Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is a progressive neurodegenerative disorder characterised by relatively selective death of upper motor neurons in the cerebral cortex and lower motor neurons in the brainstem and spinal cord (Shaw 1999). This gives rise to a combination of upper and lower motor neuron signs and symptoms such as weakness in the limb and bulbar muscles with atrophy, spasticity and weight loss. Death occurs in most people within two to five years after diagnosis, usually from ventilatory muscle weakness causing respiratory failure (Rowland 2001). The annual incidence of ALS or MND is one to two per 100,000 of the population (Worms 2001). At any one time, there are approximately 5,000 affected people in the United Kingdom (Shaw 1999) and 25,000 in North America (McGuire 1996).

The mechanisms leading to motor neuron death in ALS or MND are incompletely understood, but appear to include oxidative stress, glutamate excitotoxicity, mitochondrial dysfunction, and neuroinflammation, eventually leading to activation of cell death pathways (Shaw 2005). The release of mitochondrial cytochrome c and upregulation of stress enzymes such as p38 mitogen‐activated protein (MAP) kinase may promote the activation of proapoptotic and proinflammatory modulators in ALS or MND (Friedlander 2003; Tortarolo 2003). In ALS or MND, caspases, which are the key effectors of apoptosis (programmed cell death), are activated in motor neurons of transgenic mice (Pasinelli 2000) and human patients (Inoue 2003), while cyclooxygenase‐2 and inducible nitric oxide synthase (iNOS) are upregulated in microglia which modulate neuroinflammation (Almer 1999; Almer 2001). In addition, there is increased protein nitration in motor neurons in both sporadic and familial forms of ALS or MND and in a transgenic mouse model of the disease (Beal 1997; Ferrante 1997).

Riluzole, a putative glutamate release blocker, is currently the only licensed disease modifying drug for human use in ALS or MND. Its effect is modest, prolonging survival by two to three months in people with ALS or MND (Miller 2007).

Minocycline is a second generation tetracycline that crosses the blood brain barrier. It has been shown to be neuroprotective in various models of acute and chronic experimental neuronal injury (Yong 2004). There have been several neuroprotection studies involving the use of the minocycline in cellular and transgenic models of ALS or MND. Minocycline has been shown to inhibit apoptotic neuronal death and microglial proliferation in mixed rat spinal cord cultures that have been induced to undergo death by exposure to cerebrospinal fluid from people with familial and sporadic ALS or MND (Tikka 2002). In addition, survival benefit has been accorded by minocycline alone, and even more so in combination with the calcium channel blocker nifedipine, in the presence of oxidative stress in a motor neuronal cell line (Sathasivam 2005). In transgenic mouse models of familial ALS or MND, minocycline delays disease progression and extends survival. When used as a single agent (Kriz 2002; Van Den Bosch 2002; Zhu 2002) it increases lifespan of transgenic ALS or MND mice by six to 16 percent. It increases lifespan of transgenic ALS or MND mice by 25 percent when used in combination with creatine (Zhang 2003), and by 13 percent in combination with nimodipine plus riluzole (Kriz 2003).

There are two possible mechanisms by which minocycline may exert its neuroprotective effects in ALS or MND. Firstly, minocycline directly inhibits the release of cytochrome c from mitochondria into the cytosol, therefore blocking downstream activation of caspase‐3 of the cell death pathway cascade (Zhu 2002). Secondly, minocycline modulates the immuno‐inflammatory responses in the disease by inhibiting microglial activation (Kriz 2002; Tikka 2002; Van Den Bosch 2002), and interfering with inducible nitric oxide synthase activity and protein tyrosine nitration (Tikka 2002).

In 2004, two double‐blind, placebo‐controlled, randomised feasibility studies of minocycline in ALS or MND were reported (Gordon 2004). Intention‐to‐treat analysis was carried out in both trials. Neither trial was powered to assess the efficacy of minocycline. The primary aim of trial one was to determine whether treatment with minocycline was safe and well tolerated in conjunction with riluzole. In this trial, participants (all taking riluzole) received minocycline 200 mg/day (10 participants) or placebo (nine participants) for six months. There was 80% power to detect a 61% difference in the rates of adverse events (AE). There were no significant differences in AE or the ability to complete the trial between the two groups. Thirteen participants completed the trial. Three (two minocycline, one placebo) participants died due to progressive respiratory failure from ALS or MND. Three (two placebo, one minocycline) participants prematurely withdrew from the study due to advancing weakness and inability to attend the study centre. The primary aim of trial two was to establish whether people with ALS or MND could tolerate doses of up to 400 mg/day to obtain the maximal tolerable dosage. Trial two was an eight‐month crossover study involving 23 participants (where participants were 'crossed over' after four months) in which minocycline or placebo was administered starting at 100 mg twice a day and increasing weekly by 50 mg twice a day until reaching the highest tolerated dose of 400 mg/day. Trial two could detect a 16% difference in AE with 80% power. Twenty‐one of 23 participants took riluzole throughout the trial which did not cause statistical differences in laboratory data due to the crossover design. Nineteen of 23 participants tolerated the target dose of minocycline, with the mean tolerated dose being 387 mg/day. Twenty participants completed the full course. Three participants dropped out (one while on minocycline, two while on placebo) due to non‐drug related issues, and there was no significant difference in the dropout rate while taking drug compared with placebo. There was a non‐significant increase in gastrointestinal symptoms while taking the higher doses of minocycline compared with placebo. Elevations of blood urea nitrogen and liver enzymes while on minocycline were statistically significant, though not deemed to be clinically significant.

In 2005, another group published a six‐month randomised open label study investigating the safety of combined treatment with minocycline and riluzole in ALS or MND (Pontieri 2005). The trial was not powered to determine the efficacy of minocycline. Twenty participants were randomised to two groups of 10, one group was given riluzole, and the other riluzole and minocycline (100 mg/day). Four participants did not complete the study because of death (two riluzole, two riluzole/minocycline) and three because of inability to attend scheduled visits (two riluzole, one riluzole/minocycline). Statistical analysis was only carried out in the remaining 13 cases. Administration of minocycline was not associated with significant clinical side effects or laboratory data changes (including haematological and liver enzyme measures), although the dose of minocycline used in this study was small compared to those used in the trials by Gordon et al. (Gordon 2004).

Minocycline is currently undergoing phase III trial testing in ALS or MND patients (ClinicalTrials 2007).