Stroke Drug Development Targeting Glutamate

Glutamate is the major excitatory neurotransmitter in the central nervous system. During ischemic injury, increased glutamate release with impaired uptake leads to toxic accumulation of extracellular glutamates, resulting in overstimulation of ionotropic glutamate receptors, which can lead to neuronal cell death. As a result, there has been a proliferation of studies to treat stroke by limiting glutamate-induced excitotoxicity. Since glutamate release occurs within minutes after the onset of ischemic stroke, this poses a significant challenge for the development of stroke drugs targeting glutamate. The two main solutions are rapid administration after the onset of ischemic stroke and enhanced clearance of glutamate in the extracellular space. Therefore, Ace Neuroscience provides a one-stop research platform for the development of stroke drugs that enhance extracellular glutamate clearance.

Cascade of glutamate excitotoxicity in ischemic stroke.Fig. 1 Cascade of glutamate excitotoxicity in ischemic stroke.

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Screening of Active Molecules for Glutamate Removal

Removal of extracellular glutamate to limit its induced excitotoxicity is an important way to treat stroke. Therefore, screening can clear extracellular glutamate then is the first step to start the study.

  • Given that glutamate transporters are the most direct pathways of action, such as the astrocyte transporters GLAST and GLT-1 and the neuronal transporter EAAC1, which can directly modulate glutamate-induced excitotoxicity, Ace Neuroscience provides various neuronal cells to screen for drug candidates that modulate glutamate transporters to clear extracellular glutamate. Stable animal models have also been established by antisense oligonucleotide and gene knockout to further validate the results of in vitro models while providing relevant content assay services.
  • Second, some enzymes closely related to glutamate, such as glutamate oxaloacetate transaminase-1 (GOT-1), have a key role in regulating blood glutamate levels, so we offer in vitro and in vivo gene knockout or gene silencing models for screening candidate active drugs. We also provide ELISA, western blotting, biochemical assays, and other services to identify the activity of drug candidates.
  • Finally, we can screen potential small molecules that inhibit glutamate uptake through in vitro and in vivo models. Based on our ultra-large small molecules library, including compound libraries, natural product libraries, and fragment libraries, we can rapidly screen a large number of small molecules and then further validate their glutamate scavenging activity in combination with animal models.
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Evaluation of The Role of Candidates in Stroke

After screening for drug candidates with glutamate scavenging activity, it is important to test the effect of these drug candidates on stroke recovery. In this regard, we offer different in vitro and in vivo stroke models targeting glutamate and also provide appropriate testing services for the above models, including but not limited to understanding concentration-effect relationships, and biomarker analysis such as GLAST, GLT-1, EAAC1, and glutamate clearance.

Depending on the design of the experiment, we offer a personalized and customized service for the development of stroke drugs targeting glutamate. If you would like to learn more about our services, please feel free to contact us.

References
  1. Wang, Y.Harvey, B. K., Reducing excitoxicity with glutamate transporter-1 to treat stroke. Brain Circ, 2016. 2(3): p. 118-120.
  2. Zaghmi, A., et al., Sustained blood glutamate scavenging enhances protection in ischemic stroke. Commun Biol, 2020. 3(1): p. 729.
All of our services are intended for preclinical research use only and cannot be used to diagnose, treat or manage patients.
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