New therapy approach in amyotrophic lateral sclerosis

Amyotrophic Lateral Sclerosis (ALS) is the most frequent motor neuron disease in adulthood. It is characterized by a selective loss of motor neurons in brain and spinal cord that clinically results in a progressive paralysis and ultimately leads to death due to respiratory failure within 2-5 years after onset of symptoms. To date, only a few approved treatments, such as mechanical ventilation and riluzole, an anti-glutamatergic drug, do prolong survival to a small extent. The discovery that mutations in the gene encoding for SOD1 (Cu/Zn superoxide dismutase) are associated with a familial form of ALS and the subsequent development of a transgenic mouse model of the disease (mutant SOD1 mice) allowed valuable insights into the pathophysiology of motor neuron cell death. A substantial number of studies has provided data to support the relevance of different pathogenic mechanisms including oxidative stress, glutamate excitotoxicity and apoptosis. Rather than merely paralleling each other these processes are considered to interact with each other in a mutually reinforcing way. While the majority of experimental and clinical therapy studies has focused on either one of these mechanisms as a therapeutic target, a recent study using a cocktail of drugs targeting different sites of the pathophysiologic cascade suggested additional beneficial effects of a combination approach. Flupirtine, a substance that has been in clinical use as a non-opioid analgesic for years, has been shown to possess a unique profile of properties that suggests a considerable neuroprotective potential: the drug`s anti-oxidant, anti-glutamatergic and anti-apoptotic properties have been documented in a number of studies. Accordingly, flupirtine may interfere with the neurodegenerative process at different sites of the pathophysiological cascade and therefore represents a promising therapeutic strategy. Along this line, this project aims at the assessment of the neuroprotective potential of a multitarget therapy approach with flupirtine in the mutant SOD1 mouse model of ALS. The neuroprotective effect of flupirtine will be ascertained by evaluation of clinical parameters including motor performance by rotarod testing and survival. In addition, we will perform a morphological analysis of the murine spinal cords by immunohistochemistry for quantitative analysis of motor neuron cell death as well as western blot analysis for markers of the different pathways in order to investigate the actual neuroprotective mechanism of the drug. In the case of favourable experimental results, the drug`s clinical availability would allow a rapidly ensuing clinical trial in ALS patients and thus ensure immediate therapeutic benefit to patients suffering from this dreadful disease.