Fasudil (
INN
Inns are generally establishments or buildings where travelers can seek lodging, and usually, food and drink. Inns are typically located in the country or along a highway; before the advent of motorized transportation they also provided accommo ...
) is a potent
Rho-kinase inhibitor and
vasodilator. Since it was discovered, it has been used for the treatment of
cerebral vasospasm Cerebral vasospasm is the prolonged, intense vasoconstriction of the larger conducting arteries in the subarachnoid space which is initially surrounded by a clot.
Significant narrowing of the blood vessels in the brain develops gradually over the ...
, which is often due to
subarachnoid hemorrhage,
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.
It has been demonstrated that fasudil could improve
memory
Memory is the faculty of the mind by which data or information is encoded, stored, and retrieved when needed. It is the retention of information over time for the purpose of influencing future action. If past events could not be remembered ...
in normal mice, identifying the drug as a possible
treatment for
age-related or
neurodegenerative
A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic ...
memory loss.
It has been approved for use in Japan and China since 1995, but has not been approved by the
United States Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food s ...
or by the
European Medicines Agency. Woolsey Pharmaceuticals is developing BRAVYL (oral fasudil) for various neurodegenerative diseases.
Molecular mechanism
Fasudil (HA-1077) is a selective RhoA/
Rho kinase
Rho-associated protein kinase (ROCK) is a kinase belonging to the AGC (PKA/ PKG/PKC) family of serine-threonine specific protein kinases. It is involved mainly in regulating the shape and movement of cells by acting on the cytoskeleton.
ROCKs ( ...
(ROCK) inhibitor.
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.
ACE expression
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
Vasoconstriction is the narrowing of the blood vessels resulting from contraction of the muscular wall of the vessels, in particular the large arteries and small arterioles. The process is the opposite of vasodilation, the widening of blood vess ...
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.
eNOS expression
Endothelial nitric oxide synthase
Endothelial NOS (eNOS), also known as nitric oxide synthase 3 (NOS3) or constitutive NOS (cNOS), is an enzyme that in humans is encoded by the ''NOS3'' gene located in the 7q35-7q36 region of chromosome 7. This enzyme is one of three isoforms tha ...
(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.
ERK activation
The proliferative effects of ROCK on vascular endothelial cells is due to the activation of
extracellular signal-regulated kinase
In molecular biology, extracellular signal-regulated kinases (ERKs) or classical MAP kinases are widely expressed protein kinase intracellular signalling molecules that are involved in functions including the regulation of meiosis, mitosis, and p ...
(ERK).
ERK mediates cell proliferation via the phosphorylation of p27Kip1, thus accelerating the degradation rate of
p27Kip1. p27Kip1 is a cyclin-dependent kinase (CDK) inhibitor which down-regulates cell cycle by binding cyclin-CDK complex.
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.
Direct inhibition of α-synuclein aggregation
In addition to ROCK inhibition, fasudil has also been demonstrated to directly modulate the aggregation of
α-synculein, both
in vitro and in cellular models of neurodegenerative disease.
Aggregation of α-synuclein is a major hallmark of
Parkinson's disease
Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...
, 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.
See also
*
Ripasudil, a fasudil derivative used to treat glaucoma and ocular hypertension
References
{{Peripheral vasodilators
Diazepanes
Isoquinolines
Protein kinase inhibitors
Sulfonamides
Orphan drugs