Choline Release and Inhibition of Phosphatidylcholine Synthesis Precede Excitotoxic Neuronal Death but Not Neurotoxicity Induced by Serum Deprivation

Gasull, Teresa; DeGregorio-Rocasolano, Núria; Zapata, Agustín; Trullás, Ramón

doi:10.1074/jbc.m910468199

Cited by 27 publications

(28 citation statements)

References 38 publications

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“…The endogenous levels of extracellular choline (<10 μM) are sub-threshold for α7 activation (Uteshev et al, 2003) due to choline’s low potency for α7 activation (EC 50 ~0.5 mM) (Papke and Papke, 2002) and tendency to induce α7 desensitization (IC 50 ~40 μM) (Uteshev et al, 2003). However, under conditions of energy deprivation, cellular dysfunction and injury/death, the extracellular concentration of choline can be considerably elevated (Djuricic et al, 1991; Gasull et al, 2000; Kiewert et al, 2010; Rao et al, 2000) providing a large source of this endogenous α7 agonist. Significantly elevated levels of choline have been recently demonstrated by direct measurements in the ischemic core and penumbra in the middle cerebral artery occlusion (MCAO) model of ischemic stroke in rats (Kiewert et al, 2010).…”

Section: Exploring Nicotinic-pams As Therapeutic Alternatives To Omentioning

confidence: 99%

The therapeutic promise of positive allosteric modulation of nicotinic receptors

Uteshev

2014

European Journal of Pharmacology

106

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In the central nervous system, deficits in cholinergic neurotransmission correlate with decreased attention and cognitive impairment, while stimulation of neuronal nicotinic acetylcholine receptors improves attention, cognitive performance and neuronal resistance to injury as well as produces robust analgesic and anti-inflammatory effects. The rational basis for the therapeutic use of orthosteric agonists and positive allosteric modulators (PAMs) of nicotinic receptors arises from the finding that functional nicotinic receptors are ubiquitously expressed in neuronal and non-neuronal tissues including brain regions highly vulnerable to traumatic and ischemic types of injury (e.g., cortex and hippocampus). Moreover, functional nicotinic receptors do not vanish in age-, disease- and trauma-related neuropathologies, but their expression and/or activation levels decline in a subunit- and brain region-specific manner. Therefore, augmenting the endogenous cholinergic tone by nicotinic agents is possible and may offset neurological impairments associated with cholinergic hypofunction. Importantly, because neuronal damage elevates extracellular levels of choline (a selective agonist of α7 nicotinic acetylcholine receptors) near the site of injury, α7-PAM-based treatments may augment pathology-activated α7-dependent auto-therapies where and when they are most needed (i.e., in the penumbra, post-injury). Thus, the nicotinic-PAM-based treatments are expected to be highly efficacious with fewer side effects as compared to a more indiscriminate action of exogenous orthosteric agonists. In this review, I will summarize the existing trends in therapeutic applications of nicotinic PAMs.

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Section: Exploring Nicotinic-pams As Therapeutic Alternatives To Omentioning

confidence: 99%

The therapeutic promise of positive allosteric modulation of nicotinic receptors

Uteshev

2014

European Journal of Pharmacology

106

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“…[31] As a result, the therapeutic effects of α7 agonists may develop tolerance. [33,34] Therefore, endogenous nicotinic agonists have been dismissed as therapeutic agents even though the extracellular concentration of choline can be considerably elevated by energy deprivation, cellular dysfunction, injury and death due to the cell membrane phosphatidylcholine breakdown[35-39,29,40] providing a large source of this selective α7 agonist. Significant elevations in the extracellular level of choline have been recently demonstrated by direct measurements in the peri-infarct areas after a middle cerebral artery occlusion (MCAO) model of cerebral ischemic stroke in rats.…”

Section: Introductionmentioning

confidence: 99%

Boosting Endogenous Resistance of Brain to Ischemia

Sun

Johnson²,

Jin

et al. 2016

Mol Neurobiol

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Most survivors of ischemic stroke remain physically disabled and require prolonged rehabilitation. However, some stroke victims achieve a full neurological recovery suggesting that human brain can defend itself against ischemic injury, but the protective mechanisms are unknown. This study used selective pharmacological agents and a rat model of cerebral ischemic stroke to detect endogenous brain protective mechanisms that require activation of α7 nicotinic acetylcholine receptors (nAChRs). This endogenous protection was found to be: 1) limited to less severe injuries; 2) significantly augmented by intranasal administration of a positive allosteric modulator of α7 nAChRs, significantly reducing brain injury and neurological deficits after more severe ischemic injuries; and 3) reduced by inhibition of calcium/calmodulin-dependent kinase-II. The physiological role of α7 nAChRs remains largely unknown. The therapeutic activation of α7 nAChRs after cerebral ischemia may serve as an important physiological responsibility of these ubiquitous receptors and holds a significant translational potential.

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“…The size of the 'immobile' pool (in proximity to membranes) could be reduced, the kinetics of exchange between mobile and immobile fractions could be altered or the chemical composition and thus relaxation characteristics of the choline peak could be changed. NMDA overactivation leading to membrane damage has been shown to increase extracellular choline before excitotoxic cell death and to inhibit the incorporation of [methyl-3 H] choline in membrane PC and SM (23)(24)(25). This process could be one explanation for the observed decreased MT effect postictally.…”

Section: Discussionmentioning

confidence: 80%

Magnetisation transfer ratio of choline is reduced following epileptic seizures

2006

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The purpose of this study was to characterise the concentration and magnetisation transfer ratio (MTR) of brain metabolites following epileptic seizures. Magnetic resonance spectroscopy was performed in 10 patients with temporal or extra-temporal lobe epilepsy as soon as possible after a seizure, with a second interictal scan between 1 and 3 days after the postictal scan and 10 healthy controls were scanned twice. Voxels (26 +/- 2 mL) were placed in the frontal lobe in all patients and controls, on the side of seizure focus in the patient group. Spectra were obtained using a modified PRESS sequence (TE 30 ms, TR 3 s, with three hard pulses offset from the water frequency by 2,500 Hz for MT presaturation). Mean metabolite concentrations and median metabolite MTRs of N-acetylaspartate (NAA), creatine, choline (Cho), myo-inositol (Ins) and glutamate plus glutamine were compared between the first and second scans in each group. A significant decrease in the MTR of Cho was seen postictally in the patient group, but the metabolite concentrations showed no significant difference between interictal and postictal scans and in the control group there was no difference between the two scans. Inter-group comparison showed significantly reduced concentrations of NAA and Ins in the patients. Reduced MTR of Cho indicates a shift from a bound to a more mobile fraction. These changes might indicate membrane perturbation in areas of seizure spread.

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Choline Release and Inhibition of Phosphatidylcholine Synthesis Precede Excitotoxic Neuronal Death but Not Neurotoxicity Induced by Serum Deprivation

Cited by 27 publications

References 38 publications

The therapeutic promise of positive allosteric modulation of nicotinic receptors

The therapeutic promise of positive allosteric modulation of nicotinic receptors

Boosting Endogenous Resistance of Brain to Ischemia

Magnetisation transfer ratio of choline is reduced following epileptic seizures

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