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)

The continual suppression of emotions during fight or flight reactions results in atrophy and endogenous toxicosis in noradrenergic neurons. Diminished synaptic levels of norepinephrine are associated with depression. During periodic detoxification crises excess norepinephrine and other metabolites flood synapses. The norepinephrine overexcites postsynaptic neurons and causes symptoms ranging from mild anxiety to violent behavior. Some of the other metabolites, which may include dopamine, epinephrine, serotonin, gamma-aminobutyric acid, peptides, amino acids, and various metabolic waste products, are bound by noradrenergic receptors and alter neurotransmission. When they prevent norepinephrine from exciting postsynaptic neurons, depression returns. A mechanism is proposed for the binding of norepinephrine and for the effects of the other metabolites, many of which have been thought to be neurotransmitters. The diverse receptor proteins presumed to be specific for false neurotransmitters may instead encode specific memories. The shift in depressive and excitatory behavior is characteristic of nearly all nervous and mental disorders, including addictions, Alzheimer's disease, Parkinson's disease, and psychosomatic disorders. When toxins accumulate in regions of the brain that control specific activities, the symptoms observed will be related to those activities, giving rise to supposedly distinct disorders that represent the same detoxification process. Recovery can be facilitated by therapy and self-help measures that involve the releasing and redirecting of repressed emotions. Full text: http://homepages.nyu.edu/~er26/toxicmind.html [corrected].
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PMID:The toxic mind: the biology of mental illness and violence. 1079 Jul 41

Disturbance in phosphorylation/dephosphorylation can trigger apoptosis. Little is known as to its effects on mesencephalic dopamine neurons, the major neurons lost in Parkinson's disease. In this study, okadaic acid (OKA), a phosphatase 1 and 2A inhibitor, with greater potency toward 2A, was toxic to mesencephalic dopamine and gamma-aminobutyric acid (GABA) neurons, however, dopamine neurons were 4-fold more sensitive. The EC(50) for dopamine versus GABA toxicity was 1.5 versus 6.5 nM, respectively, and was consistent with an inhibition of phosphatase 2A. Dopamine neurons were also more sensitive to calyculin-A, a phosphatase inhibitor equipotent toward 1 and 2A. OKA-methyl-ester, which lacks phosphatase inhibitory activity, was without effect. DNA laddering typical of apoptosis was observed in cultures at a concentration that was specifically toxic to dopamine neurons (5 nM). In contrast to the sensitivity of mesencephalic neurons to phosphatase inhibition, inhibition of protein kinase activity with staurosporine or K252a showed little toxicity and protected neurons from OKA. Consistent with in vitro findings, infusion of 32 to 320 pmol of OKA into the left striatum of rats caused a dose-dependent loss of striatal dopamine without any loss of GABA 1 week following infusion. Acutely, OKA increased tyrosine hydroxylase activity, a phosphatase 2A substrate, and increased dopamine turnover. The above-mentioned findings demonstrate that dysregulation of phosphatase activity is detrimental to mesencephalic neurons, with dopamine neurons, in vitro and in vivo, being relatively more sensitive to phosphatase 2A inhibition. Disturbances in the phosphorylation control of proteins unique to dopamine neurons may contribute to their enhanced vulnerability to OKA exposure.
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PMID:Differential sensitivity of mesencephalic neurons to inhibition of phosphatase 2A. 1150 86

The substantia nigra is an important brain nucleus involved in the expression of movement disorders and seizures. The two most common movement disorders affecting the substantia nigra, Parkinson's disease and Tourette syndrome, show gender differences and age-related onset. To assess the substrates for the gender and age specificity of substantia nigra-related disorders, we determined the functional properties of the substantia nigra gamma-aminobutyric acid (GABAA) system along its anterior-posterior axis, using localized microinfusions of muscimol (a GABAA agonist) and susceptibility to motor seizures in rats. In the substantia nigra, there are sex-specific differences in the topographic segregation and functionality of GABAA systems. In mature male rats there are two distinct regions mediating opposite effects on seizures; in female rats there is only one region that can affect seizures. In the neonatal period, the presence of circulating testosterone is essential for the development of a substantia nigra region that exerts proconvulsant effects throughout the rat's life, a unique feature of the male substantia nigra. The final maturation of the substantia nigra occurs in the peripubertal period, and is in part regulated by testosterone as well. The recognition of the existence of distinct sex- and age-specific substantia nigra features can be translated into new cures of disorders affecting the substantia nigra.
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PMID:Sexual dimorphism and developmental regulation of substantia nigra function. 1170 65

High frequency electrical stimulation by means of electrodes implanted into the brain (deep brain stimulation; DBS) recently has become an accepted technique for the treatment of several movement disorders and in particular for Parkinson's disease. Because the effects produced by DBS are similar to those produced by making a lesion in the same region, it has been proposed that the overall effect of DBS is to inhibit the neural activity in the region stimulated. However, whether this is actually the case is presently not known, but various mechanisms have been proposed in an attempt to explain how DBS could mimic the effects of a lesion. We describe the various mechanisms that have been proposed to account for the inhibition or disruption of the pathologic outflow by high-frequency DBS, ranging from depolarisation block to stimulation-evoked release of gamma-aminobutyric acid and describes preliminary findings that show that stimulation within these structures can result in inhibition.
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PMID:Mechanisms of deep brain stimulation. 1194 58

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) alleviates Parkinson's disease (PD) symptoms. Although widely used, the mechanisms of action are still unknown. In an attempt to elucidate those mechanisms, we have previously demonstrated that STN-DBS increases striatal extracellular dopamine (DA) metabolites in anaesthetized rats. PD being a movement disorder, it remains to be determined whether these findings are related to any relevant motor or behavioural changes. Thus, this study investigates concomitant behavioural changes during STN-DBS and extracellular striatal DA metabolites measured using microdialysis in freely moving 6-hydroxydopamine-lesioned rats. STN-DBS induced an increase of striatal DA metabolites in awake, freely moving animals. Furthermore, we observed concomitant contralateral circling behaviour. Taken together, these results suggest that STN-DBS could disinhibit (consequently activate) substantia nigra compacta neurons via inhibition of gamma-aminobutyric acid-ergic substantia nigra reticulata neurons.
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PMID:Deep brain stimulation of subthalamic neurons increases striatal dopamine metabolism and induces contralateral circling in freely moving 6-hydroxydopamine-lesioned rats. 1213 66

Dopamine (DA), a major neurotransmitter used in the striatum, is involved in movement disorders such as Parkinson's disease and Huntington's chorea. With the loss of neurons in the striatum of patients with Huntington's disease (HD), there is an associated downregulation of DA receptors, which may alter DA-mediated responses. In the present study, DA-mediated electrophysiological depression was studied in animals with quinolinic acid (QA)-induced experimental HD. QA was directly applied to the right striatum of adult female Sprague-Dawley rats. Animals receiving QA developed ipsilateral rotation after the application of apomorphine. Fetal striatal tissue transplants grafted 1 month after lesioning attenuated apomorphine-induced rotation. Six months after lesioning, the animals were anesthetized with urethane for electrophysiological study. DA, applied directly to neurons by pressure microejection, inhibited spontaneous single-unit activity in the striatal neurons of nonlesioned, lesioned and lesioned/grafted rats. QA lesioning reduced responses to DA in the striatal neurons. The dose of DA required to inhibit striatal neuron activity in the lesioned rats was significantly increased compared to that in the nonlesioned rats. Transplantation of fetal striatal tissue restored the electrophysiological sensitivity to DA in the lesioned striatum. The dose of DA used to suppress striatal neuron activity was reduced after grafting. Immunohistostaining showed survival of gamma-aminobutyric acid neurons at the graft site. Tyrosine hydroxylase-positive terminals were found innervating the striatal grafts. In conclusion, our data demonstrate that fetal striatal transplants restore electrophysiological sensitivity to DA in the lesioned striatum of animals with experimental HD.
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PMID:Fetal striatal transplants restore electrophysiological sensitivity to dopamine in the lesioned striatum of rats with experimental Huntington's disease. 1214 27

The gamma-aminobutyric acid A (GABA(A)) receptor subunit expression of the dopaminergic cells of the substantia nigra (SN) was investigated in the present study. Especially the dopaminergic cells, located in the pars compacta of SN (SNc), are of great neurologic interest, because the functional deficit and depletion of these cells are the correlate of Parkinson's disease. We used a combination of in situ hybridization histochemistry (ISH) and immunohistochemistry (IHC) on sections of human postmortem mesencephalon to investigate the expression of GABA(A) receptor subunit messenger RNAs (mRNAs) and of the receptor protein in dopaminergic SN cells. Immunohistochemical detection of tyrosine hydroxylase (TH), the pivotal enzyme of dopamine synthesis, was used to define the boundaries of SN pars reticulata (SNr) and pars compacta subregions. In SNr, all neurons were labeled by subunit-specific oligonucleotide probes and the amount of GABA(A) receptor mRNA expression was quantified as alpha(1) = beta(2) > gamma(2) > alpha(3). In contrast, in SNc, only around 25% of neurons expressed mRNA transcripts of GABA(A) receptor subunits, quantified as alpha(1) = beta(2) > gamma(2) > alpha(3) > alpha(4) = beta(3). In approximately the same percentage of neurons, which were labeled by alpha(1)-subunit-specific probe, the alpha(1)-subunit also was detected at the protein level by a specific monoclonal antibody. We, therefore, could demonstrate that a subset of dopaminergic neurons in human SNc receive inhibitory synaptic input by means of GABA(A) receptors mainly of the alpha(1)beta(2)gamma(2) subtype. This might represent a negative feedback loop between the striatum and the SNc and be a target of pharmacologic interventions in neurodegenerative diseases such as Parkinson's disease.
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PMID:Human GABA A receptors on dopaminergic neurons in the pars compacta of the substantia nigra. 1235 18

Recent studies, mainly in animals, have shown that the pedunculopontine nucleus (PPN) in the upper brainstem has extensive connections with several motor centres in the CNS. This structure has also been implicated in the akinesia seen in patients with Parkinson's disease. Here we demonstrate that microinjection of gamma-aminobutyric acid (GABA) receptor A antagonist substance, bicuculline, into the PPN of non-human primates (n = 2) rendered parkinsonian with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) results in significant improvement of akinesia. The effect of bicuculline microinjection in the PPN matches that of oral administration of L-dopa. This finding opens up new possibilities in the management of akinesia, the most intractable symptom of advanced Parkinson's disease.
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PMID:Reversal of akinesia in experimental parkinsonism by GABA antagonist microinjections in the pedunculopontine nucleus. 1239 Sep 69

Long-term treatment with levodopa in Parkinson's disease results in the development of motor fluctuations, including reduced duration of antiparkinsonian action and involuntary movements, i.e., levodopa-induced dyskinesia. Cannabinoid receptors are concentrated in the basal ganglia, and stimulation of cannabinoid receptors can increase gamma-aminobutyric acid transmission in the lateral segment of globus pallidus and reduce glutamate release in the striatum. We thus tested the hypothesis that the cannabinoid receptor agonist nabilone (0.01, 0.03, and 0.10 mg/kg) would alleviate levodopa-induced dyskinesia in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP) -lesioned marmoset model of Parkinson's disease. Coadministration of nabilone (0.1 mg/kg) with levodopa was associated with significantly less total dyskinesia (dyskinesia score, 12; range, 6-17; primate dyskinesia rating scale) than levodopa alone (22; range, 14-23; P < 0.05). This effect was more marked during the onset period (0-20 minutes post levodopa). There was no reduction in the antiparkinsonian action of levodopa. Furthermore, the intermediate dose of nabilone used (0.03 mg/kg) increased the duration of antiparkinsonian action of levodopa by 76%. Thus, cannabinoid receptor agonists may be useful in the treatment of motor complications in Parkinson's disease.
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PMID:Stimulation of cannabinoid receptors reduces levodopa-induced dyskinesia in the MPTP-lesioned nonhuman primate model of Parkinson's disease. 1246 55

Supra-pontine lesions resulting from neurological disorders such as vascular disease, Parkinson's disease, or Alzheimer type senile dementia lead to an increase in bladder activity. This is due in part to the removal at the cortical inhibitory control of the micturition center in the brain stem - i.e. the pontine micturition center (PMC) - and in part to facilitation of excitatory control. These inhibitory or excitatory controls consist of several neurotransmitter systems, including glutamate, dopamine, gamma-aminobutyric acid (GABA), and acetylcholine. Bladder overactivity caused by cerebral infarction is mediated by upregulation of N-methyl-D-aspartate (NMDA) glutamatergic and D2 dopaminergic excitatory mechanisms, and by downregulation of NMDA glutamatergic and Ml muscarinic inhibitory mechanisms in the brain. Bladder overactivity associated with Parkinson's disease is reportedly induced by a loss of input to the D1 dopaminergic receptor. Furthermore, bladder overactivity caused by Alzheimer type dementia is thought to be mediated by downregulation of M1 muscarinic inhibitory mechanisms. Development of bladder overactivity following cerebral infarction is mediated by activation of the NMDA receptor and accompanied by an increase in c-fos, zif268 and COX-2 mRNA expression in the dorsal pontine tegmentum.
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PMID:Overactive bladder--experimental aspects. 1247 19


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