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Does It Have a Chronic Effect as Well as a Transient One?

M. Dearing Ward; Michael S. Forbes, PhD; T. R. Johns, MD

Arch Neurol. 1975;32(12):808-814.

Abstract
• Three groups of 200-gm rats were injected subcutaneously with neostigmine methylsulfate (1 mg/kg/day) for 7, 30, and 100 days. Electrophysiological changes were assessed in vitro, using microelectrode techniques to examine disphragm muscles of treated and untreated animals. Miniature end-plate potential (MEPP) amplitude decreased in neostigmine-treated preparations. Guanidine hydrochloride enhances transmitter release and increases MEPP frequency in control preparations. Neostigmine-treated animals examined between 6 to 72 hours after discontinuation of neostigmine therapy showed impaired response to the facilitating influence of guanidine. Recovery of response to guanidine was inversely related to length of treatment with neostigmine. Results of electron-microscopic examination of motor end-plates in treated animals revealed ultrastructural changes, including simplified end-plates, and, occasionally, multiple, separate, junctional regions. Therefore, the chronic administration of cholinesterase inhibitors in man may have a deleterious effect, as well as a transient beneficial one.

Author Affiliations
From the departments of neurology (Ms Ward and Dr Johns) and physiology (Dr Forbes), School of Medicine, University of Virginia, Charlottesville.

Footnotes
Accepted for publication Oct 14, 1974.

Reprint requests to the Department of Neurology, Box 147, University of Virginia School of Medicine, Charlottesville, VA 22901 (Ms Ward).

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