Scavenging of Excess Brain Glutamate following Ischemic Stroke

In 2011, Prof. Vivian Teichberg, a close friend and colleague at the Institute, passed away. Mirelman had recently retired and had helped Teichberg’s lab during Teichberg’s long illness. Weizmann President asked Mirelman to help  and continue the very promising scientific project of his deceased friend. The important objective of Teichberg was the development of a novel drug to significantly reduce the neurological damage following an ischemic cerebral stroke.

The premise of Teichberg was that after an ischemic stroke, brain cells die from lack of oxygen and spill out large quantities of glutamate. Excess extracellular glutamate  is toxic to healthy  brain cells and this increases the neurological damage. In animal models of stroke. Teichberg found that if he intravenously  injected a dose of the recombinant Glutamate oxaloacetate transaminase (rGOT) enzyme, it  dramatically lowered the glutamate levels in the blood, and this caused the exit of excess brain glutamate through the Brain Blood Barrier (BBB) into the blood. Rats with induced ischemic stroke that were treated in the first 3-4 hours, had minimal neurological damage in comparison to untreated rats. Mirelman together with Teichbergs’ group members, which included a Spanish collaborating  group in the University of  Santiago de Compostela  Medical School,  managed to interest a big Pharma Company to support this promising project.

The team corroborated and expanded Teichberg’s stroke studies and  prepared recombinant human GOT in gram quantities at a Biotech company in Lithuania.  The Company seeked FDA approval for human clinical trials  but were told to first perform further studies in macaques. Unfortunately the French bio-tech company contracted by the Pharma Company to perform the stroke studies in macaques , failed in its attempts and the financial support by the Pharma Company was terminated in 2020. The Spanish collaborators did not despair and found another corporate supporter to continue this exciting project.

D. Mirelman .Joint Publications on Ischemic Stroke and removal of excess Brain glutamate. (2013-2024)

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    Glutamate oxaloacetate transaminase: a new key in the dysregulation of glutamate in migraine patients.
    Cephalalgia. 2013 Oct;33(14):1148-54
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    Human recombinant glutamate oxaloacetate transaminase 1 (GOT1) supplemented with oxaloacetate induces a protective effect after cerebral ischemia.
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    Blood glutamate grabbing does not reduce the hematoma in an intracerebral hemorrhage model but is a safe excitotoxic treatment modality. 
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    Inhibition of endogenous blood glutamate oxaloacetate transaminase enhances the ischemic damage.
    Translational Research April 2021 (4); 230: 68-81
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    Preclinical validation of Human recombinant glutamate oxaloacetate transaminase for the treatmemt of acute ischemic stroke.
    iScience. 2024 Oct 9;27(11):111108.