Hyperthermia depletes adenosine triphosphate and decreases glutamate uptake in rat hippocampal slices

Madl, James E.; Allen, Duane

doi:10.1016/0306-4522(95)00247-g

Cited by 29 publications

(12 citation statements)

References 35 publications

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“…Some in vitro studies have suggested the involvement of impaired glutamate uptake not only in acute metabolic encephalopathies such as cerebral hypoxia and acidosis, 38,39 but also in some neurodegenerative disorders such as Alzheimer disease and ALS 7,40 . Moreover, recent studies have shown that astrocytic glutamate transport is impaired by reactive oxygen or nitrogen species, the lipid peroxidation‐derived carbonyl HNE, prostanoids, and hyperthermia 24,41–44 . Our results showed that another carbonyl glyoxal‐impaired astrocytic glutamate transport in a dose‐ and time‐dependent manner.…”

Section: Discussionsupporting

confidence: 52%

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Glyoxal inactivates glutamate transporter‐1 in cultured rat astrocytes

et al. 2005

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive motor paralysis and selective motor neuron death. There is increasing evidence that motor neuron death in ALS is mediated by glutamate toxicity resulting from reduced activity of astrocytic glutamate transporter-1 (GLT-1). Recent morphological studies have shown that Nepsilon-(carboxymethyl)lysine (CML) accumulates in reactive astrocytes of ALS spinal cords. CML is a product of post-translational protein modification by glyoxal, a reactive aldehydic intermediate. In considering these documents, it is important to determine whether GLT-1 protein modification by glyoxal might cause reduced GLT-1 activity. To address this issue, we investigated the effects of glyoxal on GLT-1 properties in cultured rat astrocytes. High performance liquid chromatography showed reduced glutamate uptake activity in the glyoxal-exposed cells. Immunocytochemical analysis displayed CML accumulation in the cytoplasm of astrocytes by glyoxal exposure. Immunoblots of immunoprecipitated GLT-1 disclosed GLT-1 CML adduct formation in the glyoxal-exposed cells. Our results indicate that glyoxal modifies GLT-1 to form CML and simultaneously deprives its glutamate uptake activity. Thus, these toxic effects of glyoxal on astrocytes might be implicated in motor neuron death in ALS.

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Section: Discussionsupporting

confidence: 52%

“…gen or nitrogen species, the lipid peroxidation-derived carbonyl HNE, prostanoids, and hyperthermia. 24,[41][42][43][44] Our results showed that another carbonyl glyoxal-impaired astrocytic glutamate transport in a dose-and timedependent manner.…”

Section: Ip-abmentioning

confidence: 98%

Glyoxal inactivates glutamate transporter‐1 in cultured rat astrocytes

et al. 2005

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“…Lowering ATP levels affects glutamate uptake, independent of EAAT-2 expression. Furthermore, reduced glutamate uptake during hyperthermia results from the depletion of ATP and reduced cotransport of Na + and K + ions across EAAT-2, thus diminishing its functional activity [6,49]. Thus, EAAT-2 activity is regulated at a functional level in response to the astrocytic energy state and microenvironment and contributes to the excitotoxic environment.…”

Section: Role Of Glutamate In the Central Nervous Systemmentioning

confidence: 99%

HIV-1, Methamphetamine and Astrocyte Glutamate Regulation: Combined Excitotoxic Implications for Neuro-AIDS

Cisneros¹,

Ghorpade²

2012

CHR

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Glutamate, the most abundant excitatory transmitter in the brain can lead to neurotoxicity when not properly regulated. Excitotoxicity is a direct result of abnormal regulation of glutamate concentrations in the synapse, and is a common neurotoxic mediator associated with neurodegenerative disorders. It is well accepted that methamphetamine (METH), a potent central nervous stimulant with high abuse potential, and human immunodeficiency virus (HIV)-1 are implicated in the progression of neurocognitive malfunction. Both have been shown to induce common neurodegenerative effects such as astrogliosis, compromised blood brain barrier integrity, and excitotoxicity in the brain. Reduced glutamate uptake from neuronal synapses likely leads to the accumulation of glutamate in the extracellular spaces. Astrocytes express the glutamate transporters responsible for majority of the glutamate uptake from the synapse, as well as for vesicular glutamate release. However, the cellular and molecular mechanisms of astrocyte-mediated excitotoxicity in the context of METH and HIV-1 are undefined. Topics reviewed include dysregulation of the glutamate transporters, specifically excitatory amino acid transporter-2, metabotropic glutamate receptor(s) expression and the release of glutamate by vesicular exocytosis. We also discuss glutamate concentration dysregulation through astrocytic expression of enzymes for glutamate synthesis and metabolism. Lastly, we discuss recent evidence of various astrocyte and neuron crosstalk mechanisms implicated in glutamate regulation. Astrocytes play an essential role in the neuropathologies associated with METH/HIV-1-induced excitotoxicity. We hope to shed light on common cellular and molecular pathways astrocytes share in glutamate regulation during drug abuse and HIV-1 infection.

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“…In contrast, hyperthermia‐induced evIPSC depression was not affected by the PKC activator PDBu. We suggest that hyperthermia may decrease ATP concentration (Madl and Allen 1995) or inhibit adenylyl cyclase activity, which leads to decreased cAMP formation and reduced activation of PKA, but without involvement of PKC. The critical points where hyperthermia may disrupt signal transduction in the adenylyl cyclase–PKA–GABA release pathway remain to be identified.…”

Section: Discussionmentioning

confidence: 96%

Mechanisms of hyperthermia‐induced depression of GABAergic synaptic transmission in the immature rat hippocampus

Qu¹,

Leung

2008

Journal of Neurochemistry

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Clinical observations and experimental studies have shown that hyperthermia can provoke febrile seizures, which are the most common type of pathological brain activity in children. We previously demonstrated that hyperthermia produced a depression of GABAergic neurotransmission in the hippocampus of immature rats in vitro. To investigate the possible mechanisms through which hyperthermia may modulate GABAergic neurotransmission in the hippocampus, whole‐cell voltage clamp recordings were performed on CA1 pyramidal neurons in the immature rat brain slices. We found that hyperthermia (38.4–40°C) when compared with baseline temperature of 32°C reduced the frequency of both spontaneous inhibitory post‐synaptic currents (sIPSCs) and miniature IPSCs (mIPSCs). Also, hyperthermia decreased the amplitudes of mIPSCs and reduced the mIPSC decay time constants and charge transfer. Non‐stationary noise analysis of mIPSCs suggested that the number of open post‐synaptic receptors but not single channel conductance was reduced during hyperthermia. Activation of adenylyl cyclase with forskolin prevented, whereas protein kinase A inhibitor N‐(2‐[p‐bromocinnamylamino]ethyl)‐5‐isoquinolinesulfonamide potentiated, the hyperthermia (40°C)‐induced depression of evoked IPSCs (evIPSCs). But protein kinase C activator phorbol 12, 13‐dibutyrate (PDBu) did not significantly affect this depression of evIPSCs induced by hyperthermia. Furthermore, hyperthermia‐induced depression of evIPSCs was attenuated by 4‐aminopyridine, but not by BaCl2. These results suggest that hyperthermia reduces GABA release from pre‐synaptic terminals, in part by blocking the adenylyl cyclase–protein kinase A signaling pathway and activating pre‐synaptic 4‐aminopyridine‐sensitive K+ channels. Also, the changes in amplitude and decay time constant of the mIPSCs may suggest that hyperthermia also decreases post‐synaptic GABAA receptor function.

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Hyperthermia depletes adenosine triphosphate and decreases glutamate uptake in rat hippocampal slices

Cited by 29 publications

References 35 publications

Glyoxal inactivates glutamate transporter‐1 in cultured rat astrocytes

Glyoxal inactivates glutamate transporter‐1 in cultured rat astrocytes

HIV-1, Methamphetamine and Astrocyte Glutamate Regulation: Combined Excitotoxic Implications for Neuro-AIDS

Mechanisms of hyperthermia‐induced depression of GABAergic synaptic transmission in the immature rat hippocampus

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