Talampanel, a novel noncompetitive AMPA antagonist, is neuroprotective after traumatic brain injury in rats

L. Belayev, O. F. Alonso, Y. Liu, A. S. Chappell, Weizhao Zhao, Myron Ginsberg, R. Busto

Research output: Contribution to journalArticle

53 Citations (Scopus)

Abstract

Talampanel {(R)-7-acetyl-5-(4-aminophenyl)-8,9-dihydro-8-methyl-7H-1,3-dioxolo[4,5-h] [2,3] benzodiazepine} is an orally active noncompetitive antagonist of the AMPA subtype of glutamate excitatory amino acid receptors. The purpose of this study was to determine whether treatment with talampanel would protect in a rat model of traumatic brain injury (TBI). Twenty-four hours prior to TBI, a fluid-percussion interface was positioned parasagittally over the right cerebral cortex. On the following day, fasted rats were anesthetized with 3% halothane, 70% nitrous oxide, and a balance of oxygen; mechanically ventilated and physiologically regulated; and subjected to right parieto-occipital parasagittal fluid-percussion injury (1.5-2.0 atm). The agent (talampanel, bolus infusion of 4 mg/kg followed by infusion of 4 mg/kg/h over 72 h) or vehicle was administered i.v. starting at either 30 min or 3 h after trauma. Seven days after TBI, brains were perfusion-fixed, coronal sections at various levels were digitized, and contusion areas were measured. Treatment with talampanel, when instituted 30 min after trauma, significantly reduced total contusion area compared to vehicle-treated rats (0.54 ± 0.25 vs. 1.79 ± 0.42 mm2, respectively). When talampanel treatment was begun at 3 h, the neuroprotective effect of the drug was lost. In addition, treatment with talampanel starting at 30 min significantly attenuated neuronal damage in all three subsectors of the hippocampal CA1 sector compared to vehicle-treated rats (normal-neuron counts, right (ipsilateral) medial CA1: 80.3 ± 2.0 [talampanel] vs. 66.3 ± 2.1 [vehicle] (mean ± SEM); middle CA1: 71.5 ± 2.0 vs. 60.3 ± 2.2; lateral CA1: 74.5 ± 3.0 vs. 63.0 ± 3.2, respectively). By contrast, when talampanel treatment was begun at 3 h, normal pyramidal-neuron counts were almost identical in both groups. Our findings document that talampanel therapy instituted 30 min after trauma significantly reduces histological damage.

Original languageEnglish
Pages (from-to)1031-1038
Number of pages8
JournalJournal of Neurotrauma
Volume18
Issue number10
StatePublished - Nov 7 2001

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GYKI 53405
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
Percussion
Contusions
Wounds and Injuries
Neuroprotective Agents
Hippocampal CA1 Region
Traumatic Brain Injury
Pyramidal Cells
Glutamate Receptors
Nitrous Oxide
Halothane
Benzodiazepines
Cerebral Cortex

Keywords

  • Histopathology
  • Neuroprotection
  • Talampanel
  • Traumatic brain injury

ASJC Scopus subject areas

  • Clinical Neurology
  • Neuroscience(all)

Cite this

Talampanel, a novel noncompetitive AMPA antagonist, is neuroprotective after traumatic brain injury in rats. / Belayev, L.; Alonso, O. F.; Liu, Y.; Chappell, A. S.; Zhao, Weizhao; Ginsberg, Myron; Busto, R.

In: Journal of Neurotrauma, Vol. 18, No. 10, 07.11.2001, p. 1031-1038.

Research output: Contribution to journalArticle

Belayev, L. ; Alonso, O. F. ; Liu, Y. ; Chappell, A. S. ; Zhao, Weizhao ; Ginsberg, Myron ; Busto, R. / Talampanel, a novel noncompetitive AMPA antagonist, is neuroprotective after traumatic brain injury in rats. In: Journal of Neurotrauma. 2001 ; Vol. 18, No. 10. pp. 1031-1038.
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