Fasudil (Rho-kinase inhibitor) targeting Rho GTPase Activating Protein to treat schizophrenia
- Shaziya J
- Mar 18, 2023
- 1 min read
Schizophrenia can cause a wide variety of symptoms to appear. Positive symptoms of schizophrenia include delusions, hallucinations, flat affect, and social disengagement, for instance. Negative signs of schizophrenia include, for example, impaired cognitive functioning (memory impairment, confused state).
Antipsychotics of the present generation, which are used to treat schizophrenia, have a number of drawbacks, including significant side effects and treatment resistance. Researchers recently found a strong association between schizophrenia and exonic copy number variations in the Rho GTPase Activating Protein 10 (ARHGAP10) gene using genome-wide analysis. ARHGAP10 encodes a member of the RhoGAP superfamily involved in small GTPase signalling. Polymorphisms in the Arhgap10 gene in mice result in the activation of the RhoA/Rho-kinase pathway. In order to study the pharmacokinetics of fasudil and hydroxyfasudil in mice, tandem mass spectrometry and liquid chromatography were used.
Fasudil and its principal metabolite, hydroxyfasudil, were identified in the brain at concentrations higher than their corresponding Ki values for Rho-kinase following intraperitoneal administration of 10 mg kg1 of fasudil. Fasudil decreased the MK-801-treated mice's hyperlocomotion, social interaction impairments, prepulse inhibition deficits, and deficits in new object identification in a dose-dependent manner. After oral administration, fasudil was no longer detectable, however brain hydroxyfasudil was discovered at levels above the Rho-kinase Ki value. Fasudil was given orally, and this also reduced the hyperlocomotion brought on by MK-801. These results suggest that the pharmacological mouse schizophrenia model treated with MK-801 by fasudil exhibits antipsychotic-like effects.
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