Abstract
BackgroundExcitotoxic neuronal injury by action of the glutamate receptors of the N-methyl-d-aspartate (NMDA) subtype have been implicated in the pathogenesis of brain damage as a consequence of bacterial meningitis. The most potent and selective blocker of NMDA receptors containing the NR2B subunit is (R,S)-alpha-(4-hydroxyphenyl)-beta-methyl-4-(phenylmethyl)-1-piperid inepropanol (RO 25-6981). Here we evaluated the effect of RO 25-6981 on hippocampal neuronal apoptosis in an infant rat model of meningitis due to Streptococcus pneumoniae. Animals were randomized for treatment with RO 25-6981 at a dosage of either 0.375 mg (15 mg/kg; n = 28) or 3.75 mg (150 mg/kg; n = 15) every 3 h or an equal volume of sterile saline (250 μl; n = 40) starting at 12 h after infection. Eighteen hours after infection, animals were assessed clinically and seizures were observed for a period of 2 h. At 24 h after infection animals were sacrificed and brains were examined for apoptotic injury to the dentate granule cell layer of the hippocampus.ResultsTreatment with RO 25-6981 had no effect on clinical scores, but the incidence of seizures was reduced (P < 0.05 for all RO 25-6981 treated animals combined). The extent of apoptosis was not affected by low or high doses of RO 25-6981. Number of apoptotic cells (median [range]) was 12.76 [3.16–25.3] in animals treated with low dose RO 25-6981 (control animals 13.8 [2.60–31.8]; (P = NS) and 9.8 [1.7–27.3] (controls: 10.5 [2.4–21.75]) in animals treated with high dose RO 25-6981 (P = NS).ConclusionsTreatment with a highly selective blocker of NMDA receptors containing the NR2B subunit failed to protect hippocampal neurons from injury in this model of pneumococcal meningitis, while it had some beneficial effect on the incidence of seizures.
Highlights
Excitotoxic neuronal injury by action of the glutamate receptors of the N-methyld-aspartate (NMDA) subtype have been implicated in the pathogenesis of brain damage as a consequence of bacterial meningitis
Neuronal damage during meningitis may be caused by excitatory amino acids (EAA) [3]
It is conceivable that glutamate may diffuse into this brain structure from the CSF in the ventricular space, when concentrations of the EAA are increased during meningitis [14]
Summary
Excitotoxic neuronal injury by action of the glutamate receptors of the N-methyld-aspartate (NMDA) subtype have been implicated in the pathogenesis of brain damage as a consequence of bacterial meningitis. We evaluated the effect of RO 25-6981 on hippocampal neuronal apoptosis in an infant rat model of meningitis due to Streptococcus pneumoniae. The second form consists of apoptosis in the dentate gyrus of the hippocampus It may be responsible for learning and memory deficits observed after meningitis [2]. The NMDA subtype of EAA receptors is believed to be responsible for excitotoxic cell death associated with neuronal disorders and injury [4,5]. The aim of the present study was to evaluate the effect of the NR2B-selective NMDA antagonist RO 256981 on hippocampal injury and seizures in an infant rat model of meningitis due to Streptococcus pneumoniae
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
