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Behavioral recovery patterns in rats receiving the NMDA receptor antagonist MDL 100,453 immediately post-stroke
C G Markgraf1, M P Johnson, D L Braun
1Hoechst Marion Roussel Inc., Cincinnati, OH 45215-6300, USA.
Abstract:
Rats were given MDL 100,453 ((R)-4-Oxo-5-phosphononorvaline) in a pre-determined neuroprotective dose consisting of a bolus of 24.8 mg/kg followed by an infusion of 1.05 mg/kg*h for 24 h (MDL group; n = 8) or saline of the same volume (SALINE group; n = 8) 30 min. after the onset of a 90 min. period of middle cerebral artery occlusion. Eight animals underwent SHAM surgery. Rats were evaluated post-operatively for 14 days using seven neurological tests, including water maze. SALINE animals exhibited a pattern of neurological impairment compared to SHAMs (poor performance in five of the six motor/reflex tests) peaking five days post-injury. Relative to the SALINE group, the MDL group exhibited significantly improved outcome on two of the tests and a pattern of improved behavior on the remainder of the battery. By day 14 post-ischemia, all groups exhibited recovery on the motor/reflex tests. Learning ability was disrupted in the SALINE group on days 17 and 18, whereas the MDL group's performance was not distinguishable from the SHAM group in the water maze. Thus, a neuroprotective dose of MDL 100,453 produced a pattern of behavioral sparing in the immediate post-ischemic days that was uniquely different than saline. The addition of behavioral outcome measures to histological neuroprotection data adds significantly to the ability to better evaluate a putative neuroprotective compound.
Insights
MDL 100,453 demonstrated neuroprotection in rats following stroke. This compound improved neurological function and learning ability, unlike saline treatment, highlighting its potential therapeutic value.
Area of Science:
- Neuroscience
- Pharmacology
- Stroke Research
Background:
- Ischemic stroke remains a leading cause of death and disability worldwide.
- Developing effective neuroprotective agents is critical for improving stroke outcomes.
- MDL 100,453 is a compound investigated for its potential neuroprotective properties.
Purpose of the Study:
- To evaluate the neuroprotective effects of MDL 100,453 in a rat model of ischemic stroke.
- To assess the impact of MDL 100,453 on neurological deficits and learning ability post-stroke.
- To determine if behavioral outcomes complement histological data in evaluating neuroprotective compounds.
Main Methods:
- Rats underwent middle cerebral artery occlusion (MCAO) followed by administration of MDL 100,453 or saline.
- Neurological function was assessed for 14 days using seven tests, including the water maze.
- Behavioral sparing and learning recovery were compared between treatment groups and sham controls.
Main Results:
- Saline-treated rats showed significant neurological impairment compared to sham controls.
- MDL 100,453 treatment resulted in improved performance on motor/reflex tests and preserved learning ability in the water maze.
- Behavioral sparing was observed in the MDL 100,453 group during the immediate post-ischemic period.
Conclusions:
- A neuroprotective dose of MDL 100,453 significantly improved behavioral outcomes after ischemic stroke in rats.
- MDL 100,453 demonstrated efficacy in mitigating both motor deficits and cognitive impairment.
- Integrating behavioral assessments with histological data provides a more comprehensive evaluation of neuroprotective agents.