Possible Mechanisms of Neurodegeneration in Schizophrenia

Pérez-Neri, Iván; Ramı́rez-Bermúdez, Jesús; Montes, Sergio; Rı́os, Camilo

doi:10.1007/s11064-006-9162-3

Cited by 92 publications

(61 citation statements)

References 240 publications

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“…Whether or not selective activation of mGlu2 receptors affects the intrinsic neurodegeneration as- sociated with schizophrenia (reviewed by Lieberman, 1999;Pérez-Neri et al, 2006;Rund, 2009) is an important question that warrants further investigation. Activation of glial mGlu3 receptors was protective against A␤ neurotoxicity to an extent sufficient to overcome the toxic activity of mGlu2 receptors when cultures were treated with the dual agonist, LY379268.…”

Section: Discussionmentioning

confidence: 99%

Targeting Group II Metabotropic Glutamate (mGlu) Receptors for the Treatment of Psychosis Associated with Alzheimer's Disease: Selective Activation of mGlu2 Receptors Amplifies β-Amyloid Toxicity in Cultured Neurons, Whereas Dual Activation of mGlu2 and mGlu3 Receptors Is Neuroprotective

Caraci¹,

Molinaro²,

Battaglia³

et al. 2010

Mol Pharmacol

109

112

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Dual orthosteric agonists of metabotropic glutamate 2 (mGlu2) and mGlu3 receptors are being developed as novel antipsychotic agents devoid of the adverse effects of conventional antipsychotics. Therefore, these drugs could be helpful for the treatment of psychotic symptoms associated with Alzheimer's disease (AD). In experimental animals, the antipsychotic activity of mGlu2/3 receptor agonists is largely mediated by the activation of mGlu2 receptors and is mimicked by selective positive allosteric modulators (PAMs) of mGlu2 receptors. We investigated the distinct influence of mGlu2 and mGlu3 receptors in mixed and pure neuronal cultures exposed to synthetic ␤-amyloid protein (A␤) to model neurodegeneration occurring in AD. The mGlu2 receptor PAM, N-4Ј-cyano-biphenyl-3-yl)-N-(3-pyridinylmethyl)-ethanesulfonamide hydrochloride (LY566332), devoid of toxicity per se, amplified A␤-induced neurodegeneration, and this effect was prevented by the mGlu2/3 receptor antagonist (2S,1ЈS,2ЈS)-2-(9-xanthylmethyl)-2-(2Ј-carboxycyclopropyl)glycine (LY341495). LY566332 potentiated A␤ toxicity regardless of the presence of glial mGlu3 receptors, but it was inactive when neurons lacked mGlu2 receptors. The dual mGlu2/3 receptor agonist, (Ϫ)-2-oxa-4-aminobicyclo[3.1.0]exhane-4,6-dicarboxylic acid (LY379268), was neuroprotective in mixed cultures via a paracrine mechanism mediated by transforming growth factor-␤1. LY379268 lost its protective activity in neurons grown with astrocytes lacking mGlu3 receptors, indicating that protection against A␤ neurotoxicity was mediated entirely by glial mGlu3 receptors. The selective noncompetitive mGlu3 receptor antagonist, (3S)-1-(5-bromopyrimidin-2-yl)-N- (2,4-dichlorobenzyl)pyrrolidin-3-amine methanesulfonate hydrate (LY2389575), amplified A␤ toxicity on its own, and, interestingly, unmasked a neurotoxic activity of LY379268, which probably was mediated by the activation of mGlu2 receptors. These data indicate that selective potentiation of mGlu2 receptors enhances neuronal vulnerability to A␤, whereas dual activation of mGlu2 and mGlu3 receptors is protective against A␤-induced toxicity.

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Section: Discussionmentioning

confidence: 99%

Targeting Group II Metabotropic Glutamate (mGlu) Receptors for the Treatment of Psychosis Associated with Alzheimer's Disease: Selective Activation of mGlu2 Receptors Amplifies β-Amyloid Toxicity in Cultured Neurons, Whereas Dual Activation of mGlu2 and mGlu3 Receptors Is Neuroprotective

Caraci¹,

Molinaro²,

Battaglia³

et al. 2010

Mol Pharmacol

109

112

View full text Add to dashboard Cite

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“…As many methods have been published for the determination of citrulline (e.g., [16][17][18][19][20][21][22][23][24][25][26][27]), the pros and cons of the present method deserve discussion. Like all techniques involving GC/MS [1,25], the current method involves a rather tedious extraction and derivatization procedure, a clear disadvantage compared to ion exchange chromatography [17], HPLC [23,24], or LC-MS [2,22].…”

Section: Discussionmentioning

confidence: 99%

“…HPLC has been used to measure citrulline in cerebrospinal fluid [26], and LC-MS for brain tissue citrulline assay [27]. Yet, fewer methods have been validated for quantifying citrulline in urine [28][29]2] and no data concerning citrulline concentrations in blood cells have been reported.…”

Section: Introductionmentioning

confidence: 99%

Determination of citrulline in human plasma, red blood cells and urine by electron impact (EI) ionization gas chromatography–mass spectrometry

Rougé

Robert

Robins

et al. 2008

Journal of Chromatography B

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“…Post- mortem studies showing the absence of gliosis in schizophrenic brains has been considered a major argument against the idea that SCH is a neurodegenerative disease (Roberts et al, 1986(Roberts et al, ,1987) but neurodegeneration does not necessarily imply gliosis: for example excessive neuritic pruning could account for progressive brain alterations such as a progressive reduction of brain volume (Woods, 1998;Lieberman et al, 2001;Perez-Neri et al, 2006;Theberge et al, 2007).…”

Section: Logistic Regression Analysesmentioning

confidence: 99%

Lempel–Ziv complexity in schizophrenia: A MEG study

Fernández

López‐Ibor

Turrero

et al. 2011

Clinical Neurophysiology

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SchizophreniaLempel-Ziv complexity Magnetoencephalography Neurodevelopmental Neurodegenerative• Schizophrenic patients show higher complexity values as compared to controls.• Schizophrenic patients showed a tendency to reduced complexity values as a function of age while controls showed the opposite tendency.• The tendency observed in schizophrenic patients parallels the tendency observed in Alzheimer disease patients. ABSTRACTObjective: The neurodevelopmental-neurodegenerative debate is a basic issue in the field of the neuropathological basis of schizophrenia (SCH). Neurophysiological techniques have been scarcely involved in such debate, but nonlinear analysis methods may contribute to it. Methods: Fifteen patients (age range 23-42 years) matching DSM IV-TR criteria for SCH, and 15 sex-and age-matched control subjects (age range 23-42 years) underwent a resting-state magnetoencephalographic evaluation and Lempel-Ziv complexity (LZC) scores were calculated. Results: Regression analyses indicated that LZC values were strongly dependent on age. Complexity scores increased as a function of age in controls, while SCH patients exhibited a progressive reduction of LZC values. A logistic model including LZC scores, age and the interaction of both variables allowed the classification of patients and controls with high sensitivity and specificity. Conclusions: Results demonstrated that SCH patients failed to follow the "normal" process of complexity increase as a function of age. In addition, SCH patients exhibited a significant reduction of complexity scores as a function of age, thus paralleling the pattern observed in neurodegenerative diseases. Significance: Our results support the notion of a progressive defect in SCH, which does not contradict the existence of a basic neurodevelopmental alteration.

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Possible Mechanisms of Neurodegeneration in Schizophrenia

Cited by 92 publications

References 240 publications

Targeting Group II Metabotropic Glutamate (mGlu) Receptors for the Treatment of Psychosis Associated with Alzheimer's Disease: Selective Activation of mGlu2 Receptors Amplifies β-Amyloid Toxicity in Cultured Neurons, Whereas Dual Activation of mGlu2 and mGlu3 Receptors Is Neuroprotective

Targeting Group II Metabotropic Glutamate (mGlu) Receptors for the Treatment of Psychosis Associated with Alzheimer's Disease: Selective Activation of mGlu2 Receptors Amplifies β-Amyloid Toxicity in Cultured Neurons, Whereas Dual Activation of mGlu2 and mGlu3 Receptors Is Neuroprotective

Determination of citrulline in human plasma, red blood cells and urine by electron impact (EI) ionization gas chromatography–mass spectrometry

Lempel–Ziv complexity in schizophrenia: A MEG study

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