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Dimethylglycine and reduction of mortality in penicillin-induced seizures.

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Refwences
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inclusion disease in identical twins. Ann Neurol 15:316-321,
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Dimethylglycine and
Reduction of Mortdty in
Penicibn-Induced Seizures
Thomas N. Ward, MD, Edward B. Smith, AB,
and Alexander G. Reeves, MD
Recently reports have been published concerning the possible efficacy of dimethylglycine (DMG) in treating human
epilepsy [3, 5,6]. T o our knowledge, no controlled study has
verified a beneficial effect of DMG on seizure activity. We
report a preliminary study showing that DMG decreases
mortality in rats with penicillin-induced seizures.
Fifteen-week-old, 300-gm, white female Sprague-Dawley
rats (Camm) were studied. A control group of 36 rats was
matched with another group of 36 DMG-treated rats. The
DMG-treated group received DMG dissolved in water
(0.026 mg per milliliter) taken ad lib. for two weeks. They
consumed 120 to 240 ml per day. Both groups were then
divided into six groups of 6 rats each and given intraperitoneal penicillin G in doses ranging from 2,200 to
4,200 units per gram. Survival, which was our end point, was
measured at 12 hours after injection. Preliminary studies had
shown that deaths beyond 12 hours were delayed a number
of days, were unusual, and were related to peritonitis.
There was a substantial difference in survival between the
control group and the DMG-treated group. Only 1 rat in the
DMG-treated group died, compared with 18 in the control
group (chi-square test = 20.66, 1 df, p < 0.001). At doses
above 2,200 units of penicillin G per gram, all rats showed
typical periods of lethargy, myoclonic jerks, posturing, and
ataxia of gait [2, 51.
Using these doses, it is shown that DMG significantly reduces mortality associated with penicillin-induced seizures in
rats. It is well documented that intraperitoneal penicillin in
doses from 600 to 1,200 units per gram in rats can cause
electroclinical epilepsy that may last more than five hours [ 1,
2). Larger doses produce a more prolonged and severe syndrome that terminates in death within twelve hours in a high
percentage of animals, as described herein.
Glycine is an inhibitory neurotransmitter believed to act
mainly in the medulla and spinal cord [7). Its concentration
in human cerebropinal fluid is approximately 2% of that in
plasma 14). DMG, being less polar, might cross the bloodbrain barrier better [ S ) . Its mode of action in the central
nervous system (CNS) is speculative, perhaps being converted to glycine or acting directly on receptors as DMG.
Previous reports on the anticonvulsant effect of DMG in
humans have either been anecdotal or failed to show efficacy
[5, 61. While status epilepticus in rats may not be analogous
to the human condition 111, it is intriguing that we found
such a dramatic protective effect. It may be that DMG alters
the seizure threshold and enhances survival by raising glycine
concentration or activity in the CNS. Further studies on both
the electroencephalographic activity and CNS glycine concentration will be of interest.
Prosser Neurology Research kboratoty
Dartmouth Medical School
Hanwer, NH 03756
Supported by the David Prosser Research Fund.
The authors wish to thank Edith Coates who typed the manuscript
and Jane Barren, MSc, who performed the statistical analysis.
References
1. Avoli M: Electroencephalographic and pathophysiologic features
of rat parented penicillin epilepsy. Exp Neurol 69:373-382,
1980
2. Fariello R: Parented penicillin in rats: an experimental model of
multifocal epilepsy. Epilepsia 17:217-222, 1976
3. Herbert V: N,N-Dimethylglycine for epilepsy. N Engl J Med
308:527-528, 1983
4. McGale EHF, Pye IF, Stonier C, et al: Studies of the interrelationship between cerebrospinal fluid and plasma amino acid
concentrations in normal individuals.J Neurochem 29:291-297,
1977
5. Roach ES, Carlin L: N,N-Dimethylglycine For epilepsy. N Engl J
Med 307:1081-1082, 1982
6. Roach ES, Gibson P Failure of N,N-dimethylglycine in epilepsy.
Ann Neurol 14:347, 1983
7. Tebecis AK, DiMaria A: Strychnine-sensitive inhibition in the
medullary reticular formation: evidence for glycine as an inhibitory transmitter. Brain Res 40:373-383, 1972
Notes and Letters
213
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induced, dimethylglycine, reduction, seizure, mortality, penicillium
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