ro13-9904 and Infarction--Middle-Cerebral-Artery

One of the major players in the pathophysiology of cerebral ischemia is disrupted homeostasis of glutamatergic neurotransmission, resulting in elevated extracellular glutamate (Glu) concentrations and excitotoxicity-related cell death. In the brain, Glu concentrations are regulated by Glu transporters, including Glu transporter-1 (GLT-1) and cystine/Glu antiporter (system xc-). Modulation of these transporters by administration of ceftriaxone (CEF, 200 mg/kg, i.p.) or N-acetylcysteine (NAC, 150 mg/kg, i.p.) for 5 days before focal cerebral ischemia may induce brain tolerance to ischemia by significantly limiting stroke-related damage and normalizing Glu concentrations. In the present study, focal cerebral ischemia was induced by 90-minute middle cerebral artery occlusion (MCAO). We compared the effects of CEF and NAC pretreatment on Glu concentrations in extracellular fluid and cellular-specific expression of GLT-1 and xCT with the effects of two reference preconditioning methods, namely, ischemic preconditioning and chemical preconditioning in rats. Both CEF and NAC significantly reduced Glu levels in the frontal cortex and hippocampus during focal cerebral ischemia, and this decrease was comparable with the Glu level achieved with the reference preconditioning strategies. The results of immunofluorescence staining of GLT-1 and xCT on astrocytes, neurons and microglia accounted for the observed changes in extracellular Glu levels to a certain extent. Briefly, after MCAO, the expression of GLT-1 on astrocytes decreased, but pretreatment with CEF seemed to prevent this downregulation. In addition, every intervention used in this study seemed to reduce xCT expression on astrocytes and neurons. The results of this study indicate that modulation of Glu transporter expression may restore Glu homeostasis. Moreover, our results suggest that CEF and NAC may induce brain tolerance to ischemia by influencing GLT-1 and system xc- expression levels. These transporters are presumably good targets for the development of novel therapies for brain ischemia.

Topics: Acetylcysteine; Amino Acid Transport Systems, Acidic; Animals; Astrocytes; Brain Ischemia; Ceftriaxone; Excitatory Amino Acid Transporter 2; Frontal Lobe; Gene Expression Regulation; Glutamic Acid; Hippocampus; Humans; Infarction, Middle Cerebral Artery; Rats; Synaptic Transmission

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

Topics: Acyclovir; Aged; Amphotericin B; Aneurysm; Aneurysm, Infected; Anti-Infective Agents; Brain Edema; Carotid Artery Diseases; Carotid Artery, Internal; Ceftriaxone; Dexamethasone; Embolization, Therapeutic; Equipment Contamination; Female; Humans; Imaging, Three-Dimensional; Infarction, Middle Cerebral Artery; Magnetic Resonance Imaging; Meningoencephalitis; Prostheses and Implants; Prosthesis-Related Infections; Tomography, X-Ray Computed