ly-379268 and Brain-Injuries

Birth asphyxia causes brain injury in neonates, but a fully successful treatment has yet to be developed. This study aimed to investigate the effect of group II mGlu receptors activation after experimental birth asphyxia (hypoxia-ischemia) on the expression of factors involved in apoptosis and neuroprotective neurotrophins. Hypoxia-ischemia (HI) on 7-day-old rats was used as an experimental model. The effects of intraperitoneal application of mGluR2 agonist LY379268 (5 mg/kg) and the specific mGluR3 agonist NAAG (5 mg/kg) (1 h or 6 h after HI) on apoptotic processes and initiation of the neuroprotective mechanism were investigated. LY379268 and NAAG applied shortly after HI prevented brain damage and significantly decreased pro-apoptotic Bax and HtrA2/Omi expression, increasing expression of anti-apoptotic Bcl-2. NAAG or LY379268 applied at both times also decreased HIF-1α formation. HI caused a significant decrease in BDNF concentration, which was restored after LY379268 or NAAG administration. HI-induced increase in GDNF concentration was decreased after administration of LY379268 or NAAG. Our results show that activation of mGluR2/3 receptors shortly after HI prevents brain damage by the inhibition of excessive glutamate release and apoptotic damage decrease. mGluR2 and mGluR3 agonists produced comparable results, indicating that both receptors may be a potential target for early treatment in neonatal HI.

Topics: Amino Acids; Animals; Animals, Newborn; Apoptosis; Asphyxia; Brain Injuries; Brain-Derived Neurotrophic Factor; Bridged Bicyclo Compounds, Heterocyclic; Dipeptides; Glial Cell Line-Derived Neurotrophic Factor; Hypoxia; Neuroprotective Agents; Rats; Receptors, Metabotropic Glutamate

The effects of group II mGluR activation by selective agonist (-)-2-oxa-4-aminobicyclo[3.1. 0]hexane-4,6-dicarboxylate (LY379268) were examined in a mouse model of controlled cortical impact (CCI)-induced brain injury and in primary neuronal/glial and neuronal cultures subjected to mechanical trauma. Systemic administration of LY379268 to mice at 30 min after CCI significantly improved both motor and cognitive recovery as compared with vehicle-treated control animals. LY379268 also significantly reduced cell death induced by mechanical injury in rat neuronal/glial and neuronal cultures, as measured by lactate dehydrogenase (LDH) release assay. The neuroprotective effect of LY379268 in vitro was abolished by co-administration of the mGluR2/3 antagonist (s)-alpha-ethylglutamic acid (EGLU); however, co-application of selective mGluR3 antagonist beta-N-acetyl-aspartyl-glutamate (NAAG) had no significant influence in the same system. Together, these findings demonstrate the neuroprotective activity of group II mGluR activation and underscore the role of the mGluR2 subtype for this effect.

Topics: Amino Acids; Animals; Brain Injuries; Bridged Bicyclo Compounds, Heterocyclic; Cell Culture Techniques; Dipeptides; Glutamates; Learning; Male; Mice; Mice, Inbred C57BL; Motor Activity; Neurons; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Receptors, Metabotropic Glutamate

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.

Topics: Amino Acids; Animals; Brain Edema; Brain Injuries; Bridged Bicyclo Compounds, Heterocyclic; Cerebral Cortex; Cerebrovascular Circulation; Disease Models, Animal; Electroencephalography; Glucose; Glutamic Acid; Lactic Acid; Male; Rats; Rats, Sprague-Dawley; Receptors, Metabotropic Glutamate; Time Factors