is due to the activation of [[extracellular signal-regulated kinase]] (ERK).<ref name="Liu_2011">{{cite journal | vauthors = Liu AJ, Ling F, Wang D, Wang Q, Lü XD, Liu YL | title = Fasudil inhibits platelet-derived growth factor-induced human pulmonary artery smooth muscle cell proliferation by up-regulation of p27kip¹ via the ERK signal pathway | journal = Chinese Medical Journal | volume = 124 | issue = 19 | pages = 3098–104 | date = Oct 2011 | pmid = 22040563 }}</ref> ERK mediates cell proliferation via the phosphorylation of p27Kip1, thus accelerating the degradation rate of [[CDKN1B|p27Kip1]].<ref>{{cite journal | vauthors = Delmas C, Manenti S, Boudjelal A, Peyssonnaux C, Eychène A, Darbon JM | title = The p42/p44 mitogen-activated protein kinase activation triggers p27Kip1 degradation independently of CDK2/cyclin E in NIH 3T3 cells | journal = The Journal of Biological Chemistry | volume = 276 | issue = 37 | pages = 34958–65 | date = Sep 2001 | pmid = 11418594 | doi = 10.1074/jbc.m101714200 | doi-access = free }}</ref> p27Kip1 is a cyclin-dependent kinase (CDK) inhibitor which down-regulates cell cycle by binding cyclin-CDK complex.<ref>{{cite journal | vauthors = Fouty BW, Rodman DM | title = Mevastatin can cause G1 arrest and induce apoptosis in pulmonary artery smooth muscle cells through a p27Kip1-independent pathway | journal = Circulation Research | volume = 92 | issue = 5 | pages = 501–9 | date = Mar 2003 | pmid = 12600884 | doi = 10.1161/01.RES.0000061180.03813.0F | doi-access = free }}</ref> Human pulmonary arterial smooth muscle cells treated with fasudil showed a decrease in cell proliferation in a dose-dependent manner. Fasudil also decreases ERK activities, as well as increases level of p27Kip1. This suggested that the anti-proliferative effects of fasudil is due to the decrease of ERK activities via the inhibition of ROCK.<ref name="Liu_2011"/>

===Direct inhibition of α-synuclein aggregation===
In addition to ROCK inhibition, fasudil has also been demonstrated to directly modulate the aggregation of [[Alpha-synuclein|α-synuclein]], both ''in vitro'' and in cellular models of neurodegenerative disease.<ref name="Tatenhorst_2016">{{cite journal | vauthors = Tatenhorst L, Eckermann K, Dambeck V, Fonseca-Ornelas L, Walle H, Lopes da Fonseca T, Koch JC, Becker S, Tönges L, Bähr M, Outeiro TF, Zweckstetter M, Lingor P | title = Fasudil attenuates aggregation of α-synuclein in models of Parkinson's disease. | journal = Acta Neuropathol. Commun.| volume = 4 | issue = 39 | date = April 22, 2016 | page = 39 | pmid = 27101974 | doi = 10.1186/s40478-016-0310-y| pmc = 4840958 | doi-access = free }}</ref> Aggregation of α-synuclein is a major hallmark of [[Parkinson's disease]], and has also been observed in other neurodegenerative diseases. Physical interactions between α-synuclein and fasudil have been shown to take place with α-synuclein in the [[intrinsically disordered proteins|intrinsically disordered]] state, which places fasudil among a small number of drug-like molecules that directly interact with intrinsically disordered proteins.<ref name="Zhu_2021">{{cite journal | vauthors = Robustelli P, Ibanez-de-Opakua A, Campbell-Bezat C, Giordanetto F, Becker S, Zweckstetter M, Pan AC, Shaw DE | title = Molecular basis of small-molecule binding to α-synuclein | journal = bioRxiv| date = January 24, 2021 | doi = 10.1101/2021.01.22.426549| s2cid = 231777082 | url = https://pub.dzne.de/search?p=id:%22DZNE-2022-00161%22 }}</ref>


== See also ==
== See also ==

Latest revision as of 11:55, 15 January 2024

Fasudil
Clinical data
AHFS/Drugs.comInternational Drug Names
ATC code
Pharmacokinetic data
MetabolitesHydroxyfasudil
Elimination half-life0.76 hours. Active metabolite (hydroxyfasudil) 4.66 hours.
Identifiers
  • 5-(1,4-Diazepane-1-sulfonyl)isoquinoline
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard100.250.347 Edit this at Wikidata
Chemical and physical data
FormulaC14H17N3O2S
Molar mass291.37 g·mol−1
3D model (JSmol)
  • C1CNCCN(C1)S(=O)(=O)C2=CC=CC3=C2C=CN=C3
  • InChI=1S/C14H17N3O2S/c18-20(19,17-9-2-6-15-8-10-17)14-4-1-3-12-11-16-7-5-13(12)14/h1,3-5,7,11,15H,2,6,8-10H2 ☒N
  • Key:NGOGFTYYXHNFQH-UHFFFAOYSA-N ☒N
 ☒NcheckY (what is this?)  (verify)

Fasudil (INN) is a potent Rho-kinase inhibitor and vasodilator.[1] Since it was discovered, it has been used for the treatment of cerebral vasospasm, which is often due to subarachnoid hemorrhage,[2] as well as to improve the cognitive decline seen in stroke patients. It has been found to be effective for the treatment of pulmonary hypertension.[3] It has been demonstrated that fasudil could improve memory in normal mice, identifying the drug as a possible treatment for age-related or neurodegenerative memory loss.[4][5][6]

It has been approved for use in Japan and China since 1995,[7] but has not been approved by the United States Food and Drug Administration or by the European Medicines Agency. Woolsey Pharmaceuticals is developing BRAVYL (oral fasudil) for various neurodegenerative diseases.[8]

Molecular mechanism

[edit]

Fasudil (HA-1077) is a selective RhoA/Rho kinase (ROCK) inhibitor.[9] ROCK is an enzyme that plays an important role in mediating vasoconstriction and vascular remodeling in the pathogenesis of pulmonary hypertension. ROCK induces vasoconstriction by phosphorylating the myosin-binding subunit of myosin light chain (MLC) phosphatase, thus decreasing MLC phosphatase activity and enhancing vascular smooth muscle contraction.[9]

ACE expression

[edit]

Angiotensin-converting enzyme (ACE) is an enzyme that catalyzes the conversion of angiotensin-I (Ang-I) to angiotensin-II (Ang-II). Ang-II is a peptide hormone which increases blood pressure by initiating vasoconstriction and aldosterone secretion. ROCK increases ACE expression and activity in pulmonary hypertension. By inhibiting ROCK with fasudil, circulating ACE and Ang-II are reduced, leading to a decrease in pulmonary vascular pressure.[10]

eNOS expression

[edit]

Endothelial nitric oxide synthase (eNOS) mediates the production of the vasodilator nitric oxide (NO). Pulmonary arterial cell cultures treated with fasudil showed a significant increase in eNOS mRNA levels in a dose dependent manner, and the half-life of eNOS mRNA increased 2-folds. These findings suggested that ROCK inhibition with fasudil increases eNOS expression by stabilizing eNOS mRNA, which contributed to an increase of NO level to enhance vasodilation.[11]

ERK activation

[edit]

The proliferative effects of ROCK on vascular endothelial cells is due to the activation of extracellular signal-regulated kinase (ERK).[12] ERK mediates cell proliferation via the phosphorylation of p27Kip1, thus accelerating the degradation rate of p27Kip1.[13] p27Kip1 is a cyclin-dependent kinase (CDK) inhibitor which down-regulates cell cycle by binding cyclin-CDK complex.[14] Human pulmonary arterial smooth muscle cells treated with fasudil showed a decrease in cell proliferation in a dose-dependent manner. Fasudil also decreases ERK activities, as well as increases level of p27Kip1. This suggested that the anti-proliferative effects of fasudil is due to the decrease of ERK activities via the inhibition of ROCK.[12]

Direct inhibition of α-synuclein aggregation

[edit]

In addition to ROCK inhibition, fasudil has also been demonstrated to directly modulate the aggregation of α-synuclein, both in vitro and in cellular models of neurodegenerative disease.[15] Aggregation of α-synuclein is a major hallmark of Parkinson's disease, and has also been observed in other neurodegenerative diseases. Physical interactions between α-synuclein and fasudil have been shown to take place with α-synuclein in the intrinsically disordered state, which places fasudil among a small number of drug-like molecules that directly interact with intrinsically disordered proteins.[16]

See also

[edit]
  • Ripasudil, a fasudil derivative used to treat glaucoma and ocular hypertension

References

[edit]
  1. ^ "Drug Found That Could Reduce Risk Of Alzheimer's". Science Daily.
  2. ^ Shibuya M, Suzuki Y (Sep 1993). "[Treatment of cerebral vasospasm by a protein kinase inhibitor AT 877]". Nō to Shinkei - Brain and Nerve (in Japanese). 45 (9): 819–24. PMID 8217408.
  3. ^ Doggrell SA (Sep 2005). "Rho-kinase inhibitors show promise in pulmonary hypertension". Expert Opinion on Investigational Drugs. 14 (9): 1157–9. doi:10.1517/13543784.14.9.1157. PMID 16144499. S2CID 35237787.
  4. ^ Huentelman MJ, Stephan DA, Talboom J, Corneveaux JJ, Reiman DM, Gerber JD, Barnes CA, Alexander GE, Reiman EM, Bimonte-Nelson HA (Feb 2009). "Peripheral delivery of a ROCK inhibitor improves learning and working memory". Behavioral Neuroscience. 123 (1): 218–23. doi:10.1037/a0014260. PMC 2701389. PMID 19170447.
  5. ^ Kumar M, Bansal N (October 2018). "Fasudil hydrochloride ameliorates memory deficits in rat model of streptozotocin-induced Alzheimer's disease: Involvement of PI3-kinase, eNOS and NFκB". Behavioural Brain Research. 351: 4–16. doi:10.1016/j.bbr.2018.05.024. PMID 29807069. S2CID 44121036.
  6. ^ Song X, He R, Han W, Li T, Xie L, Cheng L, et al. (April 2019). "Protective effects of the ROCK inhibitor fasudil against cognitive dysfunction following status epilepticus in male rats". Journal of Neuroscience Research. 97 (4): 506–519. doi:10.1002/jnr.24355. PMID 30421453. S2CID 53289377.
  7. ^ Zhao J, Zhou D, Guo J, Ren Z, Zhou L, Wang S, et al. (September 2006). "Effect of fasudil hydrochloride, a protein kinase inhibitor, on cerebral vasospasm and delayed cerebral ischemic symptoms after aneurysmal subarachnoid hemorrhage". Neurologia Medico-Chirurgica. 46 (9): 421–8. doi:10.2176/nmc.46.421. PMID 16998274.
  8. ^ Jacobson S (February 18, 2021). "Woolsey Pharmaceuticals Emerges from Stealth Mode to Announce Patients Enrolled in Two New CNS Studies". Businesswire.
  9. ^ a b Nagumo H, Sasaki Y, Ono Y, Okamoto H, Seto M, Takuwa Y (Jan 2000). "Rho kinase inhibitor HA-1077 prevents Rho-mediated myosin phosphatase inhibition in smooth muscle cells". American Journal of Physiology. Cell Physiology. 278 (1): C57–65. doi:10.1152/ajpcell.2000.278.1.c57. PMID 10644512. S2CID 1158687.
  10. ^ Ocaranza MP, Rivera P, Novoa U, Pinto M, González L, Chiong M, Lavandero S, Jalil JE (Apr 2011). "Rho kinase inhibition activates the homologous angiotensin-converting enzyme-angiotensin-(1-9) axis in experimental hypertension". Journal of Hypertension. 29 (4): 706–15. doi:10.1097/HJH.0b013e3283440665. hdl:10533/134321. PMID 21330937. S2CID 205630605.
  11. ^ Takemoto M, Sun J, Hiroki J, Shimokawa H, Liao JK (Jul 2002). "Rho-kinase mediates hypoxia-induced downregulation of endothelial nitric oxide synthase". Circulation. 106 (1): 57–62. doi:10.1161/01.cir.0000020682.73694.ab. PMID 12093770.
  12. ^ a b Liu AJ, Ling F, Wang D, Wang Q, Lü XD, Liu YL (Oct 2011). "Fasudil inhibits platelet-derived growth factor-induced human pulmonary artery smooth muscle cell proliferation by up-regulation of p27kip¹ via the ERK signal pathway". Chinese Medical Journal. 124 (19): 3098–104. PMID 22040563.
  13. ^ Delmas C, Manenti S, Boudjelal A, Peyssonnaux C, Eychène A, Darbon JM (Sep 2001). "The p42/p44 mitogen-activated protein kinase activation triggers p27Kip1 degradation independently of CDK2/cyclin E in NIH 3T3 cells". The Journal of Biological Chemistry. 276 (37): 34958–65. doi:10.1074/jbc.m101714200. PMID 11418594.
  14. ^ Fouty BW, Rodman DM (Mar 2003). "Mevastatin can cause G1 arrest and induce apoptosis in pulmonary artery smooth muscle cells through a p27Kip1-independent pathway". Circulation Research. 92 (5): 501–9. doi:10.1161/01.RES.0000061180.03813.0F. PMID 12600884.
  15. ^ Tatenhorst L, Eckermann K, Dambeck V, Fonseca-Ornelas L, Walle H, Lopes da Fonseca T, Koch JC, Becker S, Tönges L, Bähr M, Outeiro TF, Zweckstetter M, Lingor P (April 22, 2016). "Fasudil attenuates aggregation of α-synuclein in models of Parkinson's disease". Acta Neuropathol. Commun. 4 (39): 39. doi:10.1186/s40478-016-0310-y. PMC 4840958. PMID 27101974.
  16. ^ Robustelli P, Ibanez-de-Opakua A, Campbell-Bezat C, Giordanetto F, Becker S, Zweckstetter M, Pan AC, Shaw DE (January 24, 2021). "Molecular basis of small-molecule binding to α-synuclein". bioRxiv. doi:10.1101/2021.01.22.426549. S2CID 231777082.
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