DOI: 10.1523/jneurosci.17-11-04500.1997. Effects of 4-Aminopyridine on Muscle and Motor Unit Force in Canine Motor Neuron Disease

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

10.1523/jneurosci.17-11-04500.1997

Crossref journal-article

Society for Neuroscience

The Journal of Neuroscience (393)

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 neurotrans-mission. The drug 4-aminopyridine (4AP) blocks voltage-dependent 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.

Bibliography

Pinter, M. J., Waldeck, R. F., Cope, T. C., & Cork, L. C. (1997). Effects of 4-Aminopyridine on Muscle and Motor Unit Force in Canine Motor Neuron Disease. The Journal of Neuroscience, 17(11), 4500â4507.

Authors 4

M. J. Pinter (first)
R. F. Waldeck (additional)
T. C. Cope (additional)
L. C. Cork (additional)

References 42 Referenced 20

10.1016/0022-510X(94)00225-D
{'key': '2023041302354450000_17.11.4500.2', 'first-page': '1083', 'article-title': 'Terminal motor axon morphology in homozygous hereditary canine spinal muscular atrophy.', 'volume': '18', 'author': 'Alderson', 'year': '1992', 'journal-title': 'Soc Neurosci Abstr'} / Soc Neurosci Abstr / Terminal motor axon morphology in homozygous hereditary canine spinal muscular atrophy. by Alderson (1992)
10.1002/ana.410360608
10.1016/0306-4522(85)90115-0
10.1007/BF00374835
10.1212/WNL.31.2.202 / Neurology / Motor neuron disease: decrementing responses to repetitive nerve stimulation. by Bernstein (1981)
10.1113/jphysiol.1981.sp013666
10.1016/S0022-3565(25)32791-6 / J Pharmacol Exp Ther / Effects of 4-aminopyridine on nerve terminal action potentials. by Burley (1981)
10.1085/jgp.99.2.217
10.1152/jn.1991.66.4.1127 / J Neurophysiol / Motor unit recruitment in the decerebrate cat: several unit properties are equally good predictors of order. by Cope (1991)
10.1097/00005072-197905000-00002
{'key': '2023041302354450000_17.11.4500.12', 'first-page': '89', 'article-title': 'Pathology of motor neurons in accelerated hereditary canine spinal muscular atrophy.', 'volume': '46', 'author': 'Cork', 'year': '1982', 'journal-title': 'Lab Invest'} / Lab Invest / Pathology of motor neurons in accelerated hereditary canine spinal muscular atrophy. by Cork (1982)
10.1523/JNEUROSCI.14-10-05885.1994
10.1001/archneur.1979.00500400056008
10.1152/jn.1988.60.6.2168 / J Neurophysiol / Development of 4-AP and TEA sensitivities in mammalian myelinated nerve fibers. by Eng (1988)
10.1523/JNEUROSCI.15-10-06445.1995
10.1007/BF00508637
Hirano A (1988) In pursuit of the pathological alterations in ALS. in Amyotrophic lateral sclerosis, eds Tsubaki T Yase Y (Elsevier, Amsterdam), pp 193–198.
Hirano A (1991) Cytopathology of amyotrophic lateral sclerosis. in Advances in neurology, Vol 56. Amyotrophic lateral sclerosis and other motor neuron diseases, ed Rowland LP (Raven, New York), pp 91–101.
10.1111/j.1476-5381.1978.tb17325.x / Br J Pharmacol / 4-aminopyridine and evoked transmitter release from motor nerve endings. by Illes (1978)
10.1016/0006-8993(82)90649-7
10.1016/0896-6273(93)90154-J
Kocsis JD (1986) Functional characteristics of potassium channels of normal and pathological mammalian axons. Ion channels in neural membranes, pp 123–144. (Alan R. Liss, New York).
Kocsis JD Waxman SG (1987) Ionic channel organization of normal and regenerating mammalian nerves. Progress in brain research, Vol 71. (Elsevier, Amsterdam). (10.1016/S0079-6123(08)61816-6)
10.1016/0028-3908(73)90117-2
10.1016/0014-2999(77)90176-5
10.1016/0006-8993(78)90409-2
10.1136/jnnp.40.11.1109
10.1113/jphysiol.1985.sp015876 / J Physiol (Lond) / Electric current flow inside perineural sheaths of mouse motor nerves. by Mallart (1985)
10.1002/mus.880161109
10.1056/NEJM198912073212303
10.1016/S0022-3565(25)31092-X / J Pharmacol Exp Ther / Effects of 4-aminopyridine at the frog neuromuscular junction. by Molgo (1977)
10.1212/WNL.9.10.627 / Neurology / Myasthenic syndrome in patients with amyotrophic lateral sclerosis. by Mulder (1959)
10.1523/JNEUROSCI.15-05-03447.1995
10.1002/ana.410150411
10.1136/jnnp.35.1.52 / J Neurol Neurosurg Psychiatry / Transmission block in terminal nerve twigs: a single fibre electromyographic finding in man. by Stålberg (1972)
10.1016/0022-510X(75)90166-5
10.1016/0896-6273(91)90337-Y
10.1016/0006-8993(85)91049-2
10.1016/0306-4522(80)90002-0
10.1016/S0022-3565(25)22023-7 / J Pharmacol Exp Ther / Effects of 4-aminopyridine and 3,4-diaminopyridine on transmitter release at the neuromuscular junction. by Thomsen (1983)
10.1523/JNEUROSCI.16-07-02226.1996

Dates

Type	When
Created	7 years, 4 months ago (April 5, 2018, 6:32 p.m.)
Deposited	1 month, 3 weeks ago (July 3, 2025, 9:08 a.m.)
Indexed	1 month, 3 weeks ago (July 7, 2025, 2:29 a.m.)
Issued	28 years, 2 months ago (June 1, 1997)
Published	28 years, 2 months ago (June 1, 1997)
Published Online	28 years, 2 months ago (June 1, 1997)
Published Print	28 years, 2 months ago (June 1, 1997)

Funders 0

None

BibTeX

@article{Pinter_1997, title={Effects of 4-Aminopyridine on Muscle and Motor Unit Force in Canine Motor Neuron Disease}, volume={17}, ISSN={1529-2401}, url={http://dx.doi.org/10.1523/jneurosci.17-11-04500.1997}, DOI={10.1523/jneurosci.17-11-04500.1997}, number={11}, journal={The Journal of Neuroscience}, publisher={Society for Neuroscience}, author={Pinter, M. J. and Waldeck, R. F. and Cope, T. C. and Cork, L. C.}, year={1997}, month=jun, pages={4500–4507} }

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