ly-379268 and Hypoxia

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

We examined the expression of mGlu2/3 metabotropic glutamate receptors in the retina of the goldfish Carassius auratus. mGlu2/3 receptors were expressed in all retinal layers internal to the photoreceptor layer, particularly in the outer and inner nuclear layers. Although the goldfish brain is able to tolerate prolonged periods of anoxia, we examined whether anoxia could induce retinal damage. Three hours of anoxia induced in the retina the development of apoptotic cell death, as assessed 48 h later by TUNEL staining. TUNEL-positive cells were particularly found in the inner and outer nuclear layers, and were also present in the ganglion cell layer. Pharmacological activation of mGlu2/3 receptors by systemic injection of LY379268 (0.5 mg/kg, i.p., 15 min before the onset of anoxia) substantially protected retinas against anoxia-induced cell death. In contrast, systemic injection of the mGlu2/3 receptor antagonist, LY341495 (1 mg/kg, i.p., 15 min before the onset of anoxia), significantly amplified cell death. Finally, as mGlu2/3 receptors are implicated in the control of extracellular glutamate concentrations, we examined the stimulation of glutamate release in isolated goldfish retinas. Depolarizing medium containing 30 mM KCl led to a significant increase in glutamate release, which was substantially reduced by LY379268. We conclude that activation of mGlu2/3 receptors may provide a major defensive mechanism against ischemic/anoxic retinal damage.

Topics: Amino Acids; Animals; Apoptosis; Blotting, Western; Bridged Bicyclo Compounds, Heterocyclic; Excitatory Amino Acid Antagonists; Glutamic Acid; Goldfish; Hypoxia; Hypoxia, Brain; Immunohistochemistry; In Situ Nick-End Labeling; Models, Animal; Receptors, Metabotropic Glutamate; Retina; Retinal Diseases; Telencephalon; Xanthenes

Neuroprotective effects of a Group II metabotropic glutamate receptor agonist, LY379268, were examined in a neonatal rat model of hypoxia-ischemia (unilateral common carotid artery ligation followed by hypoxic exposure for 1.5h in 7-day-old rat pups). LY379268 administered 5 min after hypoxic exposure (2, 5, or 10 mg/kg, i.p.) significantly reduced brain injury as measured by reductions in the ipsilateral brain weight and in CA1 hippocampal neuron density. The significant neuroprotective effects were also observed when this compound (5 mg/kg) was administered 30 min, but not 60 min, after hypoxic exposure. The neonatal hypoxia-ischemia (HI) procedure significantly increased caspase-3 activity and induced DNA fragmentation in the ipsilateral cortex compared with that in the contralateral cortex 24 and 72h after the insult, respectively. LY379268 did not prevent this increase in caspase-3 activity and DNA fragmentation in the ipsilateral cortex. These results suggest that activation of Group II metabotropic glutamate receptors may provide neuroprotection against HI brain injury. However, blockade of caspase-3 activation and the apoptotic pathway appears not to be involved in the neuroprotective effects of LY379268 observed in the neonatal rat model of HI.

Topics: Amino Acids; Animals; Animals, Newborn; Brain; Brain Ischemia; Bridged Bicyclo Compounds, Heterocyclic; Caspase 3; Caspases; Cell Count; DNA Fragmentation; Drug Administration Schedule; Excitatory Amino Acid Agonists; Hippocampus; Hypoxia; Neurons; Neuroprotective Agents; Rats; Receptors, Metabotropic Glutamate