Early phase trials of minocycline in amyotrophic lateral sclerosis

Summary

Key words: amyotrophic lateral sclerosis; minocycline; clinical trial; neurodegeneration.

Introduction and Overview

Amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by selective motor neuron cell death, leads to progressive weakness and death in an average of 3 years (Rowland & Shneider, 2001). There is no cure or known treatment that improves function. The mechanisms of motor neuron degeneration are not fully understood, but there is evidence that mitochondrial dysfunction, free radical toxicity, glutamate excitotoxicity, and intermediate filament-aggregation lead to activation of genes and enzymes that control cell death pathways, including apoptosis (Martin, 1999; Wiedemann et al., 1998; Rothstein et al., 1992; Hirano, 1991). Up-regulation of stress enzymes such as p38 mitogen activated protein (MAP) kinase and release of mitochondrial cytochrome c may contribute to activation of pro-inflammatory and pro-apoptotic modulators (Zhu et al., 2002; Mota et al., 2001; Horstmann et al., 1998; Migheli et al., 1997; Schiffer et al., 1996). Inflammatory cells and cytokines, including inducible nitric oxide synthase (iNOS), components of the complement cascade, and pro-apoptotic caspase enzymes are activated in areas of neurodegeneration in ALS (Almer et al., 2001; Li et al., 2000; Martin et al., 2000; Kostic et al., 1997). Caspase enzyme inhibitors and anti-inflammatory agents slow progression in the transgenic mouse model of ALS (Drachman et al., 2002; Barneoud and Curet, 2000; Friedlander et al., 1997).

Minocycline, which has both anti-inflammatory and anti-apoptotic properties, crosses the blood–brain barrier, and has been shown to have neuroprotective effects in models of ALS and other neurodegenerative disorders.