piperidines and Rett-Syndrome

Severely arrhythmic breathing is a hallmark of Rett syndrome (RTT) and profoundly affects quality of life for patients and their families. The last decade has seen the identification of the disease-causing gene, methyl-CpG-binding protein 2 (Mecp2) and the development of mouse models that phenocopy many aspects of the human syndrome, including breathing dysfunction. Recent studies have begun to characterize the breathing phenotype of Mecp2 mutant mice and to define underlying electrophysiological and neurochemical deficits. The picture that is emerging is one of defects in synaptic transmission throughout the brainstem respiratory network associated with abnormal expression in several neurochemical signaling systems, including brain-derived neurotrophic factor (BDNF), biogenic amines and gamma-amino-butyric acid (GABA). Based on such findings, potential therapeutic strategies aimed at improving breathing by targeting deficits in neurochemical signaling are being explored. This review details our current understanding of respiratory dysfunction and underlying mechanisms in RTT with a particular focus on insights gained from mouse models.

Topics: Animals; Dioxoles; Disease Models, Animal; Epigenesis, Genetic; Humans; Methyl-CpG-Binding Protein 2; Mice; Mutation; Piperidines; Respiration Disorders; Respiratory Center; Respiratory System; Rett Syndrome

Rett Syndrome (RTT) is an X-linked neurodevelopmental disorder caused mainly by mutations in the MECP2 gene. One of the major RTT features is breathing dysfunction characterized by periodic hypo- and hyperventilation. The breathing disorders are associated with increased brainstem neuronal excitability, which can be alleviated with GABA agonists. Since neuronal hypoexcitability occurs in the forebrain of RTT models, it is necessary to find pharmacological agents with a relative preference to brainstem neurons. Here we show evidence for the improvement of breathing disorders of Mecp2-disrupted mice with the brainstem-acting drug cloperastine (CPS) and its likely neuronal targets. CPS is an over-the-counter cough medicine that has an inhibitory effect on brainstem neuronal networks. In Mecp2-disrupted mice, CPS (30 mg/kg, i.p.) decreased the occurrence of apneas/h and breath frequency variation. GIRK currents expressed in HEK cells were inhibited by CPS with IC

Topics: Animals; Antitussive Agents; Brain Stem; Dose-Response Relationship, Drug; Female; G Protein-Coupled Inwardly-Rectifying Potassium Channels; GABA Agonists; gamma-Aminobutyric Acid; HEK293 Cells; Humans; Mice; Mice, Transgenic; Organ Culture Techniques; Piperidines; Potassium Channel Blockers; Presynaptic Terminals; Rats; Respiration; Rett Syndrome

Rett syndrome is a neurological disorder caused by loss of function mutations in the gene that encodes the DNA binding protein methyl-CpG-binding protein 2 (Mecp2). A prominent feature of the syndrome is disturbances in respiration characterized by frequent apnea and an irregular interbreath cycle. 8-Hydroxy-2-dipropylaminotetralin has been shown to positively modulate these disturbances (Abdala AP, Dutschmann M, Bissonnette JM, Paton JF, Proc Natl Acad Sci U S A 107: 18208-18213, 2010), but the mode of action is not understood. Here we show that the selective 5-HT1a biased agonist 3-chloro-4-fluorophenyl-(4-fluoro-4-{[(5-methylpyrimidin-2-ylmethyl)-amino]-methyl}-piperidin-1-yl)-methanone (F15599) decreases apnea and corrects irregularity in both heterozygous Mecp2-deficient female and in Mecp2 null male mice. In whole cell voltage-clamp recordings from dorsal raphe neurons, F15599 potently induced an outward current, which was blocked by barium, reversed at the potassium equilibrium potential, and was antagonized by the 5-HT1a antagonist WAY100135. This is consistent with somatodendritic 5-HT1a receptor-mediated activation of G protein-coupled inwardly rectifying potassium channels (GIRK). In contrast, F15599 did not activate 5-HT1b/d receptors that mediate inhibition of glutamate release from terminals in the nucleus accumbens by a presynaptic mechanism. Thus F15599 activated somatodendritic 5-HT1a autoreceptors, but not axonal 5-HT1b/d receptors. In unanesthetized Mecp2-deficient heterozygous female mice, F15599 reduced apnea in a dose-dependent manner with maximal effect of 74.5 ± 6.9% at 0.1 mg/kg and improved breath irrregularity. Similarly, in Mecp2 null male mice, apnea was reduced by 62 ± 6.6% at 0.25 mg/kg, and breathing became regular. The results indicate respiration is improved with a 5-HT1a agonist that activates GIRK channels without affecting neurotransmitter release.

Topics: Action Potentials; Animals; Apnea; Brain; Disease Models, Animal; Female; G Protein-Coupled Inwardly-Rectifying Potassium Channels; Glutamic Acid; Male; Methyl-CpG-Binding Protein 2; Mice; Mice, Inbred C57BL; Piperidines; Potassium; Pyrimidines; Raphe Nuclei; Receptor, Serotonin, 5-HT1A; Respiration; Rett Syndrome; Serotonin; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT1 Receptor Antagonists; Synaptic Transmission

Rett syndrome (RTT) is a neurodevelopmental disability characterized by mutations in the X-linked methyl-CpG-binding protein 2 located at the Xq28 region. The severity is modified in part by X chromosomal inactivation resulting in wide clinical variability. We hypothesized that the ability to perform the activities of daily living (ADL) is correlated with the density of vesicular acetylcholine transporters in the striata of women with RTT. The density of the vesicular acetylcholine transporters in the living human brain can be estimated by single-photon emission-computed tomography (SPECT) after the administration of (-)-5-[¹²³I]iodobenzovesamicol ([¹²³I]IBVM). Twenty-four hours following the intravenous injection of ∼333 MBq (9 mCi) [¹²³ I]IBVM, four women with RTT and nine healthy adult volunteer control participants underwent SPECT brain scans for 60 min. The Vesicular Acetylcholine Transporter Binding Site Index (Kuhl et al., 1994), a measurement of the density of vesicular acetylcholine transporters, was estimated in the striatum and the reference structure, the cerebellum. The women with RTT were assessed for certain ADL. Although the striatal Vesicular Acetylcholine Transporter Binding Site Index was not significantly lower in RTT (5.2 ± 0.9) than in healthy adults (5.7 ± 1.6), RTT striatal Vesicular Acetylcholine Transporter Binding Site Indices and ADL scores were linearly associated (ADL = 0.89*(Vesicular Acetylcholine Transporter Binding Site Index) + 4.5; R² = 0.93; P < 0.01), suggesting a correlation between the ability to perform ADL and the density of vesicular acetylcholine transporters in the striata of women with RTT. [¹²³I]IBVM is a promising tool to characterize the pathophysiological mechanisms of RTT and other neurodevelopmental disabilities.

Topics: Activities of Daily Living; Adult; Brain; Female; Humans; Male; Methyl-CpG-Binding Protein 2; Mutation; Piperidines; Rett Syndrome; Tetrahydronaphthalenes; Tomography, Emission-Computed, Single-Photon; Vesicular Acetylcholine Transport Proteins

We describe a case of 8-year-old female patient with Rett syndrome undergoing bilateral tonsillectomy and adenotomy. She was monitored with BIS and neuromuscular monitor using TOF during total intravenous anesthesia (TIVA) with propofol, remifentanil, ketamine and rocuronium. A relatively high infusion rate of propofol (10 mg x kg x hr(-1)) was maintained to keep BIS between 60 and 70 during the surgical procedure, and rocuronium 10 mg IV was administered for tracheal intubation without its further administration during the surgical procedure. Although prolonged effects of anesthetics, analgesics and neuromuscular blockade were reported frequently, she took uneventful course during anesthesia and surgery. Her recovery from anesthesia and neuromuscular blockade was also smooth associated with satisfactory sedated states. BIS and neuromuscular monitor may be useful in TIVA for a patient with Rett syndrome.

Topics: Adenoviridae; Androstanols; Anesthesia, Intravenous; Child; Consciousness Monitors; Female; Humans; Ketamine; Monitoring, Intraoperative; Neuromuscular Blockade; Neuromuscular Junction; Piperidines; Propofol; Remifentanil; Rett Syndrome; Rocuronium; Tonsillectomy

Rett syndrome (RTT) is caused by loss-of-function mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2). Although MeCP2 is thought to act as a transcriptional repressor of brain-derived neurotrophic factor (BDNF), Mecp2 null mice, which develop an RTT-like phenotype, exhibit progressive deficits in BDNF expression. These deficits are particularly significant in the brainstem and nodose cranial sensory ganglia (NGs), structures critical for cardiorespiratory homeostasis, and may be linked to the severe respiratory abnormalities characteristic of RTT. Therefore, the present study used Mecp2 null mice to further define the role of MeCP2 in regulation of BDNF expression and neural function, focusing on NG neurons and respiratory control. We find that mutant neurons express significantly lower levels of BDNF than wild-type cells in vitro, as in vivo, under both depolarizing and nondepolarizing conditions. However, BDNF levels in mutant NG cells can be increased by chronic depolarization in vitro or by treatment of Mecp2 null mice with CX546, an ampakine drug that facilitates activation of glutamatergic AMPA receptors. Ampakine-treated Mecp2 null mice also exhibit marked functional improvement, characterized by restoration of normal breathing frequency and minute volume. These data demonstrate that BDNF expression remains plastic in Mecp2 null mice and raise the possibility that ampakine compounds could be of therapeutic value in the treatment of RTT.

Topics: Analysis of Variance; Anesthetics, Local; Animals; Animals, Newborn; Brain-Derived Neurotrophic Factor; Cells, Cultured; Depsipeptides; Dioxoles; Disease Models, Animal; Gene Expression Regulation; Methyl-CpG-Binding Protein 2; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurons; Nodose Ganglion; Piperidines; Plethysmography; Rett Syndrome; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tetrodotoxin

The decline in choline acetyltransferase activity has been identified previously within the brains of patients with Rett syndrome and Alzheimer's disease. The level of [3H]vesamicol binding to a terminal vesicular acetylcholine transporter is inversely related to the decline in cortical choline acetyltransferase activity in Alzheimer's disease, which may be due to compensatory processes within surviving cholinergic terminals. In order to investigate whether similar cholinergic compensatory processes are present in the Rett syndrome brain and are altered by normal aging, we investigated the density of cholinergic vesicular transporters in (i) the brains of Rett syndrome patients, and (ii) young and old rats with experimentally-induced cholinergic cell loss. In Rett syndrome, a significant decline in choline acetyltransferase activity within the putamen and thalamus was directly correlated with a decline in [3H]vesamicol binding. In both young and old rats, basal forebrain lesions decreased cortical choline acetyltransferase activity significantly, while [3H]vesamicol binding was unchanged. In contrast to young and old lesioned rats and patients with Alzheimer's disease, cholinergic cells in the brains of patients with Rett syndrome do not compensate for the loss of cholinergic cells by increasing acetylcholine vesicular storage.

Topics: Acetylcholine; Adolescent; Adult; Aging; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Basal Ganglia; Cerebral Cortex; Child; Child, Preschool; Choline O-Acetyltransferase; Excitatory Amino Acid Agonists; Female; Humans; Neuromuscular Depolarizing Agents; Piperidines; Putamen; Rats; Rats, Inbred F344; Rett Syndrome; Thalamus