Role of EphA4 signaling in the pathogenesis of amyotrophic lateral sclerosis and therapeutic potential of traditional Chinese medicine rhynchophylline.

Abstract

Amyotrophic lateral sclerosis (ALS), one of the most common neuromuscular disorders, is characterized by the progressive degeneration of motor neurons. Although riluzole is to date the only drug that prolongs the survival, its efficacy is limited. A meta-analysis showed that riluzole represented a 9 % gain in the probability of surviving 1 year (49 % in the placebo group and 58 % in the riluzole group) and that riluzole increased median survival from 11.8 to 14.8 months (Miller et al. 2012). Thus, riluzole is reasonably safe and probably prolongs median survival by about 2 to 3 months in ALS patients (Miller et al. 2012). There was also a small beneficial effect on both bulbar and limb function, but not on muscle strength (Miller et al. 2012). In contrast, a threefold increase in serum alanine transferase was more frequent in riluzole-treated patients than controls (Miller et al. 2012). Taken together, there is a critical unmet need for novel therapeutic drugs for ALS. Understanding the cellular and molecular mechanisms underpinning the pathogenesis of ALS is, therefore, key to the discovery of novel therapeutic drugs. Accumulating evidence suggests the role of the ephrin receptor (Eph)—ephrin signaling in a range of chronic and neurodegenerative diseases (Boyd et al. 2014). EphA4, a subtype of Eph, plays a key role in the synaptic plasticity by modulating the neuron-glia cell communication that affects dendritic spine morphology (Boyd et al. 2014). A recent paper demonstrated that EphA4 plays a critical role in the motor neuron degeneration and disease progression in ALS (Fig. 1) (Van Hoecke et al. 2012). Genetic deletion of the EphA4 allele in a human superoxide dismutase 1 (SOD1) mutant model of ALS improved survival and slowed motor neuron deterioration after the onset of disease. In addition, intracerebroventricular administration of EphA4-blocking peptide into ALS rats that overexpress human mutant SOD1 delays the onset of disease and enhances survival. Expression of EphA4 in the ALS model mice was higher in large motor neurons compared to small motor neurons, and the protective effects of EphA4 gene deletion was more prominent in large motor neurons. Interestingly, in ALS patients, EphA4 expression inversely correlated with disease onset and survival and loss-of-function mutations in the EPHA4 gene are associated with long survival (Van Hoecke et al. 2012). Taken together, it is likely that EphA4 genetically modulates the vulnerability of motor neurons to axonal degeneration and that lowering EphA4 expression or inhibiting EphA4 signaling could reduce disease severity in ALS patients, delay the onset of the disease, and improve survival (Van Hoecke et al. 2012). Given the key role of EphA4 in the pathogenesis of ALS, it is likely that EphA4 inhibitors would be potential therapeutic drugs for ALS (Fig. 1). Uncaria rhynchophylla (Miq) Jack (UR) is a traditional Chinese medicine that has been used to treat cardiovascular disorder and central nervous system disorders in China (Zhou and Zhou 2010). The alkaloid rhynchophylline (Fig. 1), the major component of the extracts ofUncaria species (Gouteng in Chinese), has a potent neuroprotective action (Zhou and Zhou 2010). This is also a major component of traditional * Kenji Hashimoto hashimoto@faculty.chiba-u.jp