Inhibition of glutamate release via recovery of ATP levels accounts for a neuroprotective effect of aspirin in rat cortical neurons exposed to oxygen-glucose deprivation.
OBJECTIVE
Aspirin is preventive against stroke not only because of its antithrombotic properties but also by other direct effects. The aim of this study was to elucidate its direct neuroprotective effects.


METHODS
Viability parameters, glutamate release and uptake, and ATP levels were measured in cultured cortical neurons exposed to oxygen-glucose deprivation (OGD). In addition, ATP levels and oxygen consumption were studied in isolated brain mitochondria or submitochondrial particles.


RESULTS
Aspirin inhibited OGD-induced neuronal damage at concentrations lower (0.3 mmol/L) than those reported to act via inhibition of the transcription factor nuclear factor-kappaB (which are >1 mmol/L), an effect that correlated with the inhibition caused by aspirin on glutamate release. This effect was shared by sodium salicylate but not by indomethacin, thus excluding the involvement of cyclooxygenase. A pharmacological dissection of the components involved indicated that aspirin selectively inhibits the increase in extracellular glutamate concentration that results from reversal of the glutamate transporter, a component of release that is due to ATP depletion. Moreover, aspirin-afforded neuroprotection occurred in parallel with a lesser decrease in ATP levels after OGD. Aspirin elevated ATP levels not only in intact cortical neurons but also in isolated brain mitochondria, an effect concomitant with an increase in NADH-dependent respiration by brain submitochondrial particles.


CONCLUSIONS
Taken together, our present findings show a novel mechanism for the neuroprotective effects of aspirin, which takes place at concentrations in the antithrombotic-analgesic range, useful in the management of patients with high risk of ischemic events.
De Cristóbal
Javier
J
Departamento de Farmacología and Instituto de Farmacología y Toxicología, Consejo Superior de Investigaciones Científicas, Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain.
Cárdenas
Antonio
A
Lizasoain
Ignacio
I
Leza
Juan Carlos
JC
Fernández-Tomé
Paz
P
Lorenzo
Pedro
P
Moro
M A
MA
D000255:Adenosine Triphosphate / Q000096:biosynthesis*; D000818:Animals; D001241:Aspirin / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D001921:Brain / Q000378:metabolism*; D002545:Brain Ischemia / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D015687:Cell Hypoxia; D019069:Cell Respiration / Q000187:drug effects; D002478:Cells, Cultured; D005947:Glucose / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010101:Oxygen Consumption; D051381:Rats; D017208:Rats, Wistar
D018696:Neuroprotective Agents; D018698:Glutamic Acid; D000255:Adenosine Triphosphate; D005947:Glucose; D001241:Aspirin