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The dose-response relationship and therapeutic window for dizocilpine (MK-801) in a rat focal ischaemia model
R H Hatfield1, R Gill, C Brazell
1Merck, Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, UK.
Abstract:
The purpose of the present study was to examine the dose-response relationship and the maximum time for which effective therapy could be delayed for the N-methyl-D-aspartate antagonist dizocilpine (MK-801) as a neuroprotective agent in a permanent focal ischaemia model in the rat. The ED50 for dizocilpine in the amelioration of cortical damage in this model was found to be approximately 0.3 mg/kg (single i.p. dose, 30 min post onset of ischaemia) and significant protection was only obtained when therapy (3 mg/kg i.p.) was delayed for one hour or less after the onset of ischaemia. In a further experiment, dizocilpine 3 mg/kg i.p., produced a peak plasma level of 44 ng/ml and had a t1/2 elimination of 1.65 h.
Insights
This study investigated dizocilpine (MK-801) as a neuroprotective agent. Effective neuroprotection against cortical damage in rats was observed when treatment was initiated within one hour of ischemic onset.
Area of Science:
- Neuroscience
- Pharmacology
Background:
- Ischemic stroke leads to significant neuronal damage.
- N-methyl-D-aspartate (NMDA) receptor antagonists show potential for neuroprotection.
Purpose of the Study:
- To determine the dose-response relationship of dizocilpine (MK-801) for neuroprotection.
- To establish the maximum therapeutic delay for dizocilpine (MK-801) in a focal ischemia model.
Main Methods:
- A permanent focal ischemia model was induced in rats.
- Dizocilpine (MK-801) was administered at varying doses and time points post-ischemia.
- Cortical damage was assessed to evaluate neuroprotective effects.
- Pharmacokinetic parameters including peak plasma levels and half-life were determined.
Main Results:
- The estimated 50% effective dose (ED50) for dizocilpine (MK-801) was approximately 0.3 mg/kg.
- Significant neuroprotection was achieved only when treatment (3 mg/kg) was initiated within one hour of ischemic onset.
- A 3 mg/kg dose resulted in a peak plasma concentration of 44 ng/ml and a half-life of 1.65 hours.
Conclusions:
- Dizocilpine (MK-801) demonstrates dose-dependent neuroprotective effects in a rat model of focal ischemia.
- Timely administration of dizocilpine (MK-801) is critical for effective neuroprotection, with a therapeutic window of approximately one hour.