Selective inhibition of glial cell metabolism in vivo by fluorocitrate

Hassel, Bjørnar; Paulsen, Ragnhild E.; Johnsen, Arnt; Fonnum, Frode

doi:10.1016/0006-8993(92)90616-h

Cited by 210 publications

(182 citation statements)

References 18 publications

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“…For example, fluorocitrate at low peri-spinal (intrathecal; i.t.) doses, preferentially inhibits aconitase in the tricarboxylic acid cycle in glial cells (Fonnum et al, 1997, Hassel et al, 1992, thus inhibiting glial metabolism. The development of thermal and mechanical hyperalgesia in several animal models of pathological pain is attenuated or blocked by fluorocitrate .…”

Section: Pathological Pain Statesmentioning

confidence: 99%

Glia in pathological pain: A role for fractalkine

Milligan

Sloane

Watkins

2008

Journal of Neuroimmunology

104

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Microglia and/or astrocytes play a significant role in the creation and maintenance of exaggerated pain states with inflammatory and/or neuropathic etiologies. The chemokine, fractalkine, has several functions, including the newly recognized role of mediating neuropathic pain conditions. Although constitutively expressed and released during inflammation, increased release of fractalkine binds to and activates microglia glia leading to pathological pain. We review the critical role of fractalkine in neuron-to-glial communication after peripheral nerve injury and inflammation and explore anti-inflammatory cytokines like interleukin-10 as a novel and effective approach for clinical pain control. KeywordsNeuropathic pain; spinal cord; microglia; astrocytes; interleukin-10; gene therapy Previously Understood Views of PainTraditionally, our understanding about neuronal signaling for pain transmission from the body to the central nervous system (CNS) occurs as a series of relay signals that are eventually processed in the brain. These relay signals are thought to serve protective and adaptive roles, with the first synaptic relay, between the first order (sensory) neuron and the second order neuron in the dorsal horn of the spinal cord. Neurons that receive and respond to pain information are primarily located in anatomically discrete regions of the spinal cord, that is, laminae I, II and V of the spinal cord dorsal horns. From the spinal cord dorsal horn, pain projection neurons relay their information to higher pain centers, such as to the brainstem and various relevant pain areas in the brain. Interestingly, the dorsal horn of the spinal cord can strongly modulate pain signaling (Millan, 1999). Although the neuronal functioning of these pain pathways has been examined for decades, the induction and maintenance of non-adaptive, pathological pain is poorly understood. However, since the early 1990's, there has been mounting evidence that glial cells (both astrocytes and microglia), in addition to neurons, also play a critical role in pain modulation (DeLeo et al., 2007).

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Section: Pathological Pain Statesmentioning

confidence: 99%

Glia in pathological pain: A role for fractalkine

Milligan

Sloane

Watkins

2008

Journal of Neuroimmunology

104

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“…If a radiolabeled substrate is metabolized predominantly by glial cells, then the specific activity of glutamine exceeds that of glutamate. If the substrate is primarily metabolized by neurons, then the specific activity of glutamate is higher (Hassel et al, 1992(Hassel et al, , 2002Van den Berg et al, 1969). 14 C-Labeled malonate gave a specific activity of glutamate that was higher than that of glutamine: 4,850 ± 2,730 dpm/ mol versus 2,360 ± 1,100 dpm/ mol.…”

Section: Malonate Is Primarily Taken Up By Neurons: Radiolabeling Fromentioning

confidence: 99%

Valproate is Neuroprotective against Malonate Toxicity in Rat Striatum: An Association with Augmentation of High-Affinity Glutamate Uptake

Morland

Boldingh

Iversen

et al. 2004

J Cereb Blood Flow Metab

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Summary:The antiepileptic drug valproate (VPA) may be neuroprotective. We treated rats with VPA for 14 days (300 mg/kg twice daily) before intrastriatal injection of 1.5 mol (1 M) of the succinate dehydrogenase inhibitor malonate. VPAtreated animals developed smaller lesions than control animals: 10 ± 2 mm 3 versus 26 ± 8 mm 3 (means ± SD; P ‫ס‬ 10 −4 ). Injection of NaCl that was equiosmolar with 1 M malonate caused lesions of only 1.2 ± 0.4 mm 3 in control animals, whereas physiologic saline produced no lesion. VPA pretreatment reduced the malonate-induced extracellular accumulation of glutamate. This effect paralleled an increase in the striatal level of the glutamate transporter GLT, which augmented highaffinity glutamate uptake by 25%, as determined from the uptake of [ 3 H] glutamate into striatal proteoliposomes. Malonate caused a 76% reduction in striatal adenosine triphosphate (ATP) content, but the glial, ATP-dependent formation of glutamine from radiolabeled glucose or glutamate was intact, indicating that glial ATP production supported uptake of glutamate. Striatal levels of HSP-70 and fos were reduced, and the levels of bcl-2 and phosphorylated extracellular signalregulated kinase remained unaffected, but histone acetylation was increased by VPA treatment. The results suggest that augmentation of glutamate uptake may contribute importantly to VPA-mediated neuroprotection in striatum.

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“…In the brain the only truly anaplerotic reaction is carboxylation of pyruvate to the TCA cycle intermediates malate or oxaloacetate. This process has been thought to occur in astrocytes and not in neurons, because pyruvate carboxylase, one of the pyruvatecarboxylating enzymes in the brain (Patel, 1974), is only expressed in astrocytes (Yu et al, 1983;Shank et al, 1985;Cesar and Hamprecht, 1995), and because intravenous administration of radiolabeled bicarbonate to rats leads to stronger labeling of glutamine than of glutamate (Waelsch et al, 1964), a sign of astrocytic metabolism (Van den Berg et al, 1969;Hassel et al, 1992). The resulting conclusion has been that astrocytes maintain a net export of glutamine to glutamatergic neurons and that these neurons are completely dependent on astrocytes for neurotransmission.…”

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confidence: 99%

Neuronal Pyruvate Carboxylation Supports Formation of Transmitter Glutamate

Hassel

Bråthe

2000

J. Neurosci.

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Release of transmitter glutamate implies a drain of ␣-ketoglutarate from neurons, because glutamate, which is formed from ␣-ketoglutarate, is taken up by astrocytes. It is generally believed that this drain is compensated by uptake of glutamine from astrocytes, because neurons are considered incapable of de novo synthesis of tricarboxylic acid cycle intermediates, which requires pyruvate carboxylation.

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Selective inhibition of glial cell metabolism in vivo by fluorocitrate

Cited by 210 publications

References 18 publications

Glia in pathological pain: A role for fractalkine

Glia in pathological pain: A role for fractalkine

Valproate is Neuroprotective against Malonate Toxicity in Rat Striatum: An Association with Augmentation of High-Affinity Glutamate Uptake

Neuronal Pyruvate Carboxylation Supports Formation of Transmitter Glutamate

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