Effects of MgSO Alone or Associated with 4-PBA on Behavior and White Matter Integrity in a Mouse Model of Cerebral Palsy: A Sex- and Time-Dependent Study.

Cerebral palsy (CP) is defined as permanent disorders of movement and posture. Prematurity and hypoxia-ischemia (HI) are risk factors of CP, and boys display a greater vulnerability to develop CP. Magnesium sulfate (MgSO) is administered to mothers at risk of preterm delivery as a neuroprotective agent.

In utero alcohol exposure exacerbates endothelial protease activity from pial microvessels and impairs GABA interneuron positioning.

In utero alcohol exposure can induce severe neurodevelopmental disabilities leading to long-term behavioral deficits. Because alcohol induces brain defects, many studies have focused on nervous cells. However, recent reports have shown that alcohol markedly affects cortical angiogenesis in both animal models and infants with fetal alcohol spectrum disorder (FASD).

Why considering sexual differences is necessary when studying encephalopathy of prematurity through rodent models.

Preterm birth is a high-risk factor for the development of gray and white matter abnormalities, referred to as "encephalopathy of prematurity," that may lead to life-long motor, cognitive, and behavioral impairments. The prevalence and clinical outcomes of encephalopathy of prematurity differ between sexes, and elucidating the underlying biological basis has become a high-priority challenge. Human studies are often limited to assessment of brain region volumes by MRI, which does not provide much information about the underlying mechanisms of lesions related to very preterm birth.

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

Cerebral lesions acquired in the perinatal period can induce cerebral palsy (CP), a multifactorial pathology leading to lifelong motor and cognitive deficits. Several risk factors, including perinatal hypoxia-ischemia (HI), can contribute to the emergence of CP in preterm infants. Currently, there is no international consensus on treatment strategies to reduce the risk of developing CP.

Magnesium Sulfate Prevents Neurochemical and Long-Term Behavioral Consequences of Neonatal Excitotoxic Lesions: Comparison Between Male and Female Mice.

Magnesium sulfate (MgSO4) administration to mothers at risk of preterm delivery is proposed as a neuroprotective strategy against neurological alterations such as cerebral palsy in newborns. However, long-term beneficial or adverse effects of MgSO4 and sex-specific sensitivity remain to be investigated. We conducted behavioral and neurochemical studies of MgSO4 effects in males and females, from the perinatal period to adolescence in a mouse model of cerebral neonatal lesion.

Experimental and clinical evidence of differential effects of magnesium sulfate on neuroprotection and angiogenesis in the fetal brain.

Clinical studies showed beneficial effects of magnesium sulfate regarding the risk of cerebral palsy. However, regimen protocols fluctuate worldwide and risks of adverse effects impacting the vascular system have been reported for human neonates, keeping open the question of the optimal dosing. Using clinically relevant concentrations and doses of magnesium sulfate, experiments consisted of characterizing, respectively, ex vivo and in vivo, the effects of magnesium sulfate on the nervous and vascular systems of mouse neonates by targeting neuroprotection, angiogenesis, and hemodynamic factors and in measuring, in human fetuses, the impact of a 4-g neuroprotective loading dose of magnesium sulfate on brain hemodynamic parameters.

Prefrontal tetanic stimulation, following fear reconditioning, facilitates expression of previously acquired extinction.

We have recently shown that post-extinction retraining of rats, with a shock intensity that is too weak to induce by itself significant fear acquisition, impairs the recall of fear extinction memory. Tetanic stimulation (TS) of the medial prefrontal cortex (mPFC), applied before or following this retraining, facilitates extinction recall. Here we investigated whether mPFC TS can also facilitate expression of fear extinction when rats are retrained with the same shock intensity as during the initial fear acquisition.

Prefrontal high-frequency stimulation prevents sub-conditioning procedure-provoked, but not acute stress-provoked, reemergence of extinguished fear.

We have recently shown that post-extinction exposure of rats to a sub-conditioning procedure (SCP, i.e., retraining with a shock intensity that is too weak to induce by itself significant fear conditioning) or to acute stress provokes reemergence of extinguished fear.

Low-frequency stimulation of the ventral hippocampus facilitates extinction of contextual fear.

Difficulties to treat fear-associated disorders, including posttraumatic stress disorder, are thought to result from dysfunction in fear extinction learning and/or memory. Animal studies on extinction modulation are therefore promising for the development of new treatments. Recent rat studies, including ones using low-frequency stimulation (LFS), have demonstrated that the ventral hippocampus (VH) modulates extinction memory.

Post-extinction fluoxetine treatment prevents stress-induced reemergence of extinguished fear.

Rationale: The post-extinction exposure of rats to a sub-conditioning procedure (SCP; i.e., retraining with a shock intensity that is too weak to induce by itself significant fear conditioning) has been reported to provoke the reemergence of extinguished fear.

Molecular and electrophysiological changes in the prefrontal cortex-amygdala-dorsal periaqueductal grey pathway during persistent pain state and fear-conditioned analgesia.

Fear-conditioned analgesia (FCA) is the reduction in pain responding which is expressed upon re-exposure to a context previously paired with an aversive stimulus. Projections along the prefrontal cortex (PFC)-amygdala-dorsal periaqueductal grey (dPAG) pathway may mediate FCA. However, there is a paucity of studies measuring both molecular and electrophysiological changes in this pathway in rats expressing persistent pain-related behaviour or FCA.

Promethazine protects against 3-nitropropionic acid-induced neurotoxicity.

Promethazine (PMZ), an FDA-approved antihistaminergic drug, was identified as a potentially neuroprotective compound in a NINDS screening program. It was shown to protect against ischemia in mice, to delay disease onset in a mouse model of amyotrophic lateral sclerosis and to inhibit Ca(2+)-induced mitochondrial permeability transition in rat liver mitochondria. We investigated whether PMZ could protect against the neurotoxic effects induced by 3-nitropropionic acid (3-NP), an inhibitor of the succinate dehydrogenase, used to model Huntington's disease (HD) in rats.

Therapeutic effects of coenzyme Q10 (CoQ10) and reduced CoQ10 in the MPTP model of Parkinsonism.

Coenzyme Q10 (CoQ10) is a promising agent for neuroprotection in neurodegenerative diseases. We tested the effects of various doses of two formulations of CoQ10 in food and found that administration in the diet resulted in significant protection against loss of dopamine (DA), which was accompanied by a marked increase in plasma concentrations of CoQ10. We further investigated the neuroprotective effects of CoQ10, reduced CoQ10 (ubiquinol), and CoQ10 emulsions in the (MPTP) model of Parkinson's disease (PD).

Expression profiling of Huntington's disease models suggests that brain-derived neurotrophic factor depletion plays a major role in striatal degeneration.

Many pathways have been proposed as contributing to Huntington's disease (HD) pathogenesis, but generally the in vivo effects of their perturbation have not been compared with reference data from human patients. Here we examine how accurately mechanistically motivated and genetic HD models recapitulate the striatal gene expression phenotype of human HD. The representative genetic model was the R6/2 transgenic mouse, which expresses a fragment of the huntingtin protein containing a long CAG repeat.

Functional engraftment of human ES cell-derived dopaminergic neurons enriched by coculture with telomerase-immortalized midbrain astrocytes.

To direct human embryonic stem (HES) cells to a dopaminergic neuronal fate, we cocultured HES cells that were exposed to both sonic hedgehog and fibroblast growth factor 8 with telomerase-immortalized human fetal midbrain astrocytes. These astrocytes substantially potentiated dopaminergic neurogenesis by both WA09 and WA01 HES cells, biasing them to the A9 nigrostriatal phenotype. When transplanted into the neostriata of 6-hydroxydopamine-lesioned parkinsonian rats, the dopaminergic implants yielded a significant, substantial and long-lasting restitution of motor function.

Mice lacking alpha-synuclein are resistant to mitochondrial toxins.

Abnormalities in the function of alpha-synuclein are implicated in the pathogenesis of Parkinson's disease (PD). We found that alpha-synuclein-deficient mice are resistant to MPTP-induced degeneration of dopaminergic neurons. There was dose-dependent protection against loss of both dopamine in the striatum and dopamine transporter (DAT) immunoreactive neurons in the substantia nigra.

Promethazine protects against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity.

Promethazine (PMZ) is an FDA-approved antihistaminergic drug that was identified as a potentially neuroprotective compound in the NINDS screening program. PMZ accumulates in brain mitochondria in vivo and inhibits Ca2+-induced mitochondrial permeability transition pore (PTP) in rat liver mitochondria in vitro. We hypothesized that PMZ may have a protective effect in a mitochondrial toxin model of Parkinson's disease (PD).

Celastrol protects against MPTP- and 3-nitropropionic acid-induced neurotoxicity.

Oxidative stress and inflammation are implicated in neurodegenerative diseases including Parkinson's disease (PD) and Huntington's disease (HD). Celastrol is a potent anti-inflammatory and antioxidant compound extracted from a perennial creeping plant belonging to the Celastraceae family. Celastrol is known to prevent the production of proinflammatory cytokines, inducible nitric oxide synthase and lipid peroxidation.

Neuroprotective effects of phenylbutyrate against MPTP neurotoxicity.

There is increasing evidence that administration of histone deacetylase (HDAC) inhibitors can exert neuroprotective effects by a variety of mechanisms. Phenylbutyrate is a well-known HDAC inhibitor, which increases gene transcription of a number of genes, and also exerts neuroprotective effects. These include several antioxidant enzymes, chaperones, and genes involved in cell survival.

Apparent opposite effects of tetrabenazine and reserpine on the toxic effects of 1-methyl-4-phenylpyridinium or 6-hydroxydopamine on nigro-striatal dopaminergic neurons.

It is well documented that VMAT2 protects nigrostriatal DA neurons against MPP(+) by sequestering it inside vesicles away from its mitochondrial site of neurotoxic action. However, the implication of the VMAT2 in the mechanism of action exerted by 6-OHDA has received little attention. Therefore, the aim of the present study was to determine whether the vesicular sequestration of 6-OHDA would protect dopaminergic neurons from its toxicity similarly to what is observed with MPP(+).