Effects of dextromethorphan on rat brain during ischemia and reperfusion assessed by magnetic resonance spectroscopy.

Rijen, Peter C. van; Verheul, H.B.; Echteld, C.J.A. van; Balázs, R.; Lewis, Peter B.; Nasim, Mansoor; Tulleken, C. A. F.

doi:10.1161/01.str.22.3.343

Cited by 26 publications

(3 citation statements)

References 35 publications

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“…The mechanisms leading to cortical damage have been shown to be linked to ischemia and reperfusion injury, similar to focal ischemia observed in stroke [2,31]. Moreover, treatment with DM was shown to limit neuronal death in focal and global ischemia [29,34]. In addition, EAA may enter the brain through leakage of the blood-brain barrier [32,33].…”

Section: Discussionmentioning

confidence: 97%

Effect of the NMDA-Receptor Antagonist Dextromethorphan in Infant Rat Pneumococcal Meningitis

Sellner

Ringer

Baumann³

et al. 2008

CDM

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Excitatory amino acids (EAA) and particularly glutamate toxicity have been implicated in the pathogenesis of neuronal injury occurring in bacterial meningitis by activating the N-methyl-d aspartate (NMDA) receptor complex. Here, we evaluated the effect of adjuvant treatment with the antitussive drug dextromethorphan (DM), a non-competitive NMDA receptor antagonist with neuroprotective potential, in an infant rat model of pneumococcal meningitis. The experiments were carried out in postnatal day 6 (P6) and 11 (P11) animals. Pharmacokinetics of DM and its major metabolite dextrorphan (DO) were performed for dose finding. In our study, DM did not alter clinical parameters (clinical score, motor activity, incidence of seizures, spontaneous mortality) and cortical neuronal injury but increased the occurrence of ataxia (P<0.0001). When DM treatment was started at the time of infection (DM i.p. 15 mg/kg at 0, 4, 8 and 16 hours (h) post infection) in P11 animals, an aggravation of apoptotic neuronal death in the hippocampal dentate gyrus was found (P<0.05). When treatment was initiated during acute pneumococcal meningitis (DM i.p. 15 mg/kg at 12 and 15 h and 7.5 mg/kg at 18 and 21 h after infection), DM had no effect on the extent of brain injury but reduced the occurrence of seizures (P<0.03). We conclude that in this infant rat model of pneumococcal meningitis interference of the EEA and NMDA pathway using DM causes ataxia, attenuates epileptic seizures and increases hippocampal apoptosis, but is not effective in protecting the brain from injury.

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Section: Discussionmentioning

confidence: 97%

Effect of the NMDA-Receptor Antagonist Dextromethorphan in Infant Rat Pneumococcal Meningitis

Sellner

Ringer

Baumann³

et al. 2008

CDM

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“…A previous and popular strategy was pharmacological targeting of the activation of NMDA receptors after the excessive glutamate release following ischemia. Several compounds, including dizocilpine maleate (MK-801) 4 , 5 , aptiganel hydrochloride (Cerestat) 6 , dextromethorphan (DMX) 7 and CGS 19755 (Selfotel) 8 , 9 showed promising results in rodent models. However, by 2001, all clinical trials using NMDA receptor antagonists as treatment for stroke were deemed unsuccessful 10 , 11 , 12 , 13 , 14 , 15 .…”

Section: Introductionmentioning

confidence: 99%

The role of TRPM2 channels in neurons, glial cells and the blood-brain barrier in cerebral ischemia and hypoxia

2018

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Stroke is one of the major causes of mortality and morbidity worldwide, yet novel therapeutic treatments for this condition are lacking. This review focuses on the roles of the transient receptor potential melastatin 2 (TRPM2) ion channels in cellular damage following hypoxia-ischemia and their potential as a future therapeutic target for stroke. Here, we highlight the complex molecular signaling that takes place in neurons, glial cells and the blood-brain barrier following ischemic insult. We also describe the evidence of TRPM2 involvement in these processes, as shown from numerous in vitro and in vivo studies that utilize genetic and pharmacological approaches. This evidence implicates TRPM2 in a broad range of pathways that take place every stage of cerebral ischemic injury, thus making TRPM2 a promising target for drug development for stroke and other neurodegenerative conditions of the central nervous system.

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“…Drugs that would be effective in the control of stroke related neurodegeneration should attempt to block the above mentioned glutamate cascade (18)(19)(20)(21)(22)(23)(24). NMDA antagonists such as CGS 19755 (CIBA-GEIGY), MK 801 (Merck) and Dextrorphan (Hoffman-La Roche) are supposed to impede activation of NMDA receptors.…”

Section: Introductionmentioning

confidence: 99%

MRI and MRS studies on the time course of rat brain lesions and the effect of drug treatment: Volume quantification and characterization of tissue heterogeneity by parameter selection

Pschorn

Körperich²,

Heymans³

et al. 1993

Magnetic Resonance in Med

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Magnetic resonance imaging has been used to follow the time course of lesions induced in the rat brain as an animal model for characterization of the volume of the lesion. The dispersion in spin-spin relaxation has been used to characterize the nature of the brain lesion. Parameter selective estimation of T2, quantitative determination of the lesion size and volume selective in vivo proton spectroscopy have been employed for the purpose. The work has been carried out on rats which were subject to lesioning by ibotenic acid as a model for excitotoxicity and also on rats which received doses of ibotenic acid and subsequent doses of the NMDA antagonist drug MK 801 (dizocilpine). The time course of the progress of the lesions in untreated animals and the effect of neuroprotection by MK 801 was continuously monitored in all test animals. Further, a relatively new inhalation anesthetic agent, isoflurane, has been employed. A more logical and semiquantitative T2 bandwidth demarkation useful in distinguishing different degrees of lesioning from the onset and up to the 'edema' stage through penumbra (mild lesion), medium degree lesion and severe lesion has been proposed.

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Effects of dextromethorphan on rat brain during ischemia and reperfusion assessed by magnetic resonance spectroscopy.

Cited by 26 publications

References 35 publications

Effect of the NMDA-Receptor Antagonist Dextromethorphan in Infant Rat Pneumococcal Meningitis

Effect of the NMDA-Receptor Antagonist Dextromethorphan in Infant Rat Pneumococcal Meningitis

The role of TRPM2 channels in neurons, glial cells and the blood-brain barrier in cerebral ischemia and hypoxia

MRI and MRS studies on the time course of rat brain lesions and the effect of drug treatment: Volume quantification and characterization of tissue heterogeneity by parameter selection

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