Vulnerability of oligodendroglia to glutamate: pharmacology, mechanisms, and prevention.
نویسندگان
چکیده
Periventricular white matter injury, the principal variety of brain injury of the human premature infant, involves differentiating oligodendroglia. Nothing is known of the biochemical mechanism of oligodendroglial death in this disorder. Because an early event in periventricular white matter injury is ischemia-induced axonal disruption and because such axonal destruction could lead to a marked increase in local concentrations of glutamate, we evaluated the vulnerability of differentiating oligodendroglia to glutamate in a culture model. Oligodendroglia were isolated from mixed-glial primary cultures by a selective detachment technique and grown in a primary culture under conditions that lead to differentiation. These oligodendroglia were found to be highly vulnerable to glutamate-induced cell death. The EC50 for glutamate for a 24 hr exposure was approximately 200 microM, comparable to the value reported for neurons in conventional cerebral cortical cultures. Astrocytes, in contrast, were shown to be resistant to as much as 5 mM glutamate. Study of glutamate receptor antagonists and glutamate transport substrates showed that the glutamate-induced oligodendroglial death was not related to a receptor mechanism, as operates in neurons, but rather was secondary to glutamate uptake by the oligodendroglia. Glutamate transport by high-affinity, sodium-dependent and by sodium-independent systems was shown. The central importance of glutamate uptake for the toxic effect of glutamate was shown by total prevention of the oligodendroglial toxicity by the simultaneous inhibition of glutamate uptake by the specific inhibitor D,L-threo-beta-hydroxyaspartate. Subsequent observations showed that the toxicity of glutamate was mediated by free radical attack, the consequence of glutathione depletion, apparently caused by the action of a glutamate-cystine exchange mechanism that results in cystine and thereby glutathione depletion. Thus, addition of cystine or cysteine totally prevented the glutamate toxicity to oligodendroglia. Second, glutamate exposure led to cystine efflux. Third, glutathione levels decreased markedly in cells exposed to glutamate, and this marked decrease preceded the loss of cell viability. Fourth, glutamate toxicity could be prevented totally by exposure to different free radical scavengers, vitamin E and idebenone. The data thus show that glutamate is highly toxic to oligodendroglia. Moreover, the findings raise the possibilities that such glutamate toxicity is operative in the oligodendroglial cell death associated with ischemic processes that disrupt axons, such as periventricular white matter injury of the premature infant, and that novel therapies directed against glutamate transport, glutathione depletion, and free radical attack might be beneficial in prevention of that injury.
منابع مشابه
Metabotropic glutamate receptors and their ligands applications in neurological and psychiatric disorders
Metabotropic glutamate receptors (mGluRs) consist of a large family of G-protein coupled receptors that are critical for regulating normal neuronal function in the central nervous system. The wide distribution and diverse physiological roles of various mGluR subtypes make them highly attractive targets for the treatment of a number of neurological and psychiatric disorders. The discovery of ...
متن کاملSex differences and role of gonadal hormones in development of tolerance to morphine analgesia and glutamate level in the nucleus accumbens of rats: A microdialysis study
Introduction: Sex differences are observed in the development of tolerance to antinociceptive effect of opioid drugs such as morphine, but the underlying mechanisms remain unclear. Critical role of glutamate in the development and maintenance of opioid tolerance has been reported by many investigators. There are also evidences about interaction between gonadal hormones and neuromodulatory sy...
متن کاملMORPHINE RELE ASES GLUTAMATE THROUGH AMPA RECEPTORS IN THE VENTRAL TEGMENTAL AREA: A MICRODIALYSIS STUDY IN CONSCIOUS RATS
In vivo microdialysis was used to study the effects of morphine on glutamate release from the ventral tegmentum area (VTA) in freely moving rats. Intraperitoneal (i.p.) injection of acute and repeated morphine at increasing doses significantly enhanced glutamate release. Only a minor tolerance developed to this dosage of morphine. AP-S (2-amino-5-phosphonovaleric acid, 0.5 mg/kg i.p.), a N...
متن کاملPotential protective roles of phytochemicals on glutamate-induced neurotoxicity: A review
Glutamate, as an essential neurotransmitter, has been thought to have different roles in the central nervous system (CNS), including nerve regeneration, synaptogenesis, and neurogenesis. Excessive glutamate causes an up-regulation of the multiple signaling pathways, including phosphoinositide-3 kinase/protein kinase B (PI3K/Akt), Akt/mammalian target of rapamycin (mTOR) protein, mitogen-activat...
متن کاملThe effects Metformin/Irinotecan-loaded PLGA nanoparticles on glutamate re-uptake time and alteration EAAT1 gene expression level in vitro
Objective(s): The present study was designed to evaluate of Metformin/Irinotecan-loaded poly-lactic-co-glycolic acid (PLGA) nanoparticles (NPs) effects on glutamate re-uptake time and receptor expression status in both glioblastoma multiforme (GBM) and cortex neuron cultures. The study was performed on glioblastoma cell line and primer cortex neuron.Materials and Methods: The re-uptake time and...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید
ثبت ناماگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید
ورودعنوان ژورنال:
- The Journal of neuroscience : the official journal of the Society for Neuroscience
دوره 13 4 شماره
صفحات -
تاریخ انتشار 1993