CDP-Choline Prevents Glutamate-Mediated Cell Death in Cerebellar Granule Neurons

Mir, Cecilia; Clotet, Josep; Aledo, Rosa; Durany, Núria; Argemí, Josep; Lozano, Rafael; Cervós-Navarro, Jordi; Casals, Núria

doi:10.1385/jmn:20:1:53

Cited by 48 publications

(36 citation statements)

References 25 publications

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“…Together, our results indicate that cPLA2 is upregulated when p25 is produced, resulting in subsequent neuroinflammation and neurodegeneration. Recent studies support our findings where, CDP-choline (a cPLA2 inhibitor) protected neurons from glutamate-mediated neurotoxicity (Mir et al, 2003).…”

supporting

confidence: 86%

Cdk5/p25-Induced Cytosolic PLA2-Mediated Lysophosphatidylcholine Production Regulates Neuroinflammation and Triggers Neurodegeneration

Sundaram¹,

Chan²,

Poore³

et al. 2012

J. Neurosci.

109

100

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The deregulation of cyclin-dependent kinase 5 (Cdk5) by p25 has been shown to contribute to the pathogenesis in a number of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD) and Alzheimer's disease (AD). In particular, p25/Cdk5 has been shown to produce hyperphosphorylated tau, neurofibrillary tangles as well as aberrant amyloid precursor protein processing found in AD. Neuroinflammation has been observed alongside the pathogenic process in these neurodegenerative diseases, however the precise mechanism behind the induction of neuroinflammation and the significance in the AD pathogenesis has not been fully elucidated. In this report, we uncover a novel pathway for p25-induced neuroinflammation where p25 expression induces an early trigger of neuroinflammation in vivo in mice. Lipidomic mass spectrometry, in vitro coculture and conditioned media transfer experiments show that the soluble lipid mediator lysophosphatidylcholine (LPC) is released by p25 overexpressing neurons to initiate astrogliosis, neuroinflammation and subsequent neurodegeneration. Reverse transcriptase PCR and gene silencing experiments show that cytosolic phospholipase 2 (cPLA2) is the key enzyme mediating the p25-induced LPC production and cPLA2 upregulation is critical in triggering the p25-mediated inflammatory and neurodegenerative process. Together, our findings delineate a potential therapeutic target for the reduction of neuroinflammation in neurodegenerative diseases including AD.

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supporting

confidence: 86%

Cdk5/p25-Induced Cytosolic PLA2-Mediated Lysophosphatidylcholine Production Regulates Neuroinflammation and Triggers Neurodegeneration

Sundaram¹,

Chan²,

Poore³

et al. 2012

J. Neurosci.

109

100

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“…Существует немало доказательств того, что нейропротекторный эффект цитиколина в модели острого инсульта частично объясняется его антиглутаматергическими эффектами [10,11]. Даже in vitro цитиколин защищал двигательные нейроны [31], а также лаброциты мозжечка [32] от глута-мат-опосредованного апоптоза. Кроме того, применение антагониста рецепторов NMDA MK-801 совместно с цитиколином продемонстрировало синергичный ней-ропротекторный эффект через 7 дней после временной окклюзии средней мозговой артерии [33].…”

Section: авторадиография рецепторов In Vitrounclassified

Citicoline Enhances Neuroregenerative Processes After Experimental Stroke in Rats

Diederich

Frauenknecht

Minnerup

et al. 2012

Stroke

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Background and Purpose-The neuroprotective potential of citicoline in acute ischemic stroke has been shown in many experimental studies and, although the exact mechanisms are still unknown, a clinical Phase III trial is currently underway. Our present study was designed to check whether citicoline also enhances neuroregeneration after experimental stroke. Methods-Forty Wistar rats were subjected to photothrombotic stroke and treated either with daily injections of citicoline (100 mg/kg) or vehicle for 10 consecutive days starting 24 hours after ischemia induction. Sensorimotor tests were performed after an adequate training period at Days 1, 10, 21, and 28 after stroke. Then brains were removed and analyzed for infarct size, glial scar formation, neurogenesis, and ligand binding densities of excitatory and inhibitory neurotransmitter receptors. Results-Animals treated with citicoline showed a significantly better neurological outcome at Days 10, 21, and 28 after ischemia, which could not be attributed to differences in infarct volumes or glial scar formation. However, neurogenesis in the dentate gyrus, subventricular zone, and peri-infarct area was significantly increased by citicoline. Furthermore, enhanced neurological outcome after citicoline treatment was associated with a shift toward excitation in the perilesional cortex. Conclusions-Our present data demonstrate that, apart from the well-known neuroprotective effects in acute ischemic stroke, citicoline also possesses a substantial neuroregenerative potential. Thanks to its multimodal effects, easy applicability, and history as a well-tolerated drug, Key Words: citicoline Ⅲ neurogenesis Ⅲ receptor autoradiography Ⅲ regeneration Ⅲ stroke A lthough most patients with stroke show some degree of spontaneous functional improvement, 1 recovery is generally far from complete. Therefore, there is an urgent need to identify therapeutic strategies to support endogenous poststroke repair mechanisms. One candidate stroke drug for ischemic stroke with an extended therapeutic window, which is currently under investigation in a randomized, doubleblind, placebo-controlled, multicenter clinical Phase III trial (International Citicoline Trial on Acute Stroke [ICTUS]), is citicoline (also known as cytidine-5-diphosphocholine or CDP-choline). Although citicoline seems to display a multitude of beneficial effects, the exact mechanisms of action are still enigmatic.Citicoline, a naturally occurring endogenous compound, is an essential intermediate in the biosynthesis of phosphatidylcholine. 2 Citicoline has been shown to have neuroprotective effects in a variety of central nervous system injury models, including cerebral ischemia. [3][4][5][6] The suggested mechanisms that may explain the neuroprotective actions of citicoline include prevention of fatty acid release, 7 stimulation of phosphatidylcholine synthesis, 2 preservation of cardiolipin and sphingomyelin levels, 7 increase of glutathione synthesis and glutathione reductase activity, 8 restoration of Na ϩ /K ϩ -ATPase ac...

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“…As preclinical studies suggest that CDP-choline, which is composed of cytidine and choline, may exert a neuroprotective effect by inhibiting the glutamate-induced apoptosis (Hurtado et al, 2005;Mir et al, 2003;Radad et al, 2007), further studies in healthy subjects are warranted to confirm the physiological relationship between cytidine administration and alterations in the cerebral glutamatergic system.…”

Section: Discussionmentioning

confidence: 99%

“…Although precise mechanisms remain unclear, recent preclinical evidence suggests that cytidine exerts a neuroprotective effect through an increase in cerebral highenergy phosphate levels and the reversal of excess glutamate neurotransmission (Hurtado et al, 2005;Mir et al, 2003;Radad et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Decreased Glutamate/Glutamine Levels May Mediate Cytidine’s Efficacy in Treating Bipolar Depression: A Longitudinal Proton Magnetic Resonance Spectroscopy Study

Yoon

Lyoo

Haws

et al. 2009

Neuropsychopharmacol

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Targeting the glutamatergic system has been suggested as a promising new option for developing treatment strategies for bipolar depression. Cytidine, a pyrimidine, may exert therapeutic effects through a pathway that leads to altered neuronal-glial glutamate cycling. Pyrimidines are also known to exert beneficial effects on cerebral phospholipid metabolism, catecholamine synthesis, and mitochondrial function, which have each been linked to the pathophysiology of bipolar depression. This study was aimed at determining cytidine's efficacy in bipolar depression and at assessing the longitudinal effects of cytidine on cerebral glutamate/glutamine levels. Thirty-five patients with bipolar depression were randomly assigned to receive the mood-stabilizing drug valproate plus either cytidine or placebo for 12 weeks. Midfrontal cerebral glutamate/glutamine levels were measured using proton magnetic resonance spectroscopy before and after 2, 4, and 12 weeks of oral cytidine administration. Cytidine supplementation was associated with an earlier improvement in depressive symptoms (weeks 1-4; p ¼ 0.02, 0.001, 0.002, and 0.004, respectively) and also produced a greater reduction in cerebral glutamate/glutamine levels in patients with bipolar depression (weeks 2, 4, and 12; p ¼ 0.004, 0.004, and 0.02, respectively). Cytidinerelated glutamate/glutamine decrements correlated with a reduction in depressive symptoms (p ¼ 0.001). In contrast, these relationships were not observed in the placebo add-on group. The study results suggest that cytidine supplementation of valproate is associated with an earlier treatment response in bipolar depression. Furthermore, cytidine's efficacy in bipolar depression may be mediated by decreased levels of cerebral glutamate and/or glutamine, consistent with alterations in excitatory neurotransmission.

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CDP-Choline Prevents Glutamate-Mediated Cell Death in Cerebellar Granule Neurons

Cited by 48 publications

References 25 publications

Cdk5/p25-Induced Cytosolic PLA2-Mediated Lysophosphatidylcholine Production Regulates Neuroinflammation and Triggers Neurodegeneration

Cdk5/p25-Induced Cytosolic PLA2-Mediated Lysophosphatidylcholine Production Regulates Neuroinflammation and Triggers Neurodegeneration

Citicoline Enhances Neuroregenerative Processes After Experimental Stroke in Rats

Decreased Glutamate/Glutamine Levels May Mediate Cytidine’s Efficacy in Treating Bipolar Depression: A Longitudinal Proton Magnetic Resonance Spectroscopy Study

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