Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder that is characterized by progressive degeneration of motor neurons in the spinal cord, motor cortex, and brainstem. There is currently no effective treatment for ALS. Transgenic mice expressing familiar ALS-linked mutant superoxide dismutase (SOD1) have been commonly used for preclinical trials; however, successful trails in mice mostly fail in subsequent human trials. Most preclinical trials start treatment before the onset of symptoms, while patients with ALS in clinical trials have surpassed the onset of disease. In addition, ALS is not only a multifactorial disease but also a multisystemic disease that affects several cell types [1]. Therefore, therapies should be aimed at the interception of multiple mechanisms. In this study, we investigated [1] whether the therapeutic agents, which were previously tested starting before disease onset, still showed protective effects when the treatments were initiated after disease onset and [2] whether combination therapies offered better effects after disease onset.

Minocycline, which inhibits microglia activation and apoptotic cascade, was previously found to be effective at ameliorating motor impairment and increasing the lifespan of SOD1G93A mice when administered at 5 weeks of age [2]. However, minocycline fails in human trials [3]. We assessed whether similar beneficial effects could be seen when treatment began at 90 days of age. This time point was chosen because SOD1G93A mice [4] exhibited 10~ 20% decline in motor function at this age, which may be equivalent to the stage that patients with ALS first visit a doctor. The results showed no delay in impaired motor function (Figure 1A, B, Mino) and no extension in survival (Figure 1C, D, Mino). This result is consistent with a recent report [5]. Ceftriaxone, which reduces excitotoxicity via activation of glial glutamate transporter EAAT2, was found to slow disease progression in SOD1G93A mice when administered at 12 weeks of age [6].