Atorvastatin Prevents Glutamate Uptake Reduction Induced by Quinolinic Acid Via MAPKs Signaling.

Statins have been shown to promote neuroprotection in a wide range of neurological disorders. However, the mechanisms involved in such effects of statins are not fully understood. Quinolinic acid (QA) is a neurotoxin that induces seizures when infused in vivo and promotes glutamatergic excitotoxicity in the central nervous system. The aim of this study was to evaluate the putative glutamatergic mechanisms and the intracellular signaling pathways involved in the atorvastatin neuroprotective effects against QA toxicity. Atorvastatin (10 mg/kg) treatment for 7 days prevented the QA-induced decrease in glutamate uptake, but had no effect on increased glutamate release induced by QA. Moreover, atorvastatin treatment increased the phosphorylation of ERK1 and prevented the decrease in Akt phosphorylation induced by QA. Neither atorvastatin treatment nor QA infusion altered glutamine synthetase activity or the levels of phosphorylation of p38(MAPK) or JNK1/2 during the evaluation. Inhibition of MEK/ERK signaling pathway, but not PI3K/Akt signaling, abolished the neuroprotective effect of atorvastatin against QA-induced decrease in glutamate uptake. Our data suggest that atorvastatin protective effects against QA toxicity are related to modulation of glutamate transporters via MAPK/ERK signaling pathway.

N-methyl-D-aspartate preconditioning prevents quinolinic acid-induced deregulation of glutamate and calcium homeostasis in mice hippocampus.

The search for new therapeutic strategies through modulation of glutamatergic transmission using effective neuroprotective agents is essential. Glutamatergic excitotoxicity is a major factor common to neurodegenerative diseases and in acute events such as cerebral ischemia, traumatic brain injury and epilepsy. We have previously demonstrated that N-methyl-D-aspartate (NMDA) preconditioning in mice showed 50 % of protection against seizures and full protection against damage to neuronal tissue induced by quinolinic acid (QA). In this study, cellular and molecular mechanisms involved on NMDA preconditioning and neuroprotection were investigated in mice treated with NMDA 24 h before QA insult. Calcium uptake and D-aspartate release from hippocampal slices obtained from mice treated with NMDA plus QA and not displaying seizures (protected mice) were similar to control (saline) or NMDA preconditioned mice. Increased calcium uptake and glutamate release is evidenced in unprotected (convulsed) mice as well as QA control, demonstrating that calcium and glutamate are involved in NMDA-induced preconditioning. Increased glutamate release evoked by QA was blocked by MK-801, whereas increased calcium uptake was abolished by voltage-dependent calcium channels inhibitors, but not MK-801. NMDA preconditioning is effective in normalizing the deregulation of glutamate transport and calcium homeostasis evoked by QA due to aberrant NMDA receptors activation that culminates in seizures and hippocampal cells damage.

Guanosine is neuroprotective against oxygen/glucose deprivation in hippocampal slices via large conductance Ca²+-activated K+ channels, phosphatidilinositol-3 kinase/protein kinase B pathway activation and glutamate uptake.

Guanine derivatives (GD) have been implicated in many relevant brain extracellular roles, such as modulation of glutamate transmission and neuronal protection against excitotoxic damage. GD are spontaneously released to the extracellular space from cultured astrocytes and during oxygen/glucose deprivation (OGD). The aim of this study has been to evaluate the potassium channels and phosphatidilinositol-3 kinase (PI3K) pathway involvement in the mechanisms related to the neuroprotective role of guanosine in rat hippocampal slices subjected to OGD. The addition of guanosine (100 µM) to hippocampal slices subjected to 15 min of OGD and followed by 2 h of re-oxygenation is neuroprotective. The presence of K+ channel blockers, glibenclamide (20 µM) or apamin (300 nM), revealed that neuroprotective effect of guanosine was not dependent on ATP-sensitive K+ channels or small conductance Ca²+-activated K+ channels. The presence of charybdotoxin (100 nM), a large conductance Ca²+-activated K+ channel (BK) blocker, inhibited the neuroprotective effect of guanosine. Hippocampal slices subjected to OGD and re-oxygenation showed a significant reduction of glutamate uptake. Addition of guanosine in the re-oxygenation period has blocked the reduction of glutamate uptake. This guanosine effect was inhibited when hippocampal slices were pre-incubated with charybdotoxin or wortmanin (a PI3K inhibitor, 1 µM) in the re-oxygenation period. Guanosine promoted an increase in Akt protein phosphorylation. However, the presence of charybdotoxin blocked such effect. In conclusion, the neuroprotective effect of guanosine involves augmentation of glutamate uptake, which is modulated by BK channels and the activation of PI3K pathway. Moreover, neuroprotection caused by guanosine depends on the increased expression of phospho-Akt protein.