piperidines and glutaric-acid

The endocannabinoid system (ECS) regulates several physiological processes in the Central Nervous System, including the modulation of neuronal excitability via activation of cannabinoid receptors (CBr). Both glutaric acid (GA) and quinolinic acid (QUIN) are endogenous metabolites that, under pathological conditions, recruit common toxic mechanisms. A synergistic effect between them has already been demonstrated, supporting potential implications for glutaric acidemia type I (GA I). Here we investigated the possible involvement of a cannabinoid component in the toxic model exerted by QUIN + GA in rat cortical slices and primary neuronal cell cultures. The effects of the CB1 receptor agonist anandamide (AEA), and the fatty acid amide hydrolase inhibitor URB597, were tested on cell viability in cortical brain slices and primary neuronal cultures exposed to QUIN, GA, or QUIN + GA. As a pre-treatment to the QUIN + GA condition, AEA prevented the loss of cell viability in both preparations. URB597 only protected in a moderate manner the cultured neuronal cells against the QUIN + GA-induced damage. The use of the CB1 receptor reverse agonist AM251 in both biological preparations prevented partially the protective effects exerted by AEA, thus suggesting a partial role of CB1 receptors in this toxic model. AEA also prevented the cell damage and apoptotic death induced by the synergic model in cell cultures. Altogether, these findings demonstrate a modulatory role of the ECS on the synergic toxic actions exerted by QUIN + GA, thus providing key information for the understanding of the pathophysiological events occurring in GA I.

Topics: Animals; Arachidonic Acids; Benzamides; Cannabinoid Receptor Agonists; Carbamates; Cell Survival; Cells, Cultured; Cerebral Cortex; Drug Synergism; Endocannabinoids; Female; Glutarates; Male; Neurons; Piperidines; Polyunsaturated Alkamides; Pregnancy; Pyrazoles; Quinolinic Acid; Rats; Rats, Inbred WF; Receptors, Cannabinoid

Parkinson's disease (PD) is the world's second most common dementia, which the drugs available for its treatment have not had effects beyond slowing the disease process. Recently nanotechnology has induced the chance for designing and manufacturing new medicines for neurodegenerative disease. It is demonstrated that by tuning the size of a nanoparticle, the physiological effect of the nanoparticle can be controlled. Using novel nanochelating technology, three nano complexes: Pas (150 nm), Paf (100 nm) and Pac (40 nm) were designed and in the present study their neuroprotective effects were evaluated in PC12 cells treated with 1-methyl-4-phenyl-pyridine ion (MPP (+)). PC12 cells were pre-treated with the Pas, Paf or Pac nano complexes, then they were subjected to 10 μM MPP (+). Subsequently, cell viability, intracellular free Calcium and reactive oxygen species (ROS) levels, mitochondrial membrane potential, catalase (CAT) and superoxide dismutase (SOD) activity, Glutathione (GSH) and malondialdehyde (MDA) levels and Caspase 3 expression were evaluated. All three nano complexes, especially Pac, were able to increase cell viability, SOD and CAT activity, decreased Caspase 3 expression and prevented the generation of ROS and the loss of mitochondrial membrane potential caused by MPP(+). Pre-treatment with Pac and Paf nano complexes lead to a decrease of intracellular free Calcium, but Pas nano complex could not decrease it. Only Pac nano complex decreased MDA levels and other nano complexes could not change this parameter compared to MPP(+) treated cells. Hence according to the results, all nanochelating based nano complexes induced neuroprotective effects in an experimental model of PD, but the smallest nano complex, Pac, showed the best results.

Topics: Animals; Apoptosis; Calcium; Caspase 3; Catalase; Cell Survival; Glutarates; Glutathione; Iron Chelating Agents; Malondialdehyde; Membrane Potential, Mitochondrial; Mitochondria; Nanoparticles; Neuroprotective Agents; PC12 Cells; Piperidines; Polymerization; Pyrazoles; Rats; Reactive Oxygen Species; Superoxide Dismutase

Glutaric aciduria type 1 (GA-1) is an inborn error of metabolism that results from a deficiency of glutaryl-CoA dehydrogenase. This disorder mainly manifests in early childhood and most patients with this condition develop a dystonic-dyskinetic syndrome. We report the anesthetic management of two sisters with GA-1, aged 30 and 17 months respectively at the time of surgery, who presented with macrocephaly and psychomotor delay. The children required CSF shunting procedures for hydrocephalus and subdural fluid collections, which were performed under total intravenous anesthesia with propofol and remifentanil.

Topics: Anesthesia; Anesthetics, Intravenous; Cerebrospinal Fluid Shunts; Child, Preschool; Dystonic Disorders; Female; Glutarates; Glutaryl-CoA Dehydrogenase; Head; Humans; Hydrocephalus; Infant; Metabolism, Inborn Errors; Piperidines; Propofol; Psychomotor Disorders; Remifentanil; Siblings

Glutaryl-CoA dehydrogenase deficiency is a neurometabolic disorder with a specific age- and region-dependent neuropathology. Between 6 and 18 mo of age, unspecific illnesses trigger acute encephalopathic crises resulting in acute striatal and cortical necrosis. We hypothesized that acute brain damage in glutaryl-CoA dehydrogenase deficiency is caused by the main pathologic metabolites 3-hydroxyglutaric and glutaric acids through an excitotoxic sequence. Therefore, we investigated the effect of 3-hydroxyglutaric acid and glutaric acid on primary neuronal cultures from chick embryo telencephalons and mixed neuronal and glial cell cultures from neonatal rat hippocampi. Exposure to glutaric acid and 3-hydroxyglutaric acid decreased cell viability in a concentration- and time-dependent fashion. This neurotoxic effect could be totally prevented by preincubation with an N-methyl-D-aspartate receptor subunit 2B (NR2B)-specific antagonist, NR2B antibodies, and an unspecific N-methyl-D-aspartate receptor blocker and was partially blocked with an NR2A-specific antagonist but not with NR2A antibodies or alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor and metabotropic glutamate receptor antagonists. Furthermore, metabolite toxicity increased in parallel with the increasing expression of the NR2B subunit on cultured neurons from second to sixth day in vitro. We conclude from these results that 3-hydroxyglutaric acid and glutaric acid act as false neurotransmitters, in particular through NR1/2B, and that the extent of induced neurotoxicity is dependent on the temporal and spatial expression of NR1/2B in the CNS during maturation. Beyond favorable implications for treatment and long-term prognosis, glutaryl-CoA dehydrogenase deficiency is the first neurologic disease in which specific neuropathology could be experimentally linked to ontogenetic expression of a particular neurotransmitter receptor subtype.

Topics: Animals; Antibodies; Brain Diseases, Metabolic, Inborn; Cells, Cultured; Chick Embryo; Dizocilpine Maleate; Glutarates; Glutaryl-CoA Dehydrogenase; Neurons; Oxidoreductases; Oxidoreductases Acting on CH-CH Group Donors; Piperidines; Rats