title: Neuroprotective Effects of the Glutamate Transporter Activator (R)-(-)-5-methyl-1-nicotinoyl-2-pyrazoline (MS-153) following Traumatic Brain Injury in the Adult Rat.
abstract: Traumatic brain injury (TBI) in humans and in animals leads to an acute and sustained increase in tissue glutamate concentrations within the brain, triggering glutamate-mediated excitotoxicity. Excitatory amino acid transporters (EAATs) are responsible for maintaining extracellular central nervous system glutamate concentrations below neurotoxic levels. Our results demonstrate that as early as 5 min and up to 2 h following brain trauma in brain-injured rats, the activity (Vmax) of EAAT2 in the cortex and the hippocampus was significantly decreased, compared with sham-injured animals. The affinity for glutamate (KM) and the expression of glutamate transporter 1 (GLT-1) and glutamate aspartate transporter (GLAST) were not altered by the injury. Administration of (R)-(-)-5-methyl-1-nicotinoyl-2-pyrazoline (MS-153), a GLT-1 activator, beginning immediately after injury and continuing for 24 h, significantly decreased neurodegeneration, loss of microtubule-associated protein 2 and NeuN (+) immunoreactivities, and attenuated calpain activation in both the cortex and the hippocampus at 24 h after the injury; the reduction in neurodegeneration remained evident up to 14 days post-injury. In synaptosomal uptake assays, MS-153 up-regulated GLT-1 activity in the naïve rat brain but did not reverse the reduced activity of GLT-1 in traumatically-injured brains. This study demonstrates that administration of MS-153 in the acute post-traumatic period provides acute and long-term neuroprotection for TBI and suggests that the neuroprotective effects of MS-153 are related to mechanisms other than GLT-1 activation, such as the inhibition of voltage-gated calcium channels.
authors.affiliation: 1 Department of Pharmacology and Physiology, Drexel University College of Medicine , Philadelphia, Pennsylvania.
authors.forename: Andréia Cristina
authors.initials: AC
authors.lastname: Fontana
authors.affiliation: 2 Department of Neurobiology and Anatomy, Drexel University College of Medicine , Philadelphia, Pennsylvania.
authors.forename: Douglas P
authors.initials: DP
authors.lastname: Fox
authors.affiliation: 1 Department of Pharmacology and Physiology, Drexel University College of Medicine , Philadelphia, Pennsylvania.
authors.forename: Argie
authors.initials: A
authors.lastname: Zoubroulis
authors.affiliation: 1 Department of Pharmacology and Physiology, Drexel University College of Medicine , Philadelphia, Pennsylvania.
authors.forename: Ole Valente
authors.initials: OV
authors.lastname: Mortensen
authors.affiliation: 2 Department of Neurobiology and Anatomy, Drexel University College of Medicine , Philadelphia, Pennsylvania.
authors.forename: Ramesh
authors.initials: R
authors.lastname: Raghupathi
mesh_terms: D000818:Animals; D000070642:Brain Injuries, Traumatic / Q000188:drug therapy*; D004195:Disease Models, Animal; D027341:Excitatory Amino Acid Transporter 1 / Q000187:drug effects / Q000378:metabolism*; D027342:Excitatory Amino Acid Transporter 2 / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D009539:Nicotinic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C101692:5-methyl-1-nicotinoyl-2-pyrazoline; D027341:Excitatory Amino Acid Transporter 1; D027342:Excitatory Amino Acid Transporter 2; D018696:Neuroprotective Agents; D009539:Nicotinic Acids; C493392:Slc1a3 protein, rat
keywords: EAAT2/GLT-1; MS-153; glutamate uptake; neuroprotection; traumatic brain injury