Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026838 (spasticity)
 6,471 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have investigated the influence on the excitability of lumbar motoneurons of 5-hydroxytryptamine (5-HT), substance P and thyrotropin releasing hormone (TRH), three substances which coexist in the same bulbospinal descending pathway and end in large part around motoneurons. We have also studied the effect of clonidine, an alpha 2 noradrenergic agonist. This was done in spinalized rats (T5) treated three weeks before with 5-7-dihydroxytryptamine. Under those circumstances 5-HTP (I.P.), 5-HT (intrathecally) TRH (I.P. or I.T.) and substance P (I.T.) all elicited a strong excitation of motoneurons as measured by integrated EMG of the hindlimb muscles. Substance P reduced by almost half the subsequent response to 5-HTP, 1 hour and 24 hours later. TRH given acutely did not modify the response to 5-HTP but given chronically for twenty one days by means of Alzet minipump, markedly increased the response to 5-HTP. Clonidine by itself decreased the excitability of motoneurons and antagonized the excitatory effect of 5-HTP and TRH. In a pilot trial, cyproheptadine, a 5-HT antagonist was shown to decrease the manifestations of spasticity in patients with a partial spinal lesion. Clonidine also appears to be of potential use in the treatment of spasticity.
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PMID:Action of 5-hydroxytryptamine, substance P, thyrotropin-releasing hormone and clonidine on motoneurone excitability. 244 57

In a dose of 0.1 mg/kg clonidine, an alpha-2 receptor agonist, depressed the spontaneous EMG activity of the biceps and quadriceps femoris in chronically-spinalized rats. It also antagonized in a dose-dependent manner the stimulating effect of 5-hydroxytryptophan (5-HTP, 100 mg/kg). Doses of more than 0.1 mg/kg were less potent in antagonizing the effect of 5-HTP. Clonidine reduced the tonic activity of the hindlimb muscles but allowed walking movements. The depressant effect of clonidine in animals pretreated with 5-HTP was prevented by yohimbine (1.25 mg/kg), while the depressant action of the serotonin antagonist, cyproheptadine was not. In chronically-spinalized rats, clonidine (0.1 mg/kg) increased the threshold of electrically-induced flexor and extensor reflexes and decreased their amplitude. No significant modification of reflexes was seen with this dose 24 hr after spinalization. Thus, clonidine in doses of 0.1 mg/kg or less reduced directly or indirectly the excitability of motoneurons. Clonidine may prove to be a useful therapeutic adjunct in the treatment of spasticity.
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PMID:Effect of clonidine on motoneuron excitability in spinalized rats. 300 4

Two types of spinal reflex responses, extensor reflex and ventral root potential, were compared physiologically and pharmacologically in acute and chronic spinal cord transected rats. The recovery curve of the extensor reflex, recorded as evoked electromyogram, in chronic spinal rats was strikingly different from that in acute spinal rats. Namely, shortening of the reflex amplitude suppression period (stimulus interval: 20 msec) and appearance of the supernormal period (30-60 msec) were observed in chronic spinal rats. The recovery curves of ventral root potential (monosynaptic reflex) and M wave were almost the same in both preparations. In the frequency depression curve, the amplitude of the extensor reflex in chronic spinal rats was higher at high frequency stimulation than that in acute spinal rats. 5-Hydroxytryptophan, 5-methoxy-N,N-dimethyltryptamine and quipazine enhanced the extensor reflex in chronic spinal rats with a potency of 200-400, 8 and 4 times stronger than that in acute spinal rats, respectively. These drugs did not show consistent effects on the monosynaptic reflex of ventral root potential in chronic spinal rats. These results strongly suggest that the spinal interneurons where descending serotonergic fibers terminate become supersensitive and functionally modified in chronic spinal rats. It is speculated that the supersensitivity of these interneurons may play an important role in spasticity.
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PMID:Functional change in the rat spinal cord by chronic spinal transection and possible roles of monoamine neurons. 387 2

We investigated the influence of four substances on the excitability of lumbar motoneurons. These substances, three of which coexist in the same bulbospinal descending pathways that end, for the most part, around motoneurons (MNS), are: 5-hydroxytryptamine (5-HT), substance P (SP) and thyrotropin-releasing hormone (TRH). We also studied the effects of clonidine, an alpha 2 noradrenergic (NA) agonist. This study was carried out in rats spinalized at T5 and treated three weeks earlier with 5-7 dihydroxytryptamine (5-7 DHT). Under these conditions, the following responses were observed: 5-HTP (5-HT precursor) intraperitoneally (I.P.), 5-HT intrathecally (I.T.), TRH (I.P. or I.T.) and substance P (I.T.) all elicited strong excitation of MNS as measured by integrated EMG of the hindlimb muscles; substance P reduced by almost half the response to 5-HTP given one hour and 24 hours later; TRH given acutely did not modify the response to 5-HTP, but given chronically for 21 days markedly increased the response to this substance. Clonidine by itself decreased the excitability of MNS and antagonized the excitatory effects of 5-HTP and TRH. In two separate pilot trials, cyproheptadine, a 5-HTP antagonist, decreased the manifestations of spasticity in a patient with a partial spinal lesion. It would appear that clonidine may have potential use in the management of spasticity.
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PMID:Action of 5-hydroxytryptamine, substance P, thyrotropin releasing hormone and clonidine on spinal neuron excitability. 754 99

The confirmed pharmacological treatment of cerebellar ataxia is still lacking. In a recent preliminary trial, we showed that D-cycloserine, a partial NMDA allosteric agonist, may relieve the symptoms. In this paper, major clinical trials to relieve ataxic symptoms are reviewed. Previous studies showed some efficacy of physostigmine in ataxic patients. However, physostigmine did not improve the ataxia in a recent double-blind crossover study. The replacement therapy of the deficient cholinergic system with choline or choline derivatives was tried in patients with Friedreich's ataxia and other ataxic patients, but the result was not definitive. A levorotatory form of hydroxytryptophan (a serotonin precursor), a serotoninergic 5-HT1A agonist, a serotoninergic 5-HT3 antagonist, and a serotonin reuptake inhibitor were also used for the therapy for ataxia. In a double-blind randomized study, buspirone, a 5-HT1A agonist was active in cerebellar ataxia, but the effect is partial and not major. The effects of the studies with the other serotoninergic drugs were not consistent. The effect of sulfamethoxazole-trimethoprim therapy in spinocerebellar ataxia type3/Machado-Joseph disease (MJD) was reported, although the therapy improved spasticity or rigidity, rather than ataxia. In contrast to previous studies, sulfamethoxazole-trimethoprim therapy in MJD had no effect in a 2001 double-blind crossover study. The thyrotropin-releasing hormone, D-cycloserine, and acetazolamide for SCA6 may have some efficacy. However, a well-designed double-blind crossover trial is needed to confirm the effect.
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PMID:Pharmacological treatments of cerebellar ataxia. 1523 78

We describe a unique presentation of autosomal recessive (AR) GTP cyclohydrolase I (GTPCH) deficiency, with severe CNS involvement but without hyperphenylalaninemia. A male infant presented with progressive spasticity, dystonia and oculogyric episodes. Blood phenylalanine levels were persistently normal: whereas an oral phenylalanine loading test revealed impaired phenylalanine clearance. CSF neopterin and tetrahydrobiopterin (BH(4)) were low, homovanillic acid marginally low and 5-hydroxyindoleacetic acid normal. Fibroblasts showed decreased GTPCH enzyme activity. A homozygous novel mutation of GCH1, p.V206A, was identified. On treatment (BH(4), L-Dopa/Carbidopa and 5-hydroxytryptophan), motor development improved. Mutational analysis provided neonatal diagnosis of a younger brother who, after 18 months on treatment, shows normal development. AR GTPCH I deficiency can present without hyperphenylalaninemia and with normal or subtle CSF neurotransmitter profiles. Testing for GTPCH deficiency should be considered for patients with unexplained neurological symptoms and extrapyramidal movement disorder.
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PMID:Autosomal recessive GTP cyclohydrolase I deficiency without hyperphenylalaninemia: evidence of a phenotypic continuum between dominant and recessive forms. 1827 79

Sepiapterin reductase (SR) catalyses the last step in the tetrahydrobiopterin biosynthesis pathway; it converts 6-pyruvoyl-tetrahydropterin (6-PTP) to BH(4) in an NADPH-dependent reaction. SR deficiency is a very rare autosomal recessive disorder with normal phenylalanine (Phe) concentration in blood and diagnostic abnormalities are detected in CSF. We present a 16-month-old girl with SR deficiency. From the newborn period she presented with an adaptation regulatory disorder. At the age of 3 months, abnormal eye movements with dystonic signs and at 4.5 months psychomotor retardation were noticed. Since that time axial hypotonia with limb spasticity (or rather delayed reflex development), gastro-oesophageal reflux and fatigue at the end of the day has been observed. Brain MRI was normal; EEG was without epileptiform discharges. Analysis of biogenic amine metabolites in CSF at the age of 16 months showed very low HVA and 5-HIAA concentrations. Analysis of CSF pterins revealed strongly elevated dihydrobiopterin (BH(2)), slightly elevated neopterin and elevated sepiapterin levels. Plasma and CSF amino acids concentrations were normal. A phenylalanine loading test showed increased Phe after 1 h, 2 h and 4 h and very high Phe/Tyr ratios. SR deficiency was confirmed in fibroblasts and a novel homozygous g.1330C>G (p.N127K) SPR mutation was identified. On L-dopa and then additionally 5-hydroxytryptophan, the girl showed slow but remarkable progress in motor and intellectual ability. Now, at the age of 3 years, she is able to sit; expressive speech is delayed (to 1 1/2 years), passive speech is well developed. Her visual-motor skills, eye-hand coordination and social development correspond to the age of 2 1/2 years.
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PMID:Sepiapterin reductase deficiency in a 2-year-old girl with incomplete response to treatment during short-term follow-up. 1913 Feb 91

Defects in the metabolism or regeneration of tetrahydrobiopterin (BH4) were initially discovered in patients with hyperphenylalaninaemia who had progressive neurological deterioration despite optimal metabolic control (malignant hyperphenylalaninaemia). BH4 is an essential cofactor not only for phenylalanine hydroxylase, but also for tyrosine and two tryptophan hydroxylases, three nitric oxide synthases, and glyceryl-ether monooxygenase. Defective activity of tyrosine and tryptophan hydroxylases explains the neurological deterioration in patients with BH4 deficiency with progressive mental and physical retardation, central hypotonia and peripheral spasticity, seizures and microcephaly. Five separate genetic conditions affect BH4 synthesis or regeneration: deficiency of GTP cyclohydrolase I, 6-pyruvoyl tetrahydropterin synthase, sepiapterin reductase, dihydropteridine reductase (DHPR) and pterin-4alpha-carbinolamine dehydratase. Only the latter of these conditions is relatively benign and is associated with transient hyperphenylalaninaemia. All these conditions can be identified in newborns by an elevated phenylalanine, with the exception of sepiapterin reductase and the dominant form of GTP cyclohydrolase I deficiency that results in biopterin deficiency/insufficiency only in the brain. Diagnosis relies on the measurement of pterin metabolites in urine, dihydropteridine reductase in blood spots, neurotransmitters and pterins in the CSF and on the demonstration of reduced enzyme activity (red blood cells or fibroblasts) or causative mutations in the relative genes. The outcome of BH4 deficiency is no longer malignant if therapy is promptly initiated to reduce plasma phenylalanine levels and replace missing neurotransmitters. This is accomplished by a special diet and/or BH4 supplements and administration of L-dopa, carbidopa, 5-hydroxytryptophan, and, in certain cases, a MAO-B inhibitor. Patients with DHPR deficiency also require folinic acid supplements, since DHPR may help in maintaining folate in the tetrahydro form. Several patients with BH4 deficiency treated since the newborn period have reached adult age with good outcome.
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PMID:Disorders of biopterin metabolism. 1923 59

It is well known that spinal motoneurons below a spinal transection become supersensitive to a systemic administration of serotonin (5-HT) precursors, such as 5-hydroxytryptophan. This supersensitivity has been implicated in both the process of functional recovery following chronic lesions, and also in the development of symptoms such as hyperreflexia and spasticity. However, the mechanisms of this denervation supersensitivity are still largely unknown. In this study we have investigated the changes in 5-HT2A receptor immunoreactivity following chronic spinal transections at the level of the sacrocaudal spinal cord. The results show that in the spinalized rats the immunoreactivity of 5-HT2A receptors below the lesion is dramatically increased in the motoneuron soma and its proximal dendritic territory, most likely also in their distal dendritic territory, to a level 3-5-fold higher than that of sham-operated rats. We also found a small number of intraspinal 5-HT neurons and clusters of 5-HT fibers and their varicosities in the spinal cord caudal to the lesion, which may provide an intrinsic source of 5-HT to act upon the upregulated 5-HT2A receptors. These results indicate that the upregulation of 5-HT2A receptors at least partly underlies the 5-HT denervation supersensitivity of spinal motoneurons after a complete spinal transection.
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PMID:Robust upregulation of serotonin 2A receptors after chronic spinal transection of rats: an immunohistochemical study. 2008 55