Sean M. Healey and AMG Center for ALS at Mass General
Amyotrophic lateral sclerosis is a progressive neurodegenerative disorder characterized by death of pyramidal neurons in the motor cortex and motor neurons in the brain stem and central spinal cord. ALS is characterized by upper motor neuron and lower motor neuron degeneration and death as well as reactive gliosis replacing death neurons. ALS affects spinal motor neurons of the ventral horn and brainstem motor neurons. The autopsy of ALS patients shows loss of motor neurons and atrophic motor neurons with basophilic appearance suggesting a programmed cell mechanism. Cultured motor neurons deprived of trophic factors induce nNOS expression, production of nitric oxide and peroxynitrite formation that is followed by tyrosine nitration, which precedes motor neuron death.
Deprivation of trophic factors activates the Fas pathway in motor neurons, and inhibition of the Fas pathway prevents motor neuron death. Fas activation in motor neurons triggers two parallel pathways: the classical extrinsic pathway recruiting FADD and Caspase 8; and a seemingly motor neuron specific pathway, that activates DAXX/ASK1/p38 and the induction of neuronal NOS, increasing production of nitric oxide, peroxynitrite formation and tyrosine nitration. Reduction in light subunit mRNA levels was found in motor neurons from the spinal cord of patients with ALS. Abnormal axonal transport, vacuolization and degeneration of axons and motor neurons have been reported in transgenic mice overexpressing or with reduced expression of NF subunits. Overexpression of VEGF delayed onset and progression motor neuron disease, as shown in a double transgenic mice generated by crossing mice expressing human mutant SOD1 with mice overexpressing neuronal VEGF.
The mSOD1/VEGF transgenic mice showed a delayed in motor neuron loss, motor impairment, and a prolonged survival compared with mutant SOD1 transgenic mice. Co-cultures of healthy motor neurons with astrocytes expressing mutant SOD1 resulted in more than 50% motor neuron death, while astrocytes obtained from postmortem tissue from patients with fALS and sALS were both toxic to motor neurons. In ALS animal models mutant SOD1-expressing astrocytes are neurotoxic to motor neurons, and reducing mutant SOD1 expression decreases motor neuron degeneration and increases animal life span. Motor neurons expressing mutant SOD1 are more susceptible to Fas ligand and NO-triggered cell death, suggesting that in the context of ALS progression, motor neurons expressing mutant SOD1 are more vulnerable to external stimuli such as ROS, RNS and toxic factors release by surrounding cells.
Mexiletine in Sporadic Amyotrophic Lateral Sclerosis
The purpose of this research study is to find out whether the drug mexiletine will be effective in lowering motor neuron electrical activity in the brains and nerves in the arms of people with ALS. The investigators will also determine if there are any signs that the drug may slow down the progression of ALS and reduce muscle cramps and muscle twitching. This will be determined through transcranial magnetic stimulation and threshold tracking nerve conduction studies. In this trial, the participants will be taking either 300mg/day of mexiletine, 600mg/day of mexiletine, or placebo. Amyotrophic lateral sclerosis is a neurodegenerative disorder affecting primarily motor neurons, for which treatment designed to slow or arrest progression remains lacking.
Mexiletine is a use-dependent sodium channel blocker that has been FDA-approved for decades for the treatment of cardiac arrhythmias and more recently to treat neuropathic pain in diabetic polyneuropathy. Mexiletine has been shown also to be protective of neurons following spinal cord, head injury, and cerebral ischemia, largely by blocking excitotoxicity. Based on previous studies, mexiletine appears to penetrate into the central nervous system at concentrations sufficient to confer significant protection. Recent unpublished studies in the laboratory of Dr. Robert Brown at the University of Massachusetts have also demonstrated that mexiletine ingestion in mice genetically engineered to express high levels of mutant cytosolic copper-zinc superoxide dismutase-1 transgene prolongs survival in these animals.
As mexiletine already has FDA-approval as an anti-arrhythmic agent, much is known about the pharmacology and safety of this drug in non-ALS patients. We anticipate that by excluding subjects with a known history of cardiac disease and with the known neuroprotectant properties of this medication, mexiletine is a good choice for further study in an ALS clinical trial.
Amyotrophic Lateral Sclerosis: the Role of Exercise
Given the deterioration of skeletal muscle function, historically there has been concern regarding exercise and its affect on ALS. This article reviews and explains current research, helping patients, caregivers, and providers be equipped better to make decisions regarding the treatment of ALS with exercise. Also the association between exercise and ALS has garnered attention, with various observational and population-based studies showing conflicting evidence linking exercise and athletics with a higher incidence of ALS. However, exercise has been considered more recently as an intervention to help improve function, slow disease progression, and lessen caregiver burden. Aerobic Exercise Large human studies that examine aerobic exercise in patients with ALS currently are lacking.
Conclusions/Discussion In reviewing the literature on exercise and ALS, there is clearly a lack of quality data to draw clear evidence-based conclusions about the effects of exercise. Chen A, Montes J, Mitsumoto H. The role of exercise in amyotrophic lateral sclerosis. Dal Bello-Haas VP, Florence JM. Therapeutic exercise for people with amyot
rophic lateral sclerosis or motor neuron disease.
Motoneuron survival is promoted by specific exercise in a mouse model of amyotrophic lateral sclerosis. The value of muscle exercise in patients with amyotrophic lateral sclerosis. Kirkinezos IG, Hernandez D, Bradley WG, Moraes CT. Regular exercise is beneficial to a mouse model of amyotrophic lateral sclerosis. Extensive exercise is not harmful in amyotrophic lateral sclerosis.
Lui AJ, Byl NN. A systematic review of the effect of moderate intensity exercise on function and disease progression in amyotrophic lateral sclerosis. Effects of aerobic exercise therapy and cognitive behavioural therapy on functioning and quality of life in amyotrophic lateral sclerosis: protocol of the FACTS-2-ALS trial.