title: The beta-lactam antibiotic, ceftriaxone, dramatically improves survival, increases glutamate uptake and induces neurotrophins in stroke.
abstract: OBJECTIVE
  Ceftriaxone has been reported to reduce neuronal damage in amyotrophic lateral sclerosis and in an in-vitro model of neuronal ischaemia through increased expression and activity of the glutamate transporter, GLT1. We tested the effects of ceftriaxone on mortality, neurological outcome, and infarct size in experimental stroke in rats and looked for underlying mechanisms.
  
  
  METHODS
  Male normotensive Wistar rats received ceftriaxone (200 mg/kg intraperitoneal) as a single injection 90 min after middle cerebral artery occlusion (90 min with reperfusion). Forty-eight hours after middle cerebral artery occlusion, infarct size (MRI) and neurological deficits were estimated. GLT1 expression was determined by real time RT-PCR, immunoblotting and promoter reporter assay, astrocyte GLT1 activity by measuring glutamate uptake. Bacterial load in various organs was measured by real time RT-PCR, neurotrophins and IL-6 by immunoblotting.
  
  
  RESULTS
  Ceftriaxone dramatically reduced early (24-h) mortality from 34.5% (vehicle treatment, n = 29) to 0% (P < 0.01, n = 19). In a subgroup, followed up for 4 weeks, mortality persisted at 0%. Ceftriaxone strongly tended to reduce infarct size, it significantly improved neuronal survival within the penumbra, reduced neurological deficits (P < 0.001) and led to an upregulation of neurotrophins (P < 0.01) in the peri-infarct zone. Ceftriaxone did not increase GLT1 expression, but increased GLT1 activity (P < 0.05).
  
  
  CONCLUSIONS
  Ceftriaxone causes a significant reduction in acute stroke mortality in a poststroke treatment regimen in animal studies. Improved neurological performance and survival may be due to neuroprotection by activation of GLT1 and a stimulation of neurotrophins resulting in an increased number of surviving neurons in the penumbra.
authors.affiliation: Center for Cardiovascular Research (CCR)/Institute of Pharmacology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Christa
authors.initials: C
authors.lastname: Thöne-Reineke
authors.forename: Christian
authors.initials: C
authors.lastname: Neumann
authors.forename: Pawel
authors.initials: P
authors.lastname: Namsolleck
authors.forename: Kristin
authors.initials: K
authors.lastname: Schmerbach
authors.forename: Maxim
authors.initials: M
authors.lastname: Krikov
authors.forename: Jan H
authors.initials: JH
authors.lastname: Schefe
authors.forename: Kristin
authors.initials: K
authors.lastname: Lucht
authors.forename: Heide
authors.initials: H
authors.lastname: Hörtnagl
authors.forename: Michael
authors.initials: M
authors.lastname: Godes
authors.forename: Susanne
authors.initials: S
authors.lastname: Müller
authors.forename: Kay
authors.initials: K
authors.lastname: Rumschüssel
authors.forename: Heiko
authors.initials: H
authors.lastname: Funke-Kaiser
authors.forename: Arno
authors.initials: A
authors.lastname: Villringer
authors.forename: U Muscha
authors.initials: UM
authors.lastname: Steckelings
authors.forename: Thomas
authors.initials: T
authors.lastname: Unger
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001831:Body Temperature / Q000502:physiology; D001921:Brain / Q000098:blood supply; D020520:Brain Infarction / Q000473:pathology; D002443:Ceftriaxone / Q000494:pharmacology*; D002561:Cerebrovascular Disorders / Q000150:complications; D004195:Disease Models, Animal; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D009414:Nerve Growth Factors / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology; D020521:Stroke / Q000209:etiology / Q000378:metabolism* / Q000401:mortality*; D015996:Survival Rate
chemical_list: D000900:Anti-Bacterial Agents; D027342:Excitatory Amino Acid Transporter 2; D015850:Interleukin-6; D009414:Nerve Growth Factors; D012333:RNA, Messenger; D018698:Glutamic Acid; D002443:Ceftriaxone