Time- and sex-dependent efficacy of magnesium sulfate to prevent behavioral impairments and cerebral damage in a mouse model of cerebral palsy

Daher, Ismaël; Dieu-Lugon, Bérénice Le; Lecointre, Maryline; Dupré, Nicolas; Voisin, Caroline; Leroux, Philippe; Dourmap, Nathalie; Gonzalez, Bruno J.; Marret, Stéphane; Leroux-Nicollet, Isabelle; Cléren, Carine

doi:10.1016/j.nbd.2018.08.020

Cited by 22 publications

(30 citation statements)

References 47 publications

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“…Recent studies have demonstrated that the serum and brain magnesium levels were decreased in Alzheimer's disease (AD), cerebral injury, and other neurological abnormalities (Daher et al . ; Meloni et al . ).…”

Section: Discussionmentioning

confidence: 99%

Crystal structure and catalytic activity of the PPM1K N94K mutant

Dolatabad

Guo

Peng

et al. 2019

Journal of Neurochemistry

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AbstractsProtein Phosphatase Mg 2+ /Mn 2+ -Dependent 1K (PPM1K), also named as PP2Cm or branched-chain a-ketoacid dehydrogenase complex phosphatase, is a member of the metal-dependent phosphatase family and an important metabolic regulator. Single nucleotide polymorphisms (SNPs) in PPM1K contributing to protein functional defects have been found to be associated with numerous human diseases, such as cardiovascular disease, maple syrup urine disease, type 2 diabetes, and neurological disease. PPM1K N94K is an identified missense mutant produced by one of the SNPs in the human PPM1K coding sequence. However, the effects of the N94K mutant on its activity and structural property have not been defined. Here, we performed a detailed enzymological study using steady-state kinetics in the presence of pNPP or phospho-peptide substrates and crystallographic analyses of the wild-type and N94K PPM1K. The PPM1K-N94K significantly impaired its Mg 2+ -dependent catalytic activity and structural analysis demonstrated that the N94K mutation induced a conformational change in the key residue in coordinating the Mg 2+ in the active site. Specifically, three Mg 2+ were located in the active site of 1 These authors contributed equally to this work. Abbreviations used: ALS, amyotrophic lateral sclerosis; BCAA, branched-chain amino acid; BCKA, branched-chain a-ketoacid; BCKD, branched-chain a-ketoacid dehydrogenase; BCKDE1a, branched-chain a-ketoacid decarboxylase (E1) alpha subunit; BDP, branched-chain a-ketoacid dehydrogenase phosphatase; BSA, bovine serum albumin; E. coli, Escherichia coli; E1b, branched-chain a-ketoacid decarboxylase/ dehydrogenase; EDTA, Ethylene-diaminetetraacetic acid; HEPES, 4-(2hydroxyethyl)-1-piperazine-ethanesulfonic acid; IPTG, isopropyl b-D-1thiogalactopyranoside; LB, Luria-Bertani broth; MSUD, maple syrup urine disease; PCR, polymerase chain reaction; p-E1b, phospho-E1b; PEG, polyethylene glycol; PMSF, phenylmethane sulfonyl fluoride; pNPP, p-nitrophenyl phosphate; PP2Cm, PP2C phosphatase of mitochondrial matrix residence; PPM1A, protein phosphatase Mg 2+ /Mn 2+ -Dependent 1A; PPM1G, protein phosphatase Mg 2+ /Mn 2+ -Dependent 1G; PPM1K, protein phosphatase Mg 2+ /Mn 2+ -Dependent 1K; PPM, metal-dependent protein phosphatase; RRID, research resource identifier; SDS-PAGE, sodium dodecyl sulfate-polyacrylamide gel electrophoresis; TEV, tobacco etch virus; TRIS, tris(hydroxymethyl) aminomethane; WT, wild type. 550the PPM1K N94K instead of two Mg 2+ in the PPM1K wild type. Therefore, our results provide a structure basis for the metal ion-dependent PPM1K-N94K phosphatase activity.Keywords: active site, crystal structure, phosphatase activity, protein phosphatase Mg 2+ /Mn 2+ -dependent 1K, single nucleotide polymorphisms, third metal ion.

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Section: Discussionmentioning

confidence: 99%

Crystal structure and catalytic activity of the PPM1K N94K mutant

Dolatabad

Guo

Peng

et al. 2019

Journal of Neurochemistry

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“…35 This model has been widely accepted and applied in animal studies on perinatal hypoxic-ischemic brain injury. 35,36 This was the first study based on pros and cons, to indicate that CIMT might promote the remodeling of neurons, neurofilament, dendrites/axon, and myelin in the motor cortex of mice by partially inhibiting the Nogo-A/NgR/RhoA/ROCK pathway and to suggest that brain structural remodeling drives functional reorganization which substantially improves the motor function of HCP mice. Studying the beneficial mechanism of CIMT on HCP mice might provide a promising target for drug intervention and optimize the clinical application of CIMT.…”

Section: Discussionmentioning

confidence: 99%

Constraint-Induced Movement Therapy Promotes Neural Remodeling and Functional Reorganization by Overcoming Nogo-A/NgR/RhoA/ROCK Signals in Hemiplegic Cerebral Palsy Mice

Liu

Wang

Hé

et al. 2021

Neurorehabil Neural Repair

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Background. Little is known about the induction of functional and brain structural reorganization in hemiplegic cerebral palsy (HCP) by constraint-induced movement therapy (CIMT). Objective. We aimed to explore the specific molecular mechanism of functional and structural plasticity related to CIMT in HCP. Methods. The mice were divided into a control group and HCP groups with different interventions (unconstraint-induced movement therapy [UNCIMT], CIMT or siRNA-Nogo-A [SN] treatment): the HCP, HCP+UNCIMT, HCP+CIMT, HCP+SN, and HCP+SN+CIMT groups. Rotarod and front-limb suspension tests, immunohistochemistry, Golgi-Cox staining, transmission electron microscopy, and Western blot analyses were applied to measure motor function, neurons and neurofilament density, dendrites/axon areas, myelin integrity, and Nogo-A/NgR/RhoA/ROCK expression in the motor cortex. Results. The mice in the HCP+CIMT group had better motor function, greater neurons and neurofilament density, dendrites/axon areas, myelin integrity, and lower Nogo-A/NgR/RhoA/ROCK expression in the motor cortex than the HCP and HCP+UNCIMT groups ( P < .05). Moreover, the expression of Nogo-A/NgR/RhoA/ROCK, the improvement of neural remodeling and motor function of mice in the HCP+SN group were similar to those in the HCP+CIMT group ( P > .05). The neural remodeling and motor function of the HCP+SN+CIMT group were significantly greater than those in the HCP+SN and HCP+CIMT groups ( P < .05). Motor function were positively correlated with the density of neurons ( r = 0.450 and 0.309, respectively; P < .05) and neurofilament ( r = 0.717 and 0.567, respectively; P < .05). Conclusions. CIMT might promote the remodeling of neurons, neurofilament, dendrites/axon areas, and myelin in the motor cortex by partially inhibiting the Nogo-A/NgR/RhoA/ROCK pathway, thereby promoting the improvement of motor function in HCP mice.

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“…To evaluate the impact of remifentanil on brain lesion size, a target sample size of 56 pups, equally distributed ( n = 28 in each group), was calculated, using the statistical software provided by BiostaTGV (https://biostatgv.sentiweb.fr), to detect a 30% reduction in the size of an ibotenate-induced lesion, with a type I error (two-sided) of 5% and a power of at least 90%. The other sample sizes were estimated based on previous experiments (19, 29, 30, 38, 39). A p < 0.05 was considered statistically significant.…”

Section: Methodsmentioning

confidence: 99%

Beneficial Effects of Remifentanil Against Excitotoxic Brain Damage in Newborn Mice

et al. 2019

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Background: Remifentanil, a synthetic opioid used for analgesia during cesarean sections, has been shown in ex vivo experiments to exert anti-apoptotic activity on immature mice brains. The present study aimed to characterize the impact of remifentanil on brain lesions using an in vivo model of excitotoxic neonatal brain injury. Methods: Postnatal day 2 (P2) mice received three intraperitoneal injections of remifentanil (500 ng/g over a 10-min period) or saline just before an intracortical injection of ibotenate (10 μg). Cerebral reactive oxygen species (ROS) production, cell death, in situ labeling of cortical caspase activity, astrogliosis, inflammation mediators, and lesion size were determined at various time points after ibotenate injection. Finally, behavioral tests were performed until P18. Results: In the injured neonatal brain, remifentanil significantly decreased ROS production, cortical caspase activity, DNA fragmentation, interleukin-1β levels, and reactive astrogliosis. At P7, the sizes of the ibotenate-induced lesions were significantly reduced by remifentanil treatment. Performance on negative geotaxis (P6-8) and grasping reflex (P10-12) tests was improved in the remifentanil group. At P18, a sex specificity was noticed; remifentanil-treated females spent more time in the open field center than did the controls, suggesting less anxiety in young female mice. Conclusions: In vivo exposure to remifentanil exerts a beneficial effect against excitotoxicity on the developing mouse brain, which is associated with a reduction in the size of ibotenate-induced brain lesion as well as prevention of some behavioral deficits in young mice. The long-term effect of neonatal exposure to remifentanil should be investigated.

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Time- and sex-dependent efficacy of magnesium sulfate to prevent behavioral impairments and cerebral damage in a mouse model of cerebral palsy

Cited by 22 publications

References 47 publications

Crystal structure and catalytic activity of the PPM1K N94K mutant

Crystal structure and catalytic activity of the PPM1K N94K mutant

Constraint-Induced Movement Therapy Promotes Neural Remodeling and Functional Reorganization by Overcoming Nogo-A/NgR/RhoA/ROCK Signals in Hemiplegic Cerebral Palsy Mice

Beneficial Effects of Remifentanil Against Excitotoxic Brain Damage in Newborn Mice

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