Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011168 (dysphagia)
 15,644 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the brain the extracellular concentration of glutamate is controlled by glial transporters that restrict the neurotransmitter action to synaptic sites and avoid excitotoxicity. Impaired transport of glutamate occurs in many cases of amyotrophic lateral sclerosis, a devastating motoneuron disease. Motoneurons of the brainstem nucleus hypoglossus are among the most vulnerable, giving early symptoms like slurred speech and dysphagia. However, the direct consequences of extracellular glutamate build-up, due to uptake block, on synaptic transmission and survival of hypoglossal motoneurons remain unclear and have been studied using the neonatal rat brainstem slice preparation as a model. Patch clamp recording from hypoglossal motoneurons showed that, in about one-third of these cells, inhibition of glutamate transport with the selective blocker dl-threo-beta-benzyloxyaspartate (TBOA; 50 mum) unexpectedly led to the emergence of rhythmic bursting consisting of inward currents of long duration with superimposed fast oscillations and synaptic events. Synaptic inhibition block facilitated bursting. Bursts had a reversal potential near 0 mV, and were blocked by tetrodotoxin, the gap junction blocker carbenoxolone, or antagonists of AMPA, NMDA or mGluR1 glutamate receptors. Intracellular Ca(2+) imaging showed bursts as synchronous discharges among motoneurons. Synergy of activation of distinct classes of glutamate receptor plus gap junctions were therefore essential for bursting. Ablating the lateral reticular formation preserved bursting, suggesting independence from propagated network activity within the brainstem. TBOA significantly increased the number of dead motoneurons, an effect prevented by the same agents that suppressed bursting. Bursting thus represents a novel hallmark of motoneuron dysfunction triggered by glutamate uptake block.
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PMID:Glutamate uptake block triggers deadly rhythmic bursting of neonatal rat hypoglossal motoneurons. 1645 92

Primary lateral sclerosis (PLS) is a rare progressive paralytic disorder that results from dysfunction of the upper motoneurons. Although PLS is a sporadic disorder of adult middle age, it has also been described in children as juvenile PLS or JPLS. The causative gene for JPLS was found to be ALS2, which is also responsible for a recessive form of amyotrophic lateral sclerosis, for infantile onset ascending hereditary spastic paralysis (IAHSP) and for a form of complicated hereditary spastic paraplegia (cHSP). ALS2 gene encodes a protein termed alsin, containing multiple guanine nucleotide exchange factor domains, specifically binding to small GTPase Rab5 and acting as a GEF for Rab5. In vitrostudies performed with full-length and truncating forms of alsin protein support its role in endosomal dynamics and trafficking of mitochondria. All ALS2 mutations so far reported generate alsin protein truncation. Here, we describe the first homozygous missense mutation in ALS2, p.G540E. The mutation, which falls within the RCC1 domain, was identified in a 34-year-old patient with typical signs of JPLS such as ascending generalized and severe spasticity involving the limbs and the bulbar region, dysphagia, limb atrophy, preserved cognition and sensation. The father and two proband's sisters were found to be heterozygous carriers of the mutation with no signs of the disease. Studies in the neuronal cell line SK-N-BE indicated that the known subcellular localization of wild-type alsin with the early endosome antigen 1, in enlarged endosomal structures, and transferrin receptor is completely lost by the mutant protein, thus indicating that this mutation leads to protein delocalization. Mutant alsin induced neuronal death itself and also significantly enhanced the apoptogenic effect of NMDA and staurosporine. This effect was associated with decreased Bcl-xL : Bax ratio. In contrast, wild-type alsin was neuroprotective and increased Bcl-xL : Bax ratio. Our results provide the first demonstration that a missense mutation in alsin is cytotoxic. In addition, the identification of Bcl-xL/Bax as target of protection by alsin and of cytotoxicity by the mutant form provides a new signalling event regulated by alsin protein that may be important to define its role in neuronal physiology and neurodegeneration. Finally, the phenotype-genotype correlation in our patient, in view of all other ALS2 mutant cases reported previously, suggests a functional interplay of long and short forms of alsin in relation to disease onset and progression.
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PMID:The first ALS2 missense mutation associated with JPLS reveals new aspects of alsin biological function. 1667 Jan 79

Asenapine sublingual is a novel atypical antipsychotic approved in August 2009 for the acute treatment of schizophrenia, as well as for manic or mixed episodes as part of adult bipolar I disorder. Asenapine's in vitro profile is similar to other atypical antipsychotic agents insofar as there is higher affinity for serotonin 5-HT(2A) versus dopamine D(2) receptors. Asenapine exhibits a unique effect on monoamine, histamine and muscarinic receptor affinities, as well as effects on NMDA and AMPA receptors. This pharmacodynamic signature may mediate its symptom relief in positive, negative and mood symptoms, as well as conferring upon this agent an improved tolerability and safety profile when compared with some atypical agents. Asenapine has a relatively low propensity for changes in metabolic parameters, body composition, sedation/somnolence and extrapyramidal side effects, and is not associated with prolactin elevation or clinically significant electrocardiographic changes. Asenapine is available only in sublingual formulation, which has advantages (e.g., patient acceptance, compliance, difficulty swallowing) as well as disadvantages (i.e., patients are encouraged not to eat or drink within 10 min of administration). Its efficacy in mania is unequivocally established as is the sustaining of its acute antimanic effect. Its antidepressant and recurrence prevention effects in bipolar disorder are under investigation, as is its possible role in major depressive disorder.
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PMID:Pharmacology and efficacy of asenapine for manic and mixed states in adults with bipolar disorder. 2042 Apr 86

Parkinson's disease (PD) is a common neurodegenerative disease. While its cause remains elusive, much progress has been made regarding its treatment. Available drugs have a good symptomatic effect, but none has yet been shown to slow the progression of the disease in humans. The most efficacious drug is levodopa, but it remains unclear whether the symptomatic benefit is associated with neurotoxic effects and long-term deterioration. The long-term problem associated with levodopa is the appearance of dyskinesias, which is significantly delayed among patients treated with dopamine agonists as initial therapy. Less clear is the role of other drugs in PD, such as monoamine oxidase inhibitors (MAOIs), including selegiline and rasagiline, the putative N-meihyl-o-aspartaie (NMDA) receptor antagonists amantadine and memantine, and the muscarinic receptor blockers. All these may be used as initial therapy and delay the use of dopaminergic drugs, or can be added later to reduce specific symptoms (tremor or dyskinesias). Advanced PD is frequently associated with cognitive decline. To some extent, this can be helped by treatment with cholinesterase inhibitors such as rivastigmine. Similarly, hallucinations and delusions affect PD patients in the advanced stages of their disease. The use of classical neuroleptic drugs in these patients is contraindicated because of their extrapyramidal effects, but atypical drugs, and particularly clozapine, are very helpful. The big void in the therapy of PD lies in the more advanced stages. Several motor symptoms, like postural instability, dysphagia, and dysphonia, as well as dyskinesias, are poorly controlled by existing drugs. New therapies should also be developed against autonomic symptoms, particularly constipation.
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PMID:Drug treatment of Parkinson's disease. 2203 79