Platelet-mediated changes to neuronal glutamate receptor expression at sites of microthrombosis following experimental subarachnoid hemorrhage

Joshua D. Bell, Theresa C urrier Thomas, Elliot Lass, Jinglu Ai, Hoyee Wan, Jonathan Lifshitz, Andrew J. Baker, R. Loch Macdonald

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

OBJECT: Glutamate is important in the pathogenesis of brain damage after cerebral ischemia and traumatic brain injury. Notably, brain extracellular and cerebrospinal fluid as well as blood glutamate concentrations increase after experimental and clinical trauma. While neurons are one potential source of glutamate, platelets also release glutamate as part of their recruitment and might mediate neuronal damage. This study investigates the hypothesis that platelet microthrombi release glutamate that mediates excitotoxic brain injury and neuron dysfunction after subarachnoid hemorrhage (SAH).

METHODS: The authors used two models, primary neuronal cultures exposed to activated platelets, as well as a whole-animal SAH preparation. Propidium iodide was used to evaluate neuronal viability, and surface glutamate receptor staining was used to evaluate the phenotype of platelet-exposed neurons.

RESULTS: The authors demonstrate that thrombin-activated platelet-rich plasma releases glutamate, at concentrations that can exceed 300 μM. When applied to neuronal cultures, this activated plasma is neurotoxic, and the toxicity is attenuated in part by glutamate receptor antagonists. The authors also demonstrate that exposure to thrombin-activated platelets induces marked downregulation of the surface glutamate receptor glutamate receptor 2, a marker of excitotoxicity exposure and a possible mechanism of neuronal dysfunction. Linear regression demonstrated that 7 days after SAH in rats there was a strong correlation between proximity to microthrombi and reduction of surface glutamate receptors.

CONCLUSIONS: The authors conclude that platelet-mediated microthrombosis contributes to neuronal glutamate receptor dysfunction and might mediate brain injury after SAH.

Original languageEnglish (US)
Pages (from-to)1424-1431
Number of pages8
JournalJournal of Neurosurgery
Volume121
Issue number6
DOIs
StatePublished - Dec 1 2014

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Glutamate Receptors
Subarachnoid Hemorrhage
Glutamic Acid
Blood Platelets
Neurons
Thrombin
Brain Injuries
Excitatory Amino Acid Antagonists
Platelet-Rich Plasma
Propidium
Extracellular Fluid
Brain
Brain Ischemia
Cerebrospinal Fluid
Linear Models
Down-Regulation
Staining and Labeling
Phenotype
Wounds and Injuries

Keywords

  • BSA = bovine serum albumin
  • CNQX = 6-cyano-7-nitroquinoxaline-2,3-dione
  • D-AP5 = D-(-)-2-Amino-5-phosphonopentanoic acid
  • DAB = 3,3′-diaminobenzidine
  • FAST = Fast Analytical Sensing Technology
  • GluR2 = glutamate receptor 2
  • glutamate receptor expression
  • LTP = long-term potentiation
  • MEA = microelectrode array
  • microthrombi
  • PBS = phosphate-buffered saline
  • platelet
  • RFU = relative fluorescence unit
  • SAH = subarachnoid hemorrhage
  • SEM = standard error of the mean
  • subarachnoid hemorrhage
  • TA-PrP = thrombin-activated plateletrich plasma
  • traumatic brain injury
  • vascular disorders

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Platelet-mediated changes to neuronal glutamate receptor expression at sites of microthrombosis following experimental subarachnoid hemorrhage. / Bell, Joshua D.; Thomas, Theresa C urrier; Lass, Elliot; Ai, Jinglu; Wan, Hoyee; Lifshitz, Jonathan; Baker, Andrew J.; Macdonald, R. Loch.

In: Journal of Neurosurgery, Vol. 121, No. 6, 01.12.2014, p. 1424-1431.

Research output: Contribution to journalArticle

Bell, Joshua D. ; Thomas, Theresa C urrier ; Lass, Elliot ; Ai, Jinglu ; Wan, Hoyee ; Lifshitz, Jonathan ; Baker, Andrew J. ; Macdonald, R. Loch. / Platelet-mediated changes to neuronal glutamate receptor expression at sites of microthrombosis following experimental subarachnoid hemorrhage. In: Journal of Neurosurgery. 2014 ; Vol. 121, No. 6. pp. 1424-1431.
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AU - Bell, Joshua D.

AU - Thomas, Theresa C urrier

AU - Lass, Elliot

AU - Ai, Jinglu

AU - Wan, Hoyee

AU - Lifshitz, Jonathan

AU - Baker, Andrew J.

AU - Macdonald, R. Loch

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N2 - OBJECT: Glutamate is important in the pathogenesis of brain damage after cerebral ischemia and traumatic brain injury. Notably, brain extracellular and cerebrospinal fluid as well as blood glutamate concentrations increase after experimental and clinical trauma. While neurons are one potential source of glutamate, platelets also release glutamate as part of their recruitment and might mediate neuronal damage. This study investigates the hypothesis that platelet microthrombi release glutamate that mediates excitotoxic brain injury and neuron dysfunction after subarachnoid hemorrhage (SAH).METHODS: The authors used two models, primary neuronal cultures exposed to activated platelets, as well as a whole-animal SAH preparation. Propidium iodide was used to evaluate neuronal viability, and surface glutamate receptor staining was used to evaluate the phenotype of platelet-exposed neurons.RESULTS: The authors demonstrate that thrombin-activated platelet-rich plasma releases glutamate, at concentrations that can exceed 300 μM. When applied to neuronal cultures, this activated plasma is neurotoxic, and the toxicity is attenuated in part by glutamate receptor antagonists. The authors also demonstrate that exposure to thrombin-activated platelets induces marked downregulation of the surface glutamate receptor glutamate receptor 2, a marker of excitotoxicity exposure and a possible mechanism of neuronal dysfunction. Linear regression demonstrated that 7 days after SAH in rats there was a strong correlation between proximity to microthrombi and reduction of surface glutamate receptors.CONCLUSIONS: The authors conclude that platelet-mediated microthrombosis contributes to neuronal glutamate receptor dysfunction and might mediate brain injury after SAH.

AB - OBJECT: Glutamate is important in the pathogenesis of brain damage after cerebral ischemia and traumatic brain injury. Notably, brain extracellular and cerebrospinal fluid as well as blood glutamate concentrations increase after experimental and clinical trauma. While neurons are one potential source of glutamate, platelets also release glutamate as part of their recruitment and might mediate neuronal damage. This study investigates the hypothesis that platelet microthrombi release glutamate that mediates excitotoxic brain injury and neuron dysfunction after subarachnoid hemorrhage (SAH).METHODS: The authors used two models, primary neuronal cultures exposed to activated platelets, as well as a whole-animal SAH preparation. Propidium iodide was used to evaluate neuronal viability, and surface glutamate receptor staining was used to evaluate the phenotype of platelet-exposed neurons.RESULTS: The authors demonstrate that thrombin-activated platelet-rich plasma releases glutamate, at concentrations that can exceed 300 μM. When applied to neuronal cultures, this activated plasma is neurotoxic, and the toxicity is attenuated in part by glutamate receptor antagonists. The authors also demonstrate that exposure to thrombin-activated platelets induces marked downregulation of the surface glutamate receptor glutamate receptor 2, a marker of excitotoxicity exposure and a possible mechanism of neuronal dysfunction. Linear regression demonstrated that 7 days after SAH in rats there was a strong correlation between proximity to microthrombi and reduction of surface glutamate receptors.CONCLUSIONS: The authors conclude that platelet-mediated microthrombosis contributes to neuronal glutamate receptor dysfunction and might mediate brain injury after SAH.

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KW - SEM = standard error of the mean

KW - subarachnoid hemorrhage

KW - TA-PrP = thrombin-activated plateletrich plasma

KW - traumatic brain injury

KW - vascular disorders

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