Effekte der präsymptomatischen Applikation der Rho-Kinase-Inhibitoren Fasudil und Y-27632 im SOD1-(G93A)-Mausmodell der Amyotrophen Lateralsklerose

Effekte der präsymptomatischen Applikation der Rho-Kinase-Inhibitoren Fasudil und Y-27632 im SOD1-(G93A)-Mausmodell der Amyotrophen Lateralsklerose

Effects of presymptomatic application of Rho-kinase-Inhibitors Fasudil and Y-27632 in the SOD1(G93A) mouse model of amyotrphic lateral sclerosis

Martin Erwin Hermann Suhr

Doctoral thesis

Date of Examination: 2017-02-21

Date of issue: 2017-02-20

Advisor: Tönges, Lars Prof. Dr.

Referee: Tönges, Lars Prof. Dr.

Referee: Sereda, Michael Werner Prof. Dr.

Persistent Address: http://hdl.handle.net/11858/00-1735-0000-002B-7D53-0

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Abstract

English

This study demonstrates the successful pre-clinical testing of a new pharmacological approach in the treatment of amyotrophic lateral sclerosis using Rho-kinase-(ROCK)-inhibition. The Rho/ROCK signal cascade represents an important pathway for signal transduction in axonal de- and regeneration which has already been successfully modulated in other neurodegenerative diseases. Using the SOD1(G93A) mouse model, this experimental study included different treatment cohorts of transgenic mice starting at day 50 with ROCK inhibitors Fasudil or Y-27632, respectively. Day 50 represents the pre-symptomatic phase in SOD1(G93A) transgenic animals when axonal degeneration is already detectable. In detail, this proof-of-principle study evaluates whether treatment with ROCK inhibitors can increase survival and ameliorate locomotor functions in ALS mice. Continuous and frequent neurological evaluations (clinical scoring) as well as analyses of motor function (Rotarod- and Hanging-Wire Test) were implemented. In comparison to the treatment control group, a female cohort treated with daily Fasudil 30 mg/kg (body weight) showed a significantly longer survival and in addition a significantly delayed decrease in motor performance as evaluated in the Rotarod test. Treatment of male mice was not able to yield similarly significant results implying that gender may play an important role in ROCK inhibition. An exploratory analysis of an alternative treatment with the ROCK inhibitor Y-27632 at a low dosage with daily 2 mg/kg (body weight) did not show significant differences in comparison to control treatment. The medical treatment was tolerated well in all study groups. In summary, the study shows that treatment with ROCK inhibitors using optimized dosages can yield significant beneficial results in female ALS mice with respect to survival and locomotor function. Further studies should focus on the optimization of ROCK inhibitor dosage and should also evaluate later treatment initiation at motor symptom onset. If the utility of ROCK inhibition in ALS models is further corroborated it should be quickly considered as a treatment option also for human ALS patients because Fasudil is an already clinically approved medication in stroke patients for the treatment of vasospasms.

Keywords: Rho-kinase; Fasudil; Y-27632; SOD1(G93A) mouse model; presymptomatic; amyotrophic lateral sclerosis