Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Temporal lobe epilepsy (TLE), Parkinson's disease (PD) and Huntington's disease (HD) are neurodegenerative disorders that involve disruptions in gamma-amino butyric acid (GABA) signalling. GABA is the major inhibitory neurotransmitter in the central nervous system (CNS). TLE seizures reflect excess excitation, which may result from local inhibitory circuit dysfunction. PD devastates the input to striatal GABAergic neurones and HD destroys striatal GABAergic neurones. Controlling GABA delivery to specific brain areas should benefit each of these diseases. The molecules responsible for GABA release and signalling are ideal targets for new therapies. In this paper, we discuss the role of GABA in the circuitry affected by each of these diseases and suggest potential sites for intervention. GABA is unique among neurotransmitters because it can be synthesised by either of two related enzymes. Intracellular GABA is found throughout the cytosol and in synaptic vesicles. GABA can be released either through exocytosis, or via the plasma membrane transporter. The synthesising enzyme probably determines the intracellular location and hence the mechanism for GABA release. Directing GABA synthesis, degradation, transport or receptors can control GABA signalling. We propose that new drugs and devices aimed at GABA synthesis, release and binding will offer novel and highly effective treatments for neurodegenerative diseases.
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PMID:GABA signalling: therapeutic targets for epilepsy, Parkinson's disease and Huntington's disease. 1599 78

TCH-346, an anti-apoptotic compound, is under development by Novartis for the potential treatment of Parkinson's disease (PD) and motor neuron disease [271447,342937]. By September 1999, phase I clinical trials for PD were underway [342937]. The compound was discovered in a screen for molecules with both norepinephrine uptake and MAO inhibiting properties but, although it had anti-apoptotic properties, it did not inhibit MAOA or MAO-B [333136,332004]. The compound increases lifespan in the progressive motorneuropathy mouse model and prevents ischemia in models of ischemia and seizure [288893]. In vivo, it shows neurorescuing and anti-apoptotic properties in PC12 cells and cerebellar granule cells, among others, at concentrations of 0.1 pM to 10 microM, suggesting that its action might prove potentially useful against Alzheimer's and/or Parkinson's disease [332004]. The compound has also shown neurorescuing properties in rat pups after axotomy, rat hippocampal CA1 neurons after transient ischemia/hypoxia and mouse nigral dopaminergic (DA) neurons after treatment with MPTP in doses ranging between 0.0003 and 0.1 mg/kg po or sc, depending on the model [333136]. Data presented by the University of Nijmengen and the Free University of Amsterdam show that TCH-346 improves the behavioral and enzymatic outcome in the rat 6-OH-dopamine model of Parkinson's disease. TCH-346 (0.0014 mg/kg sc bid) prevented abnormal stepping (open field test) and prevented increases in fore and hind-paw retraction time. TCH-346 also improved acquisition in the Morris water maze task and, at doses between 0.0014 and 0.14 mg/kg, prevented reduction in tyrosine hydroxylase immunoreactivity [345259]. Affinity binding studies with TCH-346 showed that GAPDH is the target [294902,283200]. Differential display RT-PCR also showed that protein-isoaspartyl-methyl transferase is induced by the drug [283200].
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PMID:TCH-346 (Novartis). 1610 Jun 86

The genetically programmed form of neuronal death known as apoptosis plays a role in many neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS) and Huntington's disease. Apoptosis is also responsible for neuronal death after traumatic brain and spinal cord injury, stroke, and seizures. The cognitive and behavioral consequences of all of these disorders can be devastating. Unfortunately the mechanisms that regulate neuronal apoptosis are complex. However, it is this very complexity that provides us with a wide array of potential targets for the development of anti-apoptotic strategies. Thus, our lab is currently exploring the molecular and cellular mechanisms responsible for neuronal apoptosis, with a particular focus on the role of the metals copper, zinc, and iron. Each of these metals is essential for normal central nervous system (CNS) development and function. However, imbalances, either excess or deficiency, can result in neuronal apoptosis. In this review, we show the relationship between these metals in neurodegenerative disorders and CNS injury, and the mechanisms that govern neuronal survival and apoptosis.
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PMID:Trace metal regulation of neuronal apoptosis: from genes to behavior. 1612 8

Zonisamide is an antiepileptic drug used as adjunctive therapy for refractory partial seizures in adults. Because of the multiple mechanisms of action, it shows a broad spectrum of anticonvulsant activity and has been effective in several types of seizures, including partial and generalized seizures, tonic-clonic seizures and absence seizures in patients unresponsive to other anticonvulsants. Myoclonic epilepsy, Lennox-Gastaut syndrome and infantile spasms have also been treated effectively with zonisamide. Recent clinical studies have demonstrated additional potential for therapeutic use in neuropathic pain, bipolar disorder, migraine, obesity, eating disorders and Parkinson's disease. Despite adverse events, zonisamide is relatively safe and well tolerated in patients, and shows low discontinuation rate. It has a good pharmacokinetic profile and a low drug interaction potential. Zonisamide is considered as a drug that effectively reduces the frequency of partial seizures.
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PMID:Zonisamide: review of its use in epilepsy therapy. 1634 Dec 90

Repetitive transcranial magnetic stimulation (rTMS) has been used as a potential therapeutic tool in various neurological and psychiatric diseases including depression, Parkinson disease, spinocerebellar degeneration, epilepsy, urinary incontinence, movement disorders, chronic pain, migraine and chronic tinnitus, etc. Several reports showed the therapeutic effects of rTMS as a treatment of depression and Parkinson disease (PD), whereas others found no significant effects. It is by now not yet fully understood whether rTMS has a therapeutic effect on those diseases. The controversy arises from the differences of the stimulation parameters and evaluation methods of the effects in those studies. The Japanese multi-center, double blinded, sham stimulation controlled trial in 85 patients with PD showed an efficacy in both the rTMS-treated and sham stimulated patients. This result does not prove the efficacy of the rTMS in PD; on the other hand, it does not rule out the efficacy. Possible mechanism of favorable effects of rTMS is related to increasing the release of dopamine in the mesolimbic and mesostriatal system. The other Japanese multi-center, double blinded, sham stimulation controlled trial in 99 patients with spinocerebellar degeneration revealed significant therapeutic effects of rTMS in 51 patients with SCA6. We studied the effects of rTMS on seizure susceptibility in rats which prevented the development of status epilepticus of pentylenetetrazol-induced convulsions. This finding suggests the possibility of therapeutic use of rTMS in epilepsy. Further studies should be performed aiming to reveal the optimal stimulation parameters, and are necessary to reveal the therapeutic role of the rTMS in neurological and psychiatric diseases.
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PMID:[Clinical applications of transcranial magnetic stimulation for the treatment of various neurological diseases]. 1644 38

The present study assessed the ability of the Dean-Woodcock Sensory-Motor Battery (DWSMB) to distinguish between normal subjects and neurologically impaired individuals. Scores from the subtests of the DWSMB for 250 normal and 250 neurologically impaired individuals were randomly assigned to two equal groups to allow for cross-validation. The DWSMB was able to correctly identify 92.8% of the cases, identifying 94.4% of the normal population and 91.2% of the neurologically impaired subjects. The cross-validation correctly identified 87.2% of the total cases, identifying 91.2% of the normal subjects and 83.2% of the neurologically impaired subjects. An additional discriminant analysis indicated that the DWSMB correctly identified the following cases: 44.9% cardio-vascular accidents, 66.7% multiple sclerosis, 40% seizures, 42% traumatic brain injuries, 62.7% dementia, and 54.5% Parkinson's disease. The results add to the validity of the DWSMB by providing evidence of its ability to differentiate between neurologically impaired and normal individuals.
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PMID:Predicting global and specific neurological impairment with sensory-motor functioning. 1651 17

Cannabinoid CB1 receptors are the most abundant G-protein-coupled receptors in the brain. Its presynaptic location suggests a role for cannabinoids in modulating the release of neurotransmitters from axon terminals by retrograde signaling. The neuroprotective effects of cannabinoid agonists in animal models of ischemia, seizures, hypoxia, Multiple Sclerosis, Huntington and Parkinson disease have been demonstrated in several reports. The proposed mechanism for the neuroprotection ranges from antioxidant effects, reduction of microglial activation and anti-inflammatory reaction to receptor-mediated reduction of glutamate release. In the present work, we analyzed the morphological changes induced by a chronic treatment with the synthetic cannabinoid receptor agonist, WIN 55,212-2, in four brain regions where the CB1 cannabinoid receptor is present in high density: the CA1 hippocampal area, corpus striatum, cerebellum and frontal cortex. After a twice-daily treatment for 14 days with the cannabinoid receptor agonist (3 mg/kg sc, each dose) to male Wistar rats (150-170 g), the expression of neurofilaments (Nf-160 and Nf-200), microtubule-associated protein-2 (MAP-2), synaptophysin (Syn) and glial fibrillary acidic protein (GFAP) was studied by immunohistochemistry and digital image analysis. Ultrastructural study of the synapses was done using electron microscopy. After the treatment, a significant increase in the expression of neuronal cytoskeletal proteins (Nf-160, Nf-200, MAP-2) was observed, but we did not find changes in the expression of GFAP, the main astroglial cytoskeletal protein. In cerebellum, there was an increase in Syn expression and in the number of synaptic vesicles, while, in the hippocampus, an increase in the Syn expression and in the thickness of the postsynaptic densities was observed. The results obtained from these studies provide evidences on the absence of astroglial reaction and a sprouting phenomena induced by the WIN treatment that might be a key contributor to the long-term neuroprotective effects observed after cannabinoid treatments in different models of central nervous system (CNS) injury reported in the literature.
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PMID:Neuronal cytoskeleton and synaptic densities are altered after a chronic treatment with the cannabinoid receptor agonist WIN 55,212-2. 1656 7

Deep brain stimulation is generally a safe and effective method of alleviating motor impairment in advanced-stage Parkinson's disease patients. However, adverse events of surgery have been noted, such as hemorrhage, infection, seizures, and device failure. In this report, we describe 2 cases of the unusual adverse event of ischemia associated with subthalamic nucleus stimulator implantation. We present the intraoperative neurological symptoms, microelectrode recording data, imaging findings, and other correlated events. In the first case, the clinical effects of ischemia were evident intraoperatively and coincided with silence during microelectrode recording from the ischemic region. In the second case, the timing of the ischemic event could not be determined precisely but also was associated with a difficult mapping. Subcortical ischemia may be an underrecognized event that confounds neurophysiological mapping of deep brain structures and affects clinical outcomes.
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PMID:Two cases of ischemia associated with subthalamic nucleus stimulator implantation for advanced Parkinson's disease. 1672 51

The side effects and complications of deep brain stimulation (DBS) and ablative lesions for tremor and Parkinson's disease were recorded in 256 procedures (129 DBS and 127 lesions). Perioperative complications (seizures, haemorrhage, confusion) were rare and did not differ between the two groups. The rate of hardware-related complications was 17.8%. In ventral intermediate (Vim) thalamotomies, the rate of side effects was 74.5%, in unilateral Vim-DBS 47.3%, while in 7 bilateral Vim-DBS 13 side effects occurred. Most of the side effects of Vim-DBS were reversible upon switching off, or altering, stimulation parameters. In unilateral pallidotomy, the frequency of side effects was 21.9%, while in bilateral staged pallidotomies it was 33.3%. Eight side effects occurred in 11 procedures with pallidal DBS. In 22 subthalamic nucleus DBS procedures, 23 side effects occurred, of which 8 were psychiatric or cognitive. Unilateral ablative surgery may not harbour more postoperative complications or side effects than DBS. Some of the side effects following lesioning are transient and most but not all DBS side effects are reversible. In the Vim DBS is safer than lesioning, while in the pallidum, unilateral lesions are well tolerated.
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PMID:Are complications less common in deep brain stimulation than in ablative procedures for movement disorders? 1679 Sep 89

EEG is an important diagnostic method for epilepsies. EEG changes in patients with Parkinson's disease and epilepsy are not unknown or unexpected events. We investigated 250 Parkinson's disease patients. Epileptic seizures were recorded in 10 patients. Four patients had generalized tonic clonic seizures; 3 partial complex seizures, 2 of which with secondary generalization; while 3 patients had right-handed simple motor partial seizure. Clinical and neurophysiological investigations, neuroimagining techniques electroencephalographic investigations (EEG, EEG in sleep) were conducted. Our patients were well controlled with antiepileptic therapy.
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PMID:Association of patients with parkinsonism and epilepsy with EEG changes. 1698 84


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