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)

In rats the application of 10 mg/kg 6-amino-nicotinamide (6-AN) leads to an accumulation of 6-phosphogluconate, by inhibition of 6-phosphogluconate dehydrogenase in the pentose phosphate pathway, in the cells of the spinal cord. The accumulation reaches its maximum after 18-24 h. It seems that there exists a relationship between the accumulation of 6-phosphogluconate and the lesion of the neuroglia, which is found in electron microscopic studies. Symptoms of a spastic paresis only develop later when the spinal interneurones are destroyed as a consequence of the lesion of the neuroglia. The accumulation of 6-phosphogluconate almost exceeds the 400 fold of the norm. No considerable differences are found between the effects of a dose of 35 mg 6-AN/kg and one of 10 mg 6-AN/kg. Free gluconate is identified enzymically in the cells of the spinal cords of the rats treated with 6-AN. The compound is very probably formed by dephosphorylation and diffuses into the blood. 6-Phosphogluconate is an inhibitor of the phosphoglucose isomerase. Its accumulation shifts the equilibrium towards glucose 6-phosphate. The lactate concentration decreases as compared with the untreated controls. Muscular action potentials are recorded extracellularly with a concentric needle electrode from the musculus gastrocnemius of rats treated with 6-AN. First activations of the electromyograms are found 48 h after the application of 10 mg 6-AN/kg. The electrical activities increase during the time in which a progressive destruction of the interneurones occurs. The electromyogram displays a permanent state of excitation with high amplitudes and an increased frequency. The continuity and intensity of the increased activity recorded by the electromyograph is the most important pathological finding. p-Chlorophenyl-GABA and, still more so, chlorpromazine cause temporary reduction of the excitation processes and an electromyogram nearly at rest. Under the same conditions, haloperidol is only slightly effective. The symptoms developed by the chemical destruction of the interneurones of the spinal cord, with rigidity and spasticity of the hind limbs, are suitable for testing antispastic drugs.
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PMID:Spastic paresis after 6-aminonicotinamide: metabolic disorders in the spinal cord and electromyographically recorded changes in the hind limbs of rats. 13 91

A double-blind crossover trial against placebo was conducted to assess the effects of the GABA derivative, baclofen, on the disabilities due to muscle spasticity in twenty children suffering from cerebral palsy. Baclofen performed very significantly better than placebo in reducing spasticity and significantly better than placebo in allowing both active and passive limb movements to be carried out. Notable improvement was also seen in scissoring. Side-effects were minimal and responded promptly to dose reduction. The evaluation of drug effects on muscle spasticity and the pharmacodynamics of baclofen are discussed. Recommendations are made regarding dosage of baclogen in childhood.
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PMID:A controlled trial of baclofen in children with cerebral palsy. 33 90

Following spinal cord transection there occurred decreases in Km and Vmax of glutamate decarboxylase (GAD) both above and below the lesion, and an initial decrease in the concentration of GABA. Concomitantly, there was a gradual decrease in presynaptic inhibition. Eight to 12 weeks after spinal cord transection, Km and Vmax for GAD returned to control values, but the GABA content of the spinal cord below the lesion increased significantly and presynaptic inhibition became maximally depressed. These results suggested that during the chronic phase of spinal cord injury there is a decrease in release of GABA, the interneuronal inhibitory neurotransmitter which mediates presynaptic inhibition. Diazepam, a GABA enhancer, increased presynaptic inhibition in acute and chronic spinal cats, this being accompanied by a reduction in somatic muscular spasticity. The degree of this enhancement by diazepam, however, is attenuated with gradual loss of presynaptic inhibition. In the acute cat, a conditioning volley applied to cutaneous afferents blocked the inhibition of the monosynaptic response to extensor motoneurones. In contrast, in chronic spinal cats (eight to 12 weeks), the duration of complete blockade was markedly reduced and was followed by a prolonged period which cutaneous nerve stimulation potentiated the monosynaptic discharge. Similar to GABA, there also occurred an increase of substance P below the level of the lesion. Other neurotransmitters (e.g., norepinephrine, serotonin) accumulated above and disappeared below the transection level. Although somatic msucular spasticity appears to be, to some extent, due to GABA dysfunction in the spinal cord, alterations in "normal" functioning of other neurotransmitters and the loss of supraspinal control also contribute to this state.
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PMID:Correlation of changes in the GABA-ergic system with the development of spasticity in paraplegic cats. 51 79

Using the clinical quantification of the neurologic symptomatology the authors made observations and avaliated the action of Ciba 34.647-Ba, a GABA derivative, in 12 patients suffering from spasticity and motor incapacity due to spinal cord lesions. The results are reported emphasizing the effects of the drug on the main components of spasticity (hypertonus, hyperactivity of the deep reflexes, clonus and automatisms). Some theories explaining the mechanism of action of the drug are mentioned. References are made about doses, duration of action, tolerance and side-effects.
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PMID:[Clinico-quatitative evaluation of the action of Ciba 34.647-Ba on spasticity]. 58 90

Sites of action of centrally active muscle relaxant drugs are not well defined. Clinical experience with such drugs suggests that the spinal cord may be one of the important regions from which pathologically increased muscle tone may be relieved. Supraspinal centers that may also be involved in the expression of muscle relaxant action have not yet been defined. We report here that microinjections of therapeutically relevant muscle relaxants into the midbrain tegmentum of genetically spastic rats decrease muscle tone. The substantia nigra is the region from which midazolam, baclofen, and tizanidine (drugs used clinically in the treatment of spasticity), or gamma-vinyl-GABA, (-)-2-amino-7-phosphonoheptanoate, and [D-pro2-D-phe7-D-trp9]-substance P (experimental drugs active in animal models of spasticity), reduce muscle tone in genetically spastic rats and Hoffmann reflexes in normal rats. The effects of muscle relaxant drugs are topographically restricted to the substantia nigra pars reticulata and are receptor specific. These observations disclose a previously unknown function of the substantia nigra in mediating muscle relaxation.
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PMID:Substantia nigra: a site of action of muscle relaxant drugs. 197 34

The first part of the paper exposes the basic characteristics of the human spasticity which should be modeled: No hypertonia at rest; velocity-dependent myotatic responses, and fatigability. To model a syndrome including these signs is a related but different problem. Results and limits of the clinical neurophysiology concerning the spasticity are briefly quoted. Animal models would better assist the human neurophysiology when having their neuroanatomy closer to the human one. The second part confirms that a local unilateral excision of the ad hoc sensorimotor cerebral cortice of the Baboon induces a permanent palsy of the contralateral foot and leg, and after delay signs of spasticity in the Sol. Neither clasp-knife phenomenon nor fatigability is observed. There is no sign of motoneuron hyper-excitability. A GABA-related pharmacology suggests a significant defect in the presynaptic inhibition of the reflexogenic IA in-put, and possibly a defect in a post-synaptique gabaergic inhibition. Finally the monkey is considered as a valuable support for modeling the human spasticity, symptom and possibly syndrome.
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PMID:[Animal modeling and experimental pharmacology of human spasticity]. 236 13

Dyskinetic, writhing-like movements, similar to those produced in mice after an intraperitoneal (IP) injection of acetic acid, were elicited by intrathecal (IT) injection of GABA, glycine, taurine or beta-alanine. Baclofen and muscimol failed to produce this behavior. While acetic acid-induced writhing is inhibited by narcotic and nonnarcotic compounds, GABA-induced writhing was found to be insensitive to pretreatment with either morphine or capsaicin. Moreover, acetic acid-induced writhing does not appear to involve GABAergic transmission as IT injections of nipecotic acid did not alter the intensity of response to IP acetic acid while it enhanced the response to IT GABA. Writhing induced by glycine was not inhibited by strychnine at subconvulsive doses, suggesting that it involves an action at strychnine-insensitive receptors. Together these data suggest that while the dyskinetic movements produced by inhibitory amino acids do not appear to reflect an alteration in nociception, they may mimic either the motor response to abdominal pain or spasticity.
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PMID:Intrathecal GABA, glycine, taurine or beta-alanine elicits dyskinetic movements in mice. 272 12

Intrathecal administration of Baclofen, a GABA agonist, through an implantable drug delivery pump has been demonstrated to be effective in the treatment of limb spasticity in patients with myelopathy. Three patients, followed before and after pump placement, experienced satisfactory spasticity relief and improvement in areas of self-care and mobility. Improvement in the bladder management programs of each patient was noted. These changes coincided with improvement on urodynamic studies, defined as either an increase in bladder capacity or a decrease in sphincter dyssynergia. Changes in bladder function were associated with the initiation of intrathecal therapy and with changes in pump-delivered dosages. In selected patients, intrathecal baclofen infusion can have a beneficial effect on bladder management programs.
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PMID:Intrathecal baclofen infusion. Effect on bladder management programs in patients with myelopathy. 273 Jul 79

Baclofen (Lioresal, Ciba-Geigy) is an analog of the inhibitory neurotransmitter GABA and is used clinically to control spasticity. Recent studies have demonstrated that this compound produces a marked inhibition of synaptically evoked responses in area CA3 of the hippocampal slice, suggesting that this drug could influence behavior mediated by the limbic system. In the present study, male rats of the Fischer-344 strain were trained on a one-trial passive avoidance task and tested for retention 1 week later. After the training trial, separate groups of rats received either 5 or 10 mg/kg/4 ml IP of baclofen or the distilled H2O vehicle immediately, 10 min, or 60 min after training. One week later, the rats that received baclofen immediately after training reentered the test chamber with a significantly higher frequency than controls, although no differences in vacillatory responses were observed between groups. Similar effects were observed following posttrial administration of chlordiazepoxide. In a separate experiment rats were tested for locomotor activity after receiving the same doses of baclofen. Although baclofen decreased activity during a 30-min period after dosing, rats exposed to baclofen showed no significant change in activity relative to controls 1 week later. These data are consistent with the interpretation that baclofen may interfere with memory consolidation or retention.
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PMID:Baclofen disrupts passive avoidance retention in rats. 281 19

Electrophysiology of BZR ligands has been reviewed from different points of view. A great effort was made to critically discuss the arguments for and against the temporarily leading hypothesis of the mechanism of action of BZR ligands, the GABA hypothesis. As has been discussed at length in the present article, an impressive body of electrophysiological and biochemical evidence suggests an enhancement of GABAergic inhibition in CNS as a mechanism of action of BZR agonists. Biochemical data even indicate a physical coupling between GABA recognition sites and BZR which, together with the effector site build-up by Cl- channels, form a supramolecular GABAA/BZR complex. By binding to a specific site on this complex, BZR agonists allosterically increase and BZR inverse agonists decrease the gating of GABA-linked Cl- channels, whereas BZR antagonists bind to the same site without an appreciable intrinsic activity and block the binding and action of both agonists as well as inverse agonists. While this model is supported by many electrophysiological experiments performed with BZR ligands in higher nanomolar and lower micromolar concentrations, it does not explain much controversial data from animal behavior and, more importantly, is not in line with electrophysiological effects obtained with low nanomolar BZ concentrations. The latter actions of BZR ligands in brain slices occur within a concentration range compatible with concentrations of BZ observed in CSF fluid, which would be expected to be found in the biophase (receptor level) during anxiolytic therapy in man. Enhanced K+ conductance seems to be a suitable candidate for this effect of BZR ligands. This direct action on neuronal membrane properties may underlie the many electrophysiological observations with extremely low systemic doses of BZR ligands in vivo which demonstrated a depressant effect on spontaneous neuronal firing in various CNS regions. Skeletomuscular spasticity and epilepsy are two neurological disorders, where both the enhanced GABAergic inhibition and increased K+ conductance may contribute to the therapeutic effect of BZR agonists, since electrophysiological and behavioral studies strongly support GABA-dependent as well as GABA-independent action of BZR ligands elicited by low to intermediate doses of BZ necessary to evoke anticonvulsant and muscle relaxant effects. Somewhat higher doses of BZR ligands, inducing sedation and sleep, lead perhaps to the only pharmacologically relevant CNS concentrations (ca. 1 microM) which might be due entirely to increased GABAergic inhibition.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Electrophysiology of benzodiazepine receptor ligands: multiple mechanisms and sites of action. 285 56


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