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Frequency-dependent action of phenytoin on lamprey spinal axons
Abstract:
The effect of the antiepileptic drug phenytoin (diphenylhydantoin, DPH) was tested on the conduction of intracellularly recorded action potentials in lamprey giant reticulospinal axons. When the isolated spinal cord was exposed to 80 microM DPH for up to 4 h, no significant effect was seen on the amplitude or conduction velocity of the action potential, although the maximum rate of rise was reduced from 247.8 to 149.6 V/s after 1 h. However, at higher stimulus frequencies both the amplitude and conduction velocity of the action potential were reduced progressively during a 500 stimulus train. The reduction was greater the higher the stimulus frequency, and was reversed upon return to 1 Hz stimulation. At frequencies greater than 40 Hz an all-or-none block developed. This also developed sooner the higher the stimulus frequency. Axons bathed in drug-free solutions did not show this effect at stimulus frequencies up to 100 Hz. Similar effects were seen in 16 microM DPH when the spinal cord was exposed to the drug overnight. This is close to the human therapeutic CSF level. The frequency-dependent depression of the action potential was greatly potentiated by increasing the extracellular potassium concentration from 2.1 to 5 mM. Under these conditions the axons rapidly developed block at stimulus frequencies as low as 2 Hz, and this was not reversible during a 5 h wash. In the absence of DPH, 5 mM potassium produced a 4-5 mV depolarization, but did not induce a frequency-dependent block. This effect of potassium may be important to the therapeutic effect of DPH because during epileptiform activity the extracellular K+ increases several fold.
Insights
The antiepileptic drug phenytoin (diphenylhydantoin, DPH) impairs action potential conduction in lamprey axons at higher frequencies. This effect is exacerbated by increased extracellular potassium, suggesting a mechanism relevant to epilepsy treatment.
Area of Science:
- Neuroscience
- Pharmacology
- Neurophysiology
Background:
- Antiepileptic drugs are crucial for managing seizure disorders.
- Phenytoin (diphenylhydantoin, DPH) is a widely used antiepileptic medication.
- Understanding the precise mechanisms of DPH action at the axonal level is essential for optimizing its therapeutic efficacy.
Purpose of the Study:
- To investigate the effects of phenytoin (DPH) on the conduction of action potentials in lamprey giant reticulospinal axons.
- To determine if DPH induces frequency-dependent alterations in action potential propagation.
- To explore the interaction between DPH and extracellular potassium concentration on axonal excitability.
Main Methods:
- Intracellular recordings of action potentials in isolated lamprey spinal cord axons.
- Application of phenytoin (DPH) at concentrations of 80 microM and 16 microM.
- Stimulation of axons at various frequencies (1 Hz to 100 Hz) and assessment of action potential parameters (amplitude, conduction velocity, rate of rise).
- Manipulation of extracellular potassium concentration (2.1 mM to 5 mM).
Main Results:
- Phenytoin (DPH) at 80 microM reduced the maximum rate of rise of action potentials but did not affect amplitude or conduction velocity at low frequencies.
- At higher stimulus frequencies (>40 Hz), DPH caused a progressive, frequency-dependent reduction in action potential amplitude and conduction velocity, leading to block.
- This frequency-dependent depression was significantly potentiated by increased extracellular potassium (5 mM), inducing rapid block even at low frequencies (2 Hz).
- Potassium alone (5 mM) caused depolarization but not frequency-dependent block in the absence of DPH.
Conclusions:
- Phenytoin (DPH) exhibits frequency-dependent effects on axonal conduction, potentially contributing to its therapeutic action by limiting excessive neuronal firing.
- The potentiation of DPH's effects by elevated extracellular potassium suggests a synergistic mechanism relevant to the hyperexcitable state during seizures.
- These findings highlight the importance of extracellular ion concentrations in modulating the efficacy of antiepileptic drugs like phenytoin.