Effects of 4-Aminopyridine on Muscle and Motor Unit Force in Canine Motor Neuron Disease

Abstract

Hereditary Canine Spinal Muscular Atrophy (HCSMA) is an autosomal dominant disorder of motor neurons that shares features with human motor neuron disease. In animals exhibiting the accelerated phenotype (homozygotes), we demonstrated previously that many motor units exhibit functional deficits that likely reflect underlying deficits in neurotransmission. The drug 4-aminopyridine (4AP) blocks voltagedependent potassium conductances and is capable of increasing neurotransmission by overcoming axonal conduction block or by increasing transmitter release. In this study, we determined whether and to what extent 4AP could enhance muscle force production in HCSMA. Systemic 4AP (1-2 mg/kg) increased nerve-evoked whole muscle twitch force and electromyograms (EMG) to a greater extent in older homozygous animals than in similarly aged, symptomless HCSMA animals or in one younger homozygous animal. The possibility that this difference was caused by the presence of failing motor units in the muscles from homozygotes was tested directly by administering 4AP while recording force produced by failing motor units. The results showed that the twitch force and EMG of failing motor units could be significantly increased by 4AP, whereas no effect was observed in a nonfailing motor unit from a symptomless, aged-matched HCSMA animal. The ability of 4AP to increase force in failing units may be related to the extent of failure. Although 4AP increased peak forces during unit tetanic activation, tetanic force failure was not eliminated. These results demonstrate that the force outputs of failing motor units in HCSMA homozygotes can be increased by 4AP. Possible sites of 4AP action are considered.

SMN Is Required for Sensory-Motor Circuit Function in Drosophila

“…Nonetheless, administration of 4-AP significantly increased both the muscle area and locomotion of smn mutants and fully corrected defects in rhythmic motor output and NMJ neurotransmission. Treatment with 4-AP has been linked to functional improvement of patients with spinal cord injury, myasthenia gravis and Lambert-Eaton syndrome (Hayes, 2007) and can improve muscle twitch tension in a canine hereditary motor neuron disease (Pinter et al, 1997). A sustained release preparation of 4-AP was recently approved by the FDA for human clinical use in multiple sclerosis (Chwieduk and Keating, 2010).…”

Mobilization of Calcium from Intracellular Stores, Potentiation of Neurotransmitter-Induced Calcium Transients, and Capacitative Calcium Entry by 4-Aminopyridine

“…4-AP and its analogs have numerous clinical applications, including treatment of neuromuscular and neurodegenerative disorders and traumatic injuries of the CNS (Li and Zhang, 1994;Pinter et al, 1997;Fujihara and Miyoshi, 1998;Gruner and Yee, 1999;Segal et al, 1999;Andreani et al, 2000). All of the therapeutic activities of 4-AP are currently explained by blockade of voltageactivated K ϩ channels (Vislobokoe et al, 1983;Davies et al, 1991;Choquet and Korn, 1992;Kirsch and Drewe, 1993;Castle et al, 1994).…”

“…4-AP has also been used as a therapeutic agent in many neurological and neuromuscular junction disorders. A number of reports address the beneficial role of 4-AP and related compounds in multiple sclerosis (Schwid et al, 1997;Fujihara and Miyoshi, 1998), myasthenia gravis (Li and Zhang, 1994), and in the canine model of motoneuron disease (Pinter et al, 1997). Clinical applications of 4-AP have been extended to traumatic spinal cord injury (Segal et al, 1999) and to neurodegenerative disorders such as Alzheimer's disease (Andreani et al, 2000).…”

Functional motor unit failure precedes neuromuscular degeneration in canine motor neuron disease

“…5 The mechanisms underlying these properties thus do not directly cause tetanic failure. Because the extent of motor unit tetanic failure depends on unit activation frequency and can be decreased by aminopyridine drugs, 6 it is likely that tetanic failure is presynaptic in origin, at least in part. While it is generally assumed that motor axon degeneration or motor neuron cell death underlies the loss of motor unit function in motor neuron disease, there is little to support this view.…”