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)

Deep brain stimulation (DBS) has been shown to generate suppression of abnormal neural activity in patients with Parkinson's disease and epilepsy. High frequency stimulation is applied to the brain through depth electrodes in the range of 50 to 200 Hz. Yet the mechanisms underlying the suppression effect have not yet been elucidated. In order to study directly the effect of HFS in the brain, sinusoidal stimulation was applied in the in-vitro brain slice preparation. Sinusoidal stimulation was chosen in order to observe the activity during the stimulation by filtering the stimulation artifact. Sinusoidal stimulation at 50 Hz applied to the CA1 region of the hippocampus was observed to block epileptiform activity in three separate models of epilepsy induced by low-calcium, high potassium and picrotoxin (GABA A blocker). Stimulation applied to the alveus showed that activity in both the cell bodies (evoked potentials) and in the axons (compound action potentials) is suppressed. The frequency range of this effect is nearly identical to that of DBS with maximum suppression effect between 50 and 200 Hz. The effect could not be attributed to desynchronization or damage and was associated with increased extracellular potassium concentrations. These data provide new insights into the effects of HFS on neuronal elements and show that HFS can block axonal activity through non-synaptic mechanisms.
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PMID:Suppression of neural activity with high frequency stimulation. 1794 13

An abnormal accumulation of cytosolic dopamine resulting in reactive oxygen species and dopamine-quinone products may play an important role in the rather selective degeneration of substantia nigra pars compacta (SNc) dopaminergic neurons in Parkinson's disease. The neuronal-specific vesicular monoamine transporter (VMAT2), responsible for uptake of dopamine into vesicles, has been shown to play a central role both in intracellular dopamine homeostasis and sequestration of dopaminergic neurotoxins. Direct or indirect enhancement of VMAT2 activity could therefore have neuroprotective effects by decreasing cytosolic dopamine levels. Here, we demonstrate that transfection of VMAT2 in the dopaminergic cell line, PC12, increases intracellular dopamine content, augments potassium-induced dopamine release and attenuates cell death induced by the cytosolic dopamine enhancer, methamphetamine, suggesting an enhancement in vesicular dopamine storage. In rat ventral mesencephalic cultures highly enriched for dopaminergic neurons, lentiviral delivery of recombinant VMAT2 using a neuronal-specific promoter also resulted in elevated intracellular dopamine content and neurotransmitter release after depolarization. The opposite was seen after downregulation of VMAT2 using virally delivered shRNAs. Furthermore, using this VMAT2 knockdown model, we are the first to report a direct link between enhanced cytoplasmic dopamine levels, measured following mild permeabilization of the plasma membrane using digitonin, and neurite degeneration in primary dopaminergic neurons. In conclusion, our data support the hypothesis that an increase in vesicular sequestration of dopamine by modulation of VMAT2 activity could restore neuronal function and enhance dopaminergic cell survival in conditions of dysregulated dopamine homeostasis such as Parkinson's disease.
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PMID:Vesicular monoamine transporter 2 regulates the sensitivity of rat dopaminergic neurons to disturbed cytosolic dopamine levels. 1802 84

The ATP-sensitive potassium (K(ATP)) channels which extensively distribute in diverse tissues (e.g. vascular smooth muscle, cardiac cells, and pancreas) are well-established for characteristics like vasodilatation, myocardial protection against ischemia, and insulin secretion. The aim of this review is to get insight into the novel roles of K(ATP) channels in Parkinson's disease (PD), with consideration of the specificities K(ATP) channels in the central nervous system (CNS), such as the control of neuronal excitability, action potential, mitochondrial function and neurotransmitter release.
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PMID:ATP-sensitive potassium channels: novel potential roles in Parkinson's disease. 1806 68

Potassium (K+) channels are the most heterogeneous and widely distributed class of ion channels. K(+) channels are dynamic pore-forming transmembrane proteins known to play important roles in all cell types underlying both normal and pathophysiological functions. Essential for such diverse physiological processes as nerve impulse propagation, muscle contraction, cellular activation and the secretion of biologically active molecules, various K(+) channels are recognized as potential therapeutic targets in the treatment of multiple sclerosis, Alzheimer's disease, Parkinson's disease, epilepsy, stroke, brain tumors, brain/spinal cord ischemia, pain and schizophrenia, migraine, as well as cardiac arrhythmias, pulmonary hypertension, diabetes, cervical cancer, urological diseases and sepsis. In addition to their importance as therapeutic targets, certain K(+) channels are gaining attention for their beneficial roles in anesthesia, neuroprotection and cardioprotection. The K(+) channel gene families (subdividing into multiple subfamilies) include voltage-gated (K(v): K(v)1-K(v)12 or KCNA-KCND, KCNF-KCNH, KCNQ, KCNS), calcium-activated (K(Ca): K(Ca)1-K(Ca)5 or KCNM-KCNN), inwardly rectifying (K(ir): K(ir)1-K(ir)7 or KCNJ) and background/leak or tandem 2-pore (K(2P): K(2P)1-K(2P)7, K(2P)9-K(2P)10, K(2P)12-K(2P)13, K(2P)15-K(2P)18 or KCNK) K(+) channels. Worldwide, the pharmaceutical industry is actively developing better strategies for targeting ion channels, in general, and K(+) channels, in particular, already generating over $6 billion in sales per annum from drugs designed to block or modulate ion channel function. This review provides an overview of recent patents on emerging K(+) channel blockers and activators (openers) with potential for development as new and improved nervous system therapeutic agents.
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PMID:Potassium channel blockers and openers as CNS neurologic therapeutic agents. 1822 Dec 32

Abnormal neuronal activity in the subthalamic nucleus (STN) plays a crucial role in the pathophysiology of Parkinson's disease (PD). Although altered extracellular potassium concentration ([K+]o) and sensitivity to [K+]o modulates neuronal activity, little is known about the potassium balance in the healthy and diseased STN. In vivo measurements of [K+]o using ion-selective electrodes demonstrated a twofold increase in the decay time constant of lesion-induced [K+]o transients in the STN of adult Wistar rats with a unilateral 6-hydroxydopamine (6-OHDA) median forebrain bundle lesion, employed as a model of PD, compared with nonlesioned rats. Various [K+]o concentrations (1.5-12.5 mM) were applied to in vitro slice preparations of three experimental groups of STN slices from nonlesioned control rats, ipsilateral hemispheres, and contralateral hemispheres of lesioned rats. The majority of STN neurons of nonlesioned rats and in slices contralateral to the lesion fired spontaneously, predominantly in a regular pattern, whereas those in slices ipsilateral to the lesion fired more irregularly or even in bursts. Experimentally increased [K+]o led to an increase in the number of spontaneously firing neurons and action potential firing rates in all groups. This was accompanied by a decrease in the amplitude of post spike afterhyperpolarization (AHP) and the amplitude and duration of the posttrain AHP. Lesion effects in ipsilateral neurons at physiological [K+]o resembled the effects of elevated [K+]o in nonlesioned rats. Our data suggest that changed potassium sensitivity due to conductivity alterations and delayed clearance may be critical for shaping STN activity in parkinsonian states.
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PMID:Increasing extracellular potassium results in subthalamic neuron activity resembling that seen in a 6-hydroxydopamine lesion. 1838 82

Modafinil is a well-known psychoactive drug used to treat narcolepsy, hypoglycemia, cerebral ischemia and Parkinson's disease. Previous studies showed that ATP-sensitive potassium channels (K(ATP)) play a key role in response to cerebral ischemia, hypoglycemia or metabolic inhibition. Modafinil (0.01-1 mM) dose-dependently decreased the GABA-activated currents (I(GABA)). Pretreatment with the K(ATP) channel blocker, glibenclamide (10 microM), significantly reduced the decrease of I(GABA) caused by modafinil. Thus, the inhibitory effect of modafinil on the I(GABA) is indirect by modulating K(ATP) channel activation, at least in part mediated by K(ATP) channel.
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PMID:Modafinil modulates GABA-activated currents in rat hippocampal pyramidal neurons. 1839 2

Parkinson's disease is a common progressive neurodegenerative disorder characterized by the degeneration of dopaminergic neurons in the substantia nigra pars compacta. Mitochondrial dysfunction has been strongly implicated in the pathogenesis of Parkinson's disease. Thus, therapeutic approaches that improve mitochondrial function may prove to be beneficial. Previously, we have documented that near-infrared light via light-emitting diode (LED) treatment was therapeutic to neurons functionally inactivated by tetrodotoxin, potassium cyanide (KCN), or methanol intoxication, and LED pretreatment rescued neurons from KCN-induced apoptotic cell death. The current study tested our hypothesis that LED treatment can protect neurons from both rotenone- and MPP(+)-induced neurotoxicity. Primary cultures of postnatal rat striatal and cortical neurons served as models, and the optimal frequency of LED treatment per day was also determined. Results indicated that LED treatments twice a day significantly increased cellular adenosine triphosphate content, decreased the number of neurons undergoing cell death, and significantly reduced the expressions of reactive oxygen species and reactive nitrogen species in rotenone- or MPP(+)-exposed neurons as compared with untreated ones. These results strongly suggest that LED treatment may be therapeutic to neurons damaged by neurotoxins linked to Parkinson's disease by energizing the cells and increasing their viability.
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PMID:Near-infrared light via light-emitting diode treatment is therapeutic against rotenone- and 1-methyl-4-phenylpyridinium ion-induced neurotoxicity. 1844 Jul 9

A large number studies indicate that potassium (K+) channels play important roles in cellular signaling in both excitable and nonexcitable cells. Moreover, a considerable number of K+ channels within the nervous system appear to mediate diverse cellular signaling, including regulation of neurotransmitter release, neuronal excitability, and cell volume. Recent studies on the K+ channel gene expression in the basal ganglia reveal dysfunctions of various K+ channels (e.g., Kv, K(ATP), Kir2 and SKCa), which may be involved in the pathogenesis of Parkinson's disease (PD). This review aims to provide an overview of our current understanding of the molecular mechanisms involved in K+ channel functions in the basal ganglia, and an insight on how to exploit K+ channels as therapeutic targets in the treatment of PD.
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PMID:Potassium channels in the basal ganglia: promising new targets for the treatment of Parkinson's disease. 1850 65

A large number studies indicate that potassium (K+) channels play important roles in cellular signaling in both excitable and nonexcitable cells. Moreover, a considerable number of K+ channels within the nervous system appear to mediate diverse cellular signaling, including regulation of neurotransmitter release, neuronal excitability, and cell volume. Recent studies on the K+ channel gene expression in the basal ganglia reveal dysfunctions of various K+ channels (e.g., Kv, K(ATP), Kir2 and SKCa), which may be involved in the pathogenesis of Parkinson's disease (PD). This review aims to provide an overview of our current understanding of the molecular mechanisms involved in K+ channel functions in the basal ganglia, and an insight on how to exploit K+ channels as therapeutic targets in the treatment of PD.
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PMID:Potassium channels in the basal ganglia: promising new targets for the treatment of Parkinson's disease. 1850 77

Small-conductance Ca(2+)-activated potassium (SK) channels are heteromeric complexes of SK alpha-subunits and calmodulin that modulate membrane excitability, are responsible for part of the after-hyperpolarization (AHP) following action potentials, and thus control the firing patterns and excitability of most central neurons. An engineered knockout allele for the SK2 subunit has previously been reported. The hippocampal neurons of these mice lacked the medium latency component of the AHP, but the animals were not described as presenting any overt behavioral phenotype. In this report, we describe a deletion in the 5' region of the Kcnn2 gene encoding the SK2 subunit in the mouse neurological frissonnant (fri) mutant. The frissonnant mutant phenotype is characterized by constant rapid tremor and locomotor instability. It has been suggested, based merely on its phenotype, as a potential model for human Parkinson disease. We used a positional cloning strategy to identify the mutation underlying the frissonnant phenotype. We narrowed the genetic disease interval and identified a 3,441-bp deletion in the Kcnn2 gene, one of the three candidate genes present in the interval. Expression studies showed complete absence of normal Kcnn2 transcripts while some tissue-specific abnormal truncated variants were detected. Intracellular electrophysiological recordings of central vestibular neurons revealed permanent alterations of the AHP and firing behavior that might cause the tremor and associated locomotor deficits. Thus, the fri mutation suggests a new, potentially important physiological role, which had not been described, for the SK2 subunit of small-conductance Ca(2+)-activated potassium channels.
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PMID:Behavioral effects of a deletion in Kcnn2, the gene encoding the SK2 subunit of small-conductance Ca2+-activated K+ channels. 1860 72


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