Rho Kinase Inhibition by Fasudil in the Striatal 6-Hydroxydopamine Lesion Mouse Model of Parkinson Disease

Abstract

Chronic degeneration of nigrostriatal projections, followed by nigral dopaminergic cell death, is a key feature of Parkinson disease (PD). This study examines the neuroprotective potential of the rho kinase inhibitor fasudil in the 6-hydroxydopamine (6-OHDA) mouse model of PD in vivo. C57Bl/6 mice were lesioned by striatal stereotactic injections with 4 μg of 6-OHDA and treated with fasudil 30 or 100 mg/kg body weight via drinking water. Motor behavior was tested biweekly; histologic and biochemical analyses were performed at 4 and 12 weeks after lesion. Motor behavior was severely impaired after 6-OHDA lesion and was not improved by fasudil treatment. Fasudil 100 mg/kg did not significantly increase the number of dopaminergic cells in the substantia nigra after 12 weeks versus lesion controls. Interestingly, however, high-performance liquid chromatography analysis of dopamine metabolites revealed that striatal levels of 3,4-dihydroxyphenylacetic acid were significantly increased after 12 weeks, suggesting a regenerative response. In contrast to recent findings in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridin model, fasudil effects seem limited in this severe 6-OHDA model of PD. Nevertheless, high therapeutic concentrations of fasudil are suggestive of a proregenerative potential for dopaminergic neurons, making further evaluations of rho kinase inhibition as a proregenerative therapeutic strategy in PD promising.

Altered Expression of Growth Associated Protein‐43 and Rho Kinase in Human Patients with Parkinson's Disease

“…Upregulated ROCK expression therefore provides evidence for an exacerbated micro‐and astroglial activity in PD patients and represents a putative therapeutic target as has been shown in several models of neurodegeneration .…”

“…Therefore, an increase in ROCK activity in PD might contribute to the progression of the pathophysiology, via regeneration block and deleterious function of micro‐ and astroglia. Previous studies from our group suggest that inhibition of ROCK improves regenerative axon growth and increases neuronal survival in models of optic nerve trauma and dopaminergic toxicity, e.g., MPTP‐ or 6‐OHDA lesions in the nigrostriatal system .…”

Modulation of Microglial Activity by Rho-Kinase (ROCK) Inhibition as Therapeutic Strategy in Parkinson’s Disease and Amyotrophic Lateral Sclerosis

“…In another toxin-induced PD model that shows a more severe lesion, the high dose (4 μg/2 μl) striatal 6-OHDA model, oral treatment with Fasudil could not reduce dopaminergic degeneration in mice (Tatenhorst et al, 2014). Using shRNAs that diminished ROCK2 in nigral neurons in the same model, we could show decreased dopaminergic cell death in the substantia nigra.…”

Parkinson-Erkrankung und Neuroinflammation – Zelluläre Pathologie, Mechanismen und therapeutische Optionen

“…Nach Aufnahme des Toxins über dopaminerge und noradrenerge Transporter akkumuliert es im Zytosol, produziert reaktive Sauerstoffspezies (ROS) und inaktiviert zahlreiche Makromoleküle. Zwischen einer und zwei Wochen nach Injektion bildet sich eine retrograd beginnende nigrostriatale Neurodegeneration aus [8]. Vorteile dieses Modells bestehen in der fokussierten lokalen Schädigung dopaminerger Neurone bei allerdings erhöhtem technischem Aufwand.…”