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Angiotensin receptor type 1 antagonists protect against neuronal injury induced by oxygen-glucose depletion

X Wu1, T Kihara, H Hongo

  • 1Department of Neuroscience for Drug Discovery, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.

British Journal of Pharmacology
|August 20, 2010
PubMed
Abstract

Insights

Blocking angiotensin receptor type 1 (AT(1)) protects neurons from ischemic injury by upregulating glutamate transporter 1 (GLT-1). This mechanism enhances glutamate uptake and reduces damage, offering a potential therapeutic strategy for stroke.

Area of Science:

  • Neuroscience
  • Pharmacology
  • Cell Biology

Background:

  • Clinical trials suggest angiotensin receptor type 1 (AT(1)) blockade improves ischemic outcomes.
  • The precise mechanisms behind AT(1) blockade's protective effects remain unclear.
  • This study investigates AT(1) antagonists' neuroprotective effects against in vitro ischemic injury.

Purpose of the Study:

  • To elucidate the mechanism of AT(1) receptor antagonists in protecting neurons from ischemic insult.
  • To examine the role of AT(1) receptor antagonists in regulating glutamate transporter 1 (GLT-1) expression and activity.
  • To assess the impact of AT(1) receptor stimulation on neuronal damage and GLT-1 function.

Main Methods:

  • Primary rat neuron-astrocyte co-cultures and pure astrocyte cultures were subjected to oxygen-glucose depletion (OGD) to model ischemic injury.
  • AT(1) receptor antagonists (losartan, telmisartan) or agonists were used for pretreatment.
  • Lactate dehydrogenase release, glutamate uptake, reactive oxygen species, and nitric oxide generation were measured.
  • Protein and mRNA levels of GLT-1 were analyzed using immunoblot and real-time PCR.

Main Results:

  • AT(1) receptor agonists exacerbated OGD-induced damage, while antagonists attenuated it.
  • AT(1) receptor antagonists reduced OGD-induced glutamate release, ROS, and nitric oxide generation.
  • AT(1) receptor antagonists significantly enhanced GLT-1 expression and glutamate uptake activity, whereas agonists impaired them.
  • AT(1) receptor stimulation suppressed GLT-1 expression at both protein and mRNA levels.

Conclusions:

  • Suppression of AT(1) receptor signaling upregulates GLT-1.
  • Increased GLT-1 expression and function ameliorate ischemic injury in neurons.
  • AT(1) receptor antagonists offer a potential therapeutic strategy for ischemic conditions by modulating GLT-1.

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