Effects of LY379268, a Selective Group II Metabotropic Glutamate Receptor Agonist on EEG Activity, Cortical Perfusion, Tissue Damage, and Cortical Glutamate, Glucose, and Lactate Levels in Brain-Injured Rats

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Abstract
Activating presynaptic group II metabotropic glutamate (mGlu II) receptors reduces synaptic glutamate release. Attenuating glutamatergic transmission without blocking ionotropic glutamate receptors, thus avoiding unfavorable psychomimetic side effects, makes mGlu II receptor agonists a promising target in treating brain-injured patients. Neuroprotective effects of LY379268 were investigated in rats following controlled cortical impact injury (CCI). At 30 min after CCI, rats received a single intraperitoneal injection of LY379268 (10 mg/kg/body weight) or NaCl. Changes in EEG activity and pericontusional cortical perfusion were determined before trauma, at 4, 24, and 48 h, and 7 days after CCI. Brain edema and contusion volume were determined at 24 h and 7 days after CCI, respectively. Before brain removal pericontusional cortical glutamate, glucose, and lactate were measured via microdialysis. During the early period following CCI, EEG activity and cortical perfusion were significantly reduced in rats receiving LY379268. At 7 days, cortical perfusion was significantly increased in rats treated with LY379268, while EEG activity was depressed as in control rats. While brain edema remained unchanged at 24 h, cortical contusion was significantly decreased by 56% at 7 days after CCI. Cortical glutamate, glucose, and lactate were not influenced. Significant reductions in EEG activity and contusion volume by LY379268 do not appear mediated by attenuated excitotoxicity and energetic impairment. Overall, an additional decrease in cortical perfusion seems to interfere with the anti-edematous potential of LY379268 during the early period following CCI, while an increase in perfusion in LY379268-treated rats at 7 days might contribute to tissue protection.