ro13-9904 and Brain-Infarction

Glutamate (Glu) plays a key role in excitotoxicity-related injury in cerebral ischemia. In the brain, Glu homeostasis depends on Glu transporters, including the excitatory amino acid transporters and the cysteine/Glu antiporter (xc-). We hypothesized that drugs acting on Glu transporters, such as ceftriaxone (CEF, 200 mg/kg, i.p.) and N-acetylcysteine (NAC, 150 mg/kg, i.p.), administered repeatedly for 5 days before focal cerebral ischemia in rats and induced by a 90-min middle cerebral artery occlusion (MCAO), may induce brain tolerance to ischemia. We compared the effects of these drugs on brain infarct volume, neurological deficits and the mRNA and protein expression of the Glu transporter-1 (GLT-1) and xc- with the effects of ischemic preconditioning and chemical preconditioning using 3-nitropropionic acid. Administration of CEF and NAC significantly reduced infarct size and neurological deficits caused by a 90-min MCAO. These beneficial effects were accompanied by changes in GLT-1 expression caused by a 90-min MCAO at both the mRNA and protein levels in the frontal cortex, hippocampus, and dorsal striatum. Thus, the results of this study suggest that the regulation of GLT-1 and xc- plays a role in the development of cerebral tolerance to ischemia and that this regulation may be a novel approach in the therapy of brain ischemia.

Topics: Acetylcysteine; Analysis of Variance; Animals; Brain; Brain Edema; Brain Infarction; Ceftriaxone; Disease Models, Animal; Drug Administration Schedule; Enzyme-Linked Immunosorbent Assay; Excitatory Amino Acid Transporter 2; Gene Expression Regulation; Infarction, Middle Cerebral Artery; Male; Nervous System Diseases; Neuroprotective Agents; Rats; Rats, Wistar; RNA, Messenger

Although the neuroprotective effect of ceftriaxone (CTX) has been reported, the underlying mechanisms are still uncertain. In this study, we investigated if rats recover better from CTX pretreatment against cerebral ischemia by inhibiting the inflammatory response.. Rats were pretreated with CTX (200 mg/kg, 1/day, i.p.) for 5 d. At 24 h after the end of the last CTX pretreatment, focal cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) for 120 min in male Sprague Dawley rats. The neurological deficit scores (NDS) and infarct volumes were evaluated. Microglia cells were observed by immunofluorescence staining and IL-1β was assayed by ELISA and Western Blot.. The results showed that CTX pretreatment improved the neurological deficit scores and decreased the infarct volumes 24 h after reperfusion. The activation of microglia cells was reduced and the expression of IL-1β was partially inhibited 24 h after reperfusion.. These findings demonstrate that CTX pretreatment may provide a neuroprotective effect against transient cerebral ischemic injury, partially inhibit in microglial activation and reduce the expression of IL-1β.

Topics: Animals; Brain Infarction; Brain Injuries; CD11b Antigen; Ceftriaxone; Disease Models, Animal; Drug Administration Schedule; Gene Expression Regulation; Glial Fibrillary Acidic Protein; Infarction, Middle Cerebral Artery; Interleukin-1beta; Male; Microglia; Neurologic Examination; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Renal Circulation; Reperfusion

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.. 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.. 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).. 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.

Topics: Animals; Anti-Bacterial Agents; Body Temperature; Brain; Brain Infarction; Ceftriaxone; Cerebrovascular Disorders; Disease Models, Animal; Excitatory Amino Acid Transporter 2; Glutamic Acid; Interleukin-6; Male; Nerve Growth Factors; Rats; Rats, Wistar; Regional Blood Flow; RNA, Messenger; Stroke; Survival Rate