Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0040822 (tremor)
 18,428 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An attempt was made to establish a decision algorithm for the treatment of idiopathic Parkinson's disease at various stages and in different subgroups such as akinetic-rigid or tremor dominance type. We suggest treating young patients with selegiline and a dopamine agonist. In the tremor dominance type we use either budipine or a dopamine agonist. Due to levodopa-induced dyskinesia, we try to avoid levodopa in the early stages of the disease and use it only later in more advanced situations in a combination therapy with dopamine agonists. Since IPS is not only based upon dopamine deficiency but also on resulting glutamatergic overstimulation, we advocate the use of a glutamate antagonist such as amantadine or budipine. Catechol-O-methyl inhibitors are very helpful when wearing-off occurs. Anticholinergics are only used in the early stages of tremor-dominant IPS because we fear enhancing the risk of dementia.
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PMID:Workshop IV: drug treatment guidelines for the long-term management of Parkinson's disease. 1119 19

A clear picture of the mechanisms of action of the anti-epileptic agent gabapentin is far from being accomplished. We have analyzed the effects of gabapentin on ligand- and voltage-gated currents in isolated adult rat cortical neurons. Gabapentin failed to modify glutamate currents and produced a slight reduction of GABA responses. Negligible inhibition of sodium, but consistent inhibition of high-voltage-activated calcium conductance was promoted by gabapentin. In addition, gabapentin reduced calcium current sensitivity to dihydropyridine agonist and antagonists. Interestingly, gabapentin also decreased a not-inactivating, cadmium-sensitive, potassium current. These unconventional effects might underlie its efficacy in a variety of diseases which involve periodic discharge patterns as neuropathic pain or essential tremor.
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PMID:The effects of gabapentin on different ligand- and voltage-gated currents in isolated cortical neurons. 1124 35

The glutamatergic system is deeply involved in the development of opiate dependence and in the manifestation of opiate abstinence syndrome. In this study the effect of the increase in the endogenous glutamate (GLU) release due to 4-aminopyridine (4-AP), a potassium channel blocker, during the development of morphine (M) physical dependence and during the naloxone (NL)-precipitated abstinence syndrome was investigated. For the development of physical dependence M was intraperitoneally (i.p.) injected for 9 days 105 min following i.p. saline administration to a group of rats. In the first 3 days the dose of M was 10 mg x kg(-1). In the second 3 days the initial dose was doubled (20 mg x kg(-1)) and in the last 3 days the dose of M was raised to 40 mg x kg(-1). On day 10, the rats were divided into three groups at random and these three groups were i.p. given saline 105 min before 80 mg x kg(-1)M, 2 mg x kg(-1) 4-AP 105 min after 80 mg x kg(-1) M, and 80 mg x kg(-1) M 105 min before 2 mg x kg(-1) 4-AP, respectively. In a second group of rats, the rats were i.p. given 2 mg x kg(-1) 4-AP 105 min prior to M administration, which was increased every 3 days (10 mg x kg(-1), 20 mg x kg(-1), 40 mg x kg(-1)). On day 10, the rats were divided into two groups whose first injection was saline and 2 mg x kg(-1) 4-AP, respectively. The second injections of both groups after an interval of 105 min following the first one contained 80 mg x kg(-1) M. In contrast, one group of rats received only i.p. saline at every other injection time (the control group). Furthermore, another group of rats was i.p. administered 2 mg x kg(-1) 4-AP once a day, as the first injection. At the second injection time they were i.p. given saline. After a period of 15 min following the last administration on day 10, the rats belonging to all groups were i.p. injected with 2 mg x kg(-1) NL and immediately placed in a metal cage. Body weight loss (g), teeth chattering, rearing, wet-dog shaking, grooming, and jumping were determined or counted for 15 min. Penile erection, defecation, and diarrhoea were separately scored with one point for every individual occurrence, and the total score was named 'total number of others'. The administration of 4-AP before M appeared to intensify the development of dependence, and was most probably due to the Ca2+-induced inactivation of NMDA receptors as a result of excess release of GLU when the 4-AP took effect. The inactivation of NMDA receptors should have acted as a transient blockade of the receptors during the chronic administration period, and as well as after a single administration on day 10 before M injection and before abstinence. The intensification of the abstinence syndrome may be dependent on the excessive GLU released by 4-AP.
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PMID:The effects of different 4-aminopyridine and morphine combinations on the intensity of morphine abstinence. 1140 16

There is little debate that deep brain stimulation (DBS) has been an effective tool in the treatment of Parkinson's disease as well as other movement disorders. There remains however, considerable debate concerning the mechanism(s) underlying its beneficial effect. The comparable effect of stimulation to ablation in the thalamus on tremor, and in the subthalamic nucleus (STN) and internal segment of the globus pallidus (GPi) on the motor signs associated with PD, have led many investigators to conclude that DBS acts to suppress neuronal activity, decreasing output from the stimulated site. There are, however, data that do not support this argument. Microdialysis studies in GPi showed increased levels of glutamate during STN stimulation, suggesting activation of glutamatergic output from the STN to the GPi. Studies in parkinsonian primates have demonstrated increased mean discharge rates of neurons in GPi during chronic stimulation in STN, and GPi stimulation in humans has been associated with a suppression of neuronal activity in the thalamus. Contrary to what one would expect if stimulation inhibits output from the stimulated structure, stimulation in GPe has been demonstrated to improve bradykinesia. Although arguments for increased output from the stimulated structure seem to conflict with the hypothesis that stimulation acts to inhibit neuronal activity, it is possible to explain these observations through a common mechanism, e.g. activation of fiber pathways. Based on this mechanism, the effect of stimulation on cellular activity in the stimulated site would be increased or decreased dependent on the neurotransmitter of the afferent fibers projecting to that site. However, in addition to activation of afferent fibers, projection axons from neurons in the stimulated structure, also readily excitable by electrical stimulation, would also be tonically activated and discharge independently of the soma, thereby increasing output from the structure during extracellular stimulation. Thus, although high frequency stimulation may inhibit neurons via activation of inhibitory afferents, the output from that structure may be increased as the result of activation of axonal elements leaving the target structure. This hypothesis would explain the present experimental results, is consistent with excitability profiles of neuronal elements based on their biophysical properties, and fits with more recent models emphasizing the role of altered patterns of neuronal activity in the development of hypokinetic and hyperkinetic movement disorders.
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PMID:Mechanisms of deep brain stimulation: excitation or inhibition. 1194 56

Shaken baby syndrome, a rotational acceleration injury, is most common between 3 and 6 months of age and causes death in about 10 to 40% of cases and permanent neurological abnormalities in survivors. We developed a mouse model of shaken baby syndrome to investigate the pathophysiological mechanisms underlying the brain damage. Eight-day-old mouse pups were shaken for 15 seconds on a rotating shaker. Animals were sacrificed at different ages after shaking and brains were processed for histology. In 31-day-old pups, mortality was 27%, and 75% of survivors had focal brain lesions consisting of hemorrhagic or cystic lesions of the periventricular white matter, corpus callosum, and brainstem and cerebellar white matter. Hemorrhagic lesions were evident from postnatal day 13, and cysts developed gradually between days 15 and 31. All shaken animals, with or without focal lesions, had thinning of the hemispheric white matter, which was significant on day 31 but not earlier. Fragmented DNA labeling revealed a significant increase in cell death in the periventricular white matter, on days 9 and 13. White matter damage was reduced by pre-treatment with the NMDA receptor antagonist MK-801. This study showed that shaking immature mice produced white matter injury mimicking several aspects of human shaken baby syndrome and provided evidence that excess release of glutamate plays a role in the pathophysiology of the lesions.
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PMID:Delayed white matter injury in a murine model of shaken baby syndrome. 1214

Certain forms of seizure involve excessive glutamate transmission. We have recently identified a protein, referred to as the inhibitory protein factor (IPF), which potently inhibits glutamate uptake into isolated synaptic vesicles. In an effort to understand the mechanism underlying excessive glutamate transmission associated with seizure, we have analyzed IPF content in various brain regions of the spontaneously epileptic rat, SER (tm/tm, zi/zi), the absence-seizure tremor rat, TM (tm/tm), and the seizure-free control rats zitter ZI (zi/zi) and Wistar tremor control, each at 13 weeks of age. IPF content was found to be markedly reduced in the hippocampus, but not in the other brain regions, of SER, compared to the control and TM rats. TM rats also exhibited reduced IPF content compared to seizure-free controls. These changes appear developmentally regulated; no such alteration was observed in 8-week-old rats, which rarely show seizure. These observations indicate that an aberrant decrease in IPF is associated with certain forms of seizure; this decrease could lead to an abnormal increase in the amount of exocytotically released glutamate through its excessive accumulation in synaptic vesicles.
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PMID:Aberrant reduction of an inhibitory protein factor in a rat epileptic model. 1235 Mar 84

Other investigators have reported that the cerebrospinal fluid (CSF) from patients with Parkinson's disease (PD) might contain endogenous dystrophic factors. Using CSF samples drawn from individual PD patients during surgery, we investigated the toxic effect of ventricular CSF (vCSF) on the growth of PC12 cells and the correlation between the clinical profiles of the patients and CSF neurochemistry. Ventricular CSF samples from 28 patients with PD or essential tremor (ET) were collected during ventriculography for stereotactic pallidotomy or thalamotomy. PC12 cells were incubated with 20% vCSF from both clinical groups for up to 72 h. Microdialysis was used to analyze four neurochemical parameters (glucose, lactate, pyruvate, and glutamate) in each vCSF sample. We observed that vCSF drawn from PD patients exerted nonspecific growth inhibition on PC12 cells in a time-dependent manner. The growth inhibitory action of PD-vCSF decreased significantly after heat treatment. Microdialysis demonstrated no statistical differences between PD and ET samples among the four parameters studied. In addition, PC12 cell survival after 72 h incubation with PD-vCSF correlated with no neurochemical parameter or individual clinical profile (age, onset age, duration of disease, Hoehn & Yahr stage, disease progression rate), except for a slight correlation between vCSF and disease progression rate in heat treated samples from female patients. One or more endogenous cytotoxic factors in PD-vCSF inhibit PC12 cell growth. This factor or factors are partially sensitive to heat which suggests proteins or peptides as possible agents. The cytotoxic effect of PD-vCSF did not directly correlate with any clinical profiles studied or energy metabolism of PD brain.
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PMID:Cytotoxicity of ventricular cerebrospinal fluid from Parkinson patients: correlation with clinical profiles and neurochemistry. 1256 36

The major psychoactive constituent of Cannabis sativa, delta(9)-tetrahydrocannabinol (delta(9)-THC), and endogenous cannabinoid ligands, such as anandamide, signal through G-protein-coupled cannabinoid receptors localised to regions of the brain associated with important neurological processes. Signalling is mostly inhibitory and suggests a role for cannabinoids as therapeutic agents in CNS disease where inhibition of neurotransmitter release would be beneficial. Anecdotal evidence suggests that patients with disorders such as multiple sclerosis smoke cannabis to relieve disease-related symptoms. Cannabinoids can alleviate tremor and spasticity in animal models of multiple sclerosis, and clinical trials of the use of these compounds for these symptoms are in progress. The cannabinoid nabilone is currently licensed for use as an antiemetic agent in chemotherapy-induced emesis. Evidence suggests that cannabinoids may prove useful in Parkinson's disease by inhibiting the excitotoxic neurotransmitter glutamate and counteracting oxidative damage to dopaminergic neurons. The inhibitory effect of cannabinoids on reactive oxygen species, glutamate and tumour necrosis factor suggests that they may be potent neuroprotective agents. Dexanabinol (HU-211), a synthetic cannabinoid, is currently being assessed in clinical trials for traumatic brain injury and stroke. Animal models of mechanical, thermal and noxious pain suggest that cannabinoids may be effective analgesics. Indeed, in clinical trials of postoperative and cancer pain and pain associated with spinal cord injury, cannabinoids have proven more effective than placebo but may be less effective than existing therapies. Dronabinol, a commercially available form of delta(9)-THC, has been used successfully for increasing appetite in patients with HIV wasting disease, and cannabinoid receptor antagonists may reduce obesity. Acute adverse effects following cannabis usage include sedation and anxiety. These effects are usually transient and may be less severe than those that occur with existing therapeutic agents. The use of nonpsychoactive cannabinoids such as cannabidiol and dexanabinol may allow the dissociation of unwanted psychoactive effects from potential therapeutic benefits. The existence of other cannabinoid receptors may provide novel therapeutic targets that are independent of CB(1) receptors (at which most currently available cannabinoids act) and the development of compounds that are not associated with CB(1) receptor-mediated adverse effects. Further understanding of the most appropriate route of delivery and the pharmacokinetics of agents that act via the endocannabinoid system may also reduce adverse effects and increase the efficacy of cannabinoid treatment. This review highlights recent advances in understanding of the endocannabinoid system and indicates CNS disorders that may benefit from the therapeutic effects of cannabinoid treatment. Where applicable, reference is made to ongoing clinical trials of cannabinoids to alleviate symptoms of these disorders.
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PMID:Therapeutic potential of cannabinoids in CNS disease. 1261 97

We administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to adult, male cats to model Parkinson's disease (PD), and utilized proton magnetic resonance imaging (MRI) and spectroscopy (MRS) at a field strength of 1.5 T to identify metabolic degenerative changes in the striatum in vivo. Neurologic status and somatosensory-evoked potentials in vivo, as well as postmortem striatal histopathological and immunohistochemical parameters, were examined. Nine cats were equally divided into three groups and treated daily for 10 days as follows: saline, MPTP, and pargyline (a monoamine oxidase inhibitor) plus MPTP. The MPTP-treated cats displayed bradykinesia, head tremor, and reduced oculovestibular reflex activity. MRI showed a diffuse increase of the T2-weighted signal in the striatum of two MPTP-treated cats. Analysis of the MRS spectra indicated significantly lower N-acetylaspartate/creatine (CR) and glutamine-glutamate complex/CR ratios than the control baseline. Two MPTP-treated cats had low choline-containing compounds/CR ratio, whereas a lactate peak was present in all MPTP-treated cats. In the striatum of the MPTP-treated cats, there was a significant decline of tyrosine hydroxylase immunoreactivity and histological evidence for a diffuse cytotoxic reaction. Pretreatment with pargyline attenuated the MPTP-induced clinical signs, MRI and MRS changes, and the histopathological and immunoreactivity alterations. We conclude that proton MRI/MRS is a sensitive, noninvasive measure of neural toxicity and biochemical alteration of the striatum in a feline model of PD.
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PMID:Proton magnetic resonance imaging and spectroscopy identify metabolic changes in the striatum in the MPTP feline model of parkinsonism. 1261 22

This study examined the nociceptive effects of the intrathecal administration of various doses of the following endogenous excitatory sulphur-containing amino acids (SAAs): L-cysteic acid (L-CA), L-cysteine sulfinic acid (L-CSA), L-homocysteic acid (L-HCA) and L-homocysteic sulfinic acid (L-HCSA). For a period of 10min, rats were observed for spontaneous nociceptive behaviours (SNBs), including: tail elevation, twitching or licking; hindpaw elevation, licking or shaking; and caudally directed biting or scratching. The amount of time each rat spent eliciting these individual behaviours was recorded and a total time (in seconds) spent exhibiting SNBs was then calculated. To determine which glutamate receptors are primarily responsible for these nociceptive behaviours, we pretreated additional groups of rats with selective antagonists for N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid/kainate (AMPA/KA) and group I metabotropic glutamate receptors (mGluR1 and 5). Results indicate that SAAs dose-dependently produce SNBs that are attenuated by NMDA receptor and group I mGluR antagonists.
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PMID:Nociceptive effects of intrathecal administration of sulphur-containing amino acids. 1294


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