MRS of brain metabolite levels demonstrates the ability of scavenging of excess brain glutamate to protect against nerve agent induced seizures

Angela Ruban, Inbal E Biton, Arik Markovich, David Mirelman, Angela Ruban, Inbal E Biton, Arik Markovich, David Mirelman

Abstract

This study describes the use of in vivo magnetic resonance spectrocopy (MRS) to monitor brain glutamate and lactate levels in a paraoxon (PO) intoxication model. Our results show that the administration of recombinant glutamate-oxaloacetate transaminase (rGOT) in combination with oxaloacetate (OxAc) significantly reduces the brain-accumulated levels of glutamate. Previously we have shown that the treatment causes a rapid decrease of blood glutamate levels and creates a gradient between the brain and blood glutamate levels which leads to the efflux of excess brain glutamate into the blood stream thereby reducing its potential to cause neurological damage. The fact that this treatment significantly decreased the brain glutamate and lactate levels following PO intoxication suggests that it could become a new effective neuroprotective agent.

Figures

Figure 1
Figure 1
(A) Racine’s scale evaluation of seizure’s post paraoxon (PO) exposure; (B) magnetic resonance spectrocopy (MRS) experiment protocol scheme; (C) four axial T2 (spin–spin relaxation)-MR-weighted images of representative rat brains treated with saline or oxaloacetate (OxAc)/glutamate-oxaloacetate transaminase (rGOT). The field of view of the the image was 4 × 4 cm2; (D) Axial MR image of the rat brain obtained by RARE (rapid acquisition with relaxation enhancement) sequence showing the position of the selected voxel (4 × 4 × 4 mm3) covering predominantly the hippocampus region. The field of view of the entire image was 4 × 4 cm2.
Figure 2
Figure 2
(A) Post PO exposure before treatment, lactate and glutamate levels increased in comparison with baseline values before the exposure to PO. Data were expressed as mean ± S.E. p < 0.05 for both metabolites as determined by t-test (in comparison with baseline values); (B) Representative in vivo proton MRS spectra in the hippocampus after OxAc/rGOT and saline treatments at the latest MRS time point. Lactate (Lac) is resolved at 1.3 ppm, glutamate (Glu) at 2.2 ppm and phosphocreatine (PCr) at 3.0 ppm; (C) Normalized glutamate levels in the hippocampus after OxAc/rGOT and saline treatments as a function of time. Data were expressed as mean ± S.E. p < 0.005 as determined by t-test; (D) The hippocampus glutamate levels after the OxAc/GOT or saline treatments at the end of the experiment; (E) Normalized lactate levels in the hippocampus after OxAc/rGOT and saline treatments as a function of time; (F) The hippocampus lactate levels after the OxAc/GOT or saline treatments at the end of the experiment. Data were expressed as mean ± S.E. p < 0.04 as determined by t-test.

References

    1. Lallement G., Delamanche I.S., Pernot-Marino I., Baubichon D., Denoyer M., Carpentier P., Blanchet G. Neuroprotective activity of glutamate receptor antagonists against soman-induced hippocampal damage: Quantification with an ω3 site ligand. Brain Res. 1993;618:227–237.
    1. Granacher R.P., Jr. Traumatic Brain Injury: Methods for Clinical and Forensic Neuropsychiatric Assessment. 2nd ed. Taylor & Francis Group (CRC Press); Boca Raton, FL, USA: 2008. pp. 18–31.
    1. Lallement G., Denoyer M., Collet A., Pernot-Marino I., Baubichon D., Monmaur P., Blanchet G. Changes in hippocampal acetylcholine and glutamate extracellular levels during soman-induced seizures: Influence of septal cholinoceptive cells. Neurosci. Lett. 1992;139:104–107.
    1. Tattersall J. Seizure activity post-organophosphate exposure. Front. Biosci. 2009;14:3688–3711.
    1. Sparenborg S., Brennecke L.H., Jaax N.K., Braitman D.J. Dizocilpine (MK-801) arrests status epilepticus and prevents brain damage induced by soman. Neuropharmacology. 1992;31:357–368.
    1. Cohen-Kashi-Malina K., Cooper I., Teichberg V.I. Mechanisms of glutamate efflux at the blood-brain barrier: Involvement of glial cells. J. Cereb. Blood Flow Metab. 2012;32:177–189.
    1. Teichberg V.I. GOT to rid the body of excess glutamate. J. Cereb. Blood Flow Metab. 2011;31:1376–1377.
    1. Cederberg-Helms H.C., Uhd-Nielsen C., Brodin B. Glutamate efflux at the blood-brain barrier: Cellular mechanisms and potential clinical relevance. Arch. Med. Res. 2015 in press.
    1. Teichberg V.I., Cohen-Kashi-Malina K., Cooper I., Zlotnik A. Homeostasis of glutamate in brain fluids: An accelerated brain-to-blood efflux of excess glutamate is produced by blood glutamate scavenging and offers protection from neuropathologies. Neuroscience. 2009;158:301–308.
    1. Zlotnik A., Gruenbaum S.E., Artru A.A., Rozet I., Dubilet M., Tkachov S., Brotfain E., Klin Y., Shapira Y., Teichberg V.I. The neuroprotective effects of oxaloacetate in closed head injury in rats is mediated by its blood glutamate scavenging activity. J. Neurosurg. Anesth. 2009;21:235–241.
    1. Campos F., Sobrino T., Ramos-Cabrer P., Argibay B., Agulla J., Pérez-Mato M., Rodrigues-Gonzalez R., Brea D., Castillo J. Neuroprotection by glutamate oxaloacetate transaminase in ischemic stroke: an experimental study. J. Cereb. Blood Flow Metab. 2011;31:1378–1386.
    1. Ruban A., Berkutzki T., Cooper I., Mohar B., Teichberg V.I. Blood glutamate scavengers prolong the survival of rats and mice with brain-implanted gliomas. Investig. New Drugs. 2012;30:2226–2235.
    1. Ruban A., Mohar B., Jona G., Teichberg V.I. Blood glutamate scavenging as a novel neuroprotective treatment for paraoxon intoxication. J. Cereb. Blood Flow Metab. 2013;34:221–227.
    1. Rink C., Gnyawali S., Peterson L., Khanna S. Oxygen-inducible glutamate oxaloacetate transaminase as protective switch transforming neurotoxic glutamate to metabolic fuel during acute ischemic stroke. Antioxid. Redox Signal. 2011;14:1777–1785.
    1. Fauvelle F., Carpentier P., Dorandeu F., Foquin A., Testylier G. Prediction of neuroprotective treatment efficiency using a HRMAS NMR-based statistical model of refractory status epilepticus on mouse: A metabolomic approach supported by histology. J. Proteome Res. 2012;11:3782–3795.
    1. Sun P.Z., Cheung J.S., Wang E., Lo E.H. Association between pH-weighted endogenous amide proton chemical exchange saturation transfer MRI and tissue lactic acidosis during acute ischemic stroke. J. Cereb. Blood Flow Metab. 2011;31:1743–1750.
    1. Shrot S., Anaby D., Krivoy A., Makarovsky I., Rosman Y., Bloch-Shilderman E., Lazar S., Bar-Shir A., Cohen Y. Early in vivo MR spectroscopy findings in organophosphate-induced brain damage-potential biomarkers for short-term survival. Magn. Reson. Med. 2012;68:1390–1398.
    1. Zhang W., Wang P.J., Li M.H., Gao X.L., Gu G.J., Shao Z.H. 1H-MRS can monitor metabolites changes of lateral intraventrcular BDNF infusion into a mouse model of Alzheimer’s disease in vivo. Neuroscience. 2013;245:40–49.
    1. Deshpande L.S., Carter D.S., Blair R.E., DeLorenzo R.J. Development of a prolonged calcium plateau in hippocampal neurons in rats surviving status epilepticus induced by the organophosphate diisopropylfluorophosphate. Toxicol. Sci. 2010;116:623–631.
    1. Valadka A.B., Andrews B.T. Neurotrauma: Evidence-Based Answers to Common Questions. Thieme; New York, NY, USA: 2005. pp. 3–4.
    1. Siesjö B.K., Siesjö P. Mechanisms of secondary brain injury. Eur. J. Anesth. 1996;13:247–268.
    1. Sun P.Z., Benner T., Copen W.A., Sorensen A.G. Early experience of translating pH-weighted MRI to image human subjects at 3 Tesla. Stroke J. Cereb. Circ. 2010;41:S147–S151.
    1. Lallement G., Baubichon D., Clarençon D., Galonnier M., Peoc’h M., Carpentier P. Review of the value of gacyclidine (GK-11) as adjuvant medication to conventional treatments of organophosphate poisoning: primate experiments mimicking various scenarios of military or terrorist attack by soman. Neurotoxicology. 1999;20:675–684.
    1. Solberg Y., Belkin M. The role of excitotoxicity in organophosphorous nerve agents central poisoning. Trends Pharmacol. Sci. 1997;18:183–185.

Source: PubMed

Sponsorer och medarbetare

Medicinska tillstånd

Läkemedelsinterventioner

3
Prenumerera