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)

Neuronal damage following stroke or neurodegenerative diseases is thought to stem in part from overexcitation of N -methyl-D-aspartate (NMDA) receptors by glutamate. NMDA receptors triggered neurotoxicity is mediated in large part by activation of neuronal nitric oxide synthase (nNOS) and production of nitric oxide (NO). Simultaneous production of superoxide anion in mitochondria provides a permissive environment for the formation of peroxynitrite (ONOO-). Peroxynitrite damages DNA leading to strand breaks and activation of poly(ADP-ribose) polymerase-1 (PARP-1). This signal cascade plays a key role in NMDA excitotoxicity, and experimental models of stroke and Parkinson's disease. The mechanisms of PARP-1-mediated neuronal death are just being revealed. While decrements in ATP and NAD are readily observed following PARP activation, it is not yet clear whether loss of ATP and NAD contribute to the neuronal death cascade or are simply a biochemical marker for PARP-1 activation. Apoptosis-inducing factor (AIF) is normally localized to mitochondria but following PARP-1 activation, AIF translocates to the nucleus triggering chromatin condensation, DNA fragmentation and nuclear shrinkage. Additionally, phosphatidylserine is exposed and at a later time point cytochrome c is released and caspase-3 is activated. In the setting of excitotoxic neuronal death, AIF toxicity is caspase independent. These observations are consistent with reports of biochemical features of apoptosis in neuronal injury models but modest to no protection by caspase inhibitors. It is likely that AIF is the effector of the morphologic and biochemical events and is the commitment point to neuronal cell death, events that occur prior to caspase activation, thus accounting for the limited effects of caspase inhibitors. There exists significant cross talk between the nucleus and mitochondria, ultimately resulting in neuronal cell death. In exploiting this pathway for the development of new therapeutics, it will be important to block AIF translocation from the mitochondria to the nucleus without impairing important physiological functions of AIF in the mitochondria.
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PMID:Deadly conversations: nuclear-mitochondrial cross-talk. 1537 59

Neuronal death associated with Parkinson's disease is commonly believed to be caused by oxygen- and nitrogen-derived free radical species. Some years ago, however, we showed that peroxidase from the midbrain of dogs is able to kill various cell types, including neuroblastoma cells (M. B. Grisham et al., J. Neurochem. 48: 876-882: 1987). We postulated that a nigral peroxidase may play a significant role in the degeneration of dopaminergic neurons in Parkinson's disease. To further establish proof of principle, we recently performed a series of experiments using horseradish peroxidase and lactoperoxidase. We showed that the cytotoxic activity of lactoperoxidase is fully inhibited by physiological concentrations of dopamine, reduced glutathione, and L-cysteine, as well as by micromolar concentrations of apomorphine, desferal, aspirin, and uric acid. l-Methyl-4-phenyl-1,2-dihydropyridine (MPDP) and l-methyl-4-phenylpyridinium (MPP+) augment the cytotoxic activity, whereas l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, deprenyl, and pargyline had minimal or no effect. We also showed that horseradish peroxidase catalyzes the oxidation of MPDP to MPP+. Thus, contrary to the generally accepted theory that the in vivo oxidation of MPDP occurs spontaneously, this reaction may be catalyzed by a brain peroxidase. These observations lend further support to the suggestion that a brain peroxidase may play an important role in the metabolic events associated with Parkinson's disease.
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PMID:The cytotoxic activity of lactoperoxidase: enhancement and inhibition by neuroactive compounds. 1538 4

Unilateral pallidotomy is an effective treatment for contralateral parkinsonism and dyskinesia, yet symptoms progress in many patients. Little is known about whether such patients obtain a useful response to subsequent bilateral subthalamic nucleus deep brain stimulation (STN DBS). Changes in Unified Parkinson's Disease Rating Scale (UPDRS) Motor and Activities of Daily Living (ADL) scores, medication requirements, and dyskinesias were measured. Clinical outcomes were compared to patients with de novo STN DBS. Neuronal recordings were performed. STN DBS resulted in a significant reduction in UPDRS Motor scores (42.1%; 95% confidence interval [CI], 26.9-57.4; P = 0.03), comparable with de novo STN DBS surgery (41%; 95% CI, 26-46%; P < 0.001). There was also less change in dyskinesia duration and disability scores (P = 0.017, 0.005). There were no side-to-side differences clinically or in the STN neuronal firing rates and patterns. Bilateral STN DBS is safe and efficacious in improving motor symptoms in patients with prior pallidotomy.
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PMID:Subthalamic nucleus deep brain stimulation for parkinson's disease after successful pallidotomy: clinical and electrophysiological observations. 1539 8

Neuronal cell death induced by oxidative stress is correlated with numerous neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and stroke. The causes of sporadic forms of age-related neurodegenerative diseases are still unknown. Recently, a correlation between paraquat exposure and neurodegenerative diseases has been observed. Paraquat, a nonselective herbicide, was once widely used in North America and is still routinely used in Taiwan. We have used differentiated Human Neuroblastoma (SHSY-5Y) cells as an in vitro model to study the mechanism of cell death induced by paraquat. We observed that paraquat-induced oxidative stress in differentiated SHSY-5Y cells as indicated by an increase in the production of cellular reactive oxygen species (ROS). Furthermore, apoptosis was evident as indicated by cellular and nuclear morphology and DNA fragmentation. Interestingly, pretreatment of SHSY-5Y cells with water-soluble Coenzyme Q10 (CoQ10) before paraquat exposure inhibited ROS generation. Pretreatment with CoQ10 also significantly reduced the number of apoptotic cells and DNA fragmentation. We also analyzed the effect of paraquat and CoQ10 on isolated mitochondria. Our results indicated that treatment with paraquat induced the generation of ROS from isolated mitochondria and depolarization of the inner mitochondrial membrane. Pretreatment with CoQ10 was able to inhibit ROS generation from isolated mitochondria as well as the collapse of mitochondrial membrane potential. Our results indicate that water-soluble CoQ10 can prevent oxidative stress and neuronal damage induced by paraquat and therefore, can be used for the prevention and therapy of neurodegenerative diseases caused by environmental toxins.
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PMID:Paraquat induces oxidative stress and neuronal cell death; neuroprotection by water-soluble Coenzyme Q10. 1551 5

Progress in stem cell biology research is enhancing our ability to generate specific neuron types for basic and applied studies and to design new treatments for neurodegenerative diseases. In the case of Parkinson's disease (PD), alternative human dopaminergic (DAergic) neurons other than primary fetal tissue do not yet exist. One possible source could be human neural stem cells (hNSCs), although the yield in DAergic neurons and their survival are very limited. [see figure]. In this study, we found that Bcl-X(L) enhances (one-to-two orders of magnitude) the capacity for spontaneous dopaminergic differentiation of hNSCs, which then exceeds that of cultured human ventral mesencephalic tissue. Bcl-X(L) also enhanced total neuron generation by hNSCs, but to a lower extent. Neuronal phenotypes other than DA were not affected by Bcl-X(L), indicating an exquisitely specific effect on DAergic neurons. In vivo, grafts of Bcl-X(L)-overexpressing hNSCs do generate surviving human TH+ neurons in the adult rat 6-OH-dopamine lesioned striatum, something never seen when naive hNSCs were transplanted. Most of the data obtained here in terms of the effects of Bcl-X(L) are consistent with an enhanced survival type of mechanism and not supportive of induction, specification, or proliferation of DAergic precursors. From this in vitro and in vivo evidence, we conclude that enhancing Bcl-X(L) expression is important to obtain human DAergic neurons from hNSCs. These findings may facilitate the development of drug-screening and cell-replacement activities to discover new therapeutic strategies for PD.
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PMID:The generation of dopaminergic neurons by human neural stem cells is enhanced by Bcl-XL, both in vitro and in vivo. 1557 29

The cytoskeleton plays a key role in maintaining the highly asymmetrical shape and structural polarity of neurons that are essential for neuronal physiology. Cytoskeletal reorganization plays a key role in neuritogenesis. In neurodegenerative diseases, the cytoskeleton is abnormally assembled and impairment of neurotransmission occurs. In Alzheimer's disease, abundant amyloid plaques and neurofibrillary tangles constitute the two major neuropathologic alterations present in the brain. Neurofibrillary tangles are formed of paired helical filaments consisting nearly entirely of the microtubule-associated protein tau. Under normal conditions tau binds to microtubules, stabilizing neuron structure and integrity. Hyperphosphorylation of tau is assumed to be the cause of formation of paired helical filaments. Another example of cytoskeletal abnormalities present in neurodegenerative diseases are the Lewy bodies considered as cytopathologic markers of Parkinson's disease. Lewy bodies are constituted of tubulin, MAP1, and MAP2. Neuronal shape, loss of dendrites and spines, as well as irregular distribution of neuronal elongations occur in specific brain areas of schizophrenic patients. Increase in non-phosphorylated MAP2 and MAP1B at hippocampus has been suggested as responsible for somatodendritic and cytoarchitectural abnormalities found in schizophrenia. In addition, neurofibrillary tangles are more frequent among schizophrenic patients who received pharmacologic antipsychotic treatment. Cumulative evidence suggests that neurodegenerative diseases and psychiatric illnesses are associated with cytoskeletal alterations in neurons that, in turn, loose synaptic connectivity and the ability to transmit incoming axonal information to the somatodendritic domain. We will review evidence supporting that the neuronal cytoskeleton is disrupted in neurodegenerative and some psychiatric diseases, and therefore could be a target for drug therapy. In addition, current data indicating that melatonin, a hormone secreted by the pineal gland, promotes neuritogenesis through cytoskeletal rearrangements and in addition to the potential therapeutic use of melatonin in neurodegenerative diseases will be discussed.
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PMID:The neuronal cytoskeleton as a potential therapeutical target in neurodegenerative diseases and schizophrenia. 1558 21

Neuronal progenitor cells (NPCs) residing in the adult subependymal zone (SEZ) are a potential source of expandable cells for autologous transplantation to treat Parkinson's Disease and other types of brain injury. We have previously demonstrated the capacity of transplanted adult SEZ NPCs for heterotypic differentiation in the hippocampus. To further characterize the therapeutic potential of these cells, NPCs expanded from the adult rat SEZ were grafted to the striatum of normal and 6-OHDA lesioned adult rats. Grafted cells were assessed for neuronal differentiation, and lesioned animals were tested for amphetamine-induced rotational asymmetry. In addition, the effect of inducing differentiation in vitro prior to transplantation was assessed. Although grafted cells survived after 2 weeks in all animals, neither striatal deafferentation nor in vitro induction of differentiation resulted in significant neuronal differentiation of transplanted cells. Grafts, however, did produce a behavioral effect. While sham animals exhibited increased rotational behavior (+67%) from 2 to 4 weeks post-lesioning, grafted animals did not (-21%). Grafted cells continued to express nestin at the survival time point, and dopamine transporter (DAT) immunoreactivity was restored in the graft body. These results suggest that although neither the normal nor the deafferented striatum alone support the neuronal differentiation of transplanted adult SEZ NPCs, grafts maintaining a progenitor phenotype may produce a therapeutic benefit.
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PMID:Grafts of adult subependymal zone neuronal progenitor cells rescue hemiparkinsonian behavioral decline. 1568 Sep 36

The motor symptoms of Parkinson's disease (PD) are thought to result from increased inhibitory outflow from the basal ganglia to the pallidal receiving areas of thalamus (ventral oral anterior and posterior-Voa,Vop). To test this hypothesis, we examined the firing rates of neurons in pallidal and cerebellar receiving areas of thalamus in five PD patients and compared them to those of neurons in comparable regions of motor thalamus in two other patient groups where hyperactivity of GPi is not believed to occur [essential tremor (ET), pain]. Neuronal recordings were made during microelectrode-guided functional stereotactic neurosurgery. The mean spontaneous firing rate (MSFR) of neurons classified as voluntary neurons and presumed to be in pallidal receiving areas of thalamus in PD patients [7.4 +/- 1.0 (SE) Hz] was significantly lower (P < 0.01) than in the ET (18.1 +/- 3.0 Hz) and pain (19.0 +/- 1.9Hz) groups. In contrast, the MSFR of neurons classified as kinesthetic and presumed to be primarily in the cerebellar receiving area of thalamus (ventral intermediate-Vim), although some are probably in the deep shell region of the ventrocaudal nucleus (VPLa), was significantly greater in ET patients (25.8 +/- 3.5 Hz) than in the PD (14.3 +/- 1.6 Hz; P < 0.01) and pain (16.1 +/- 1.5 Hz; P < 0.05) groups. Similar findings were obtained when the neurons were grouped according to their estimated locations in Voa/Vop and Vim of motor thalamus. These data provide support for the prediction of the classical pathophysiological model of PD and moreover suggest that pathophysiology in the cerebello-thalamo-cortical pathway may be a possible cause of tremor in ET patients.
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PMID:Differences in neuronal firing rates in pallidal and cerebellar receiving areas of thalamus in patients with Parkinson's disease, essential tremor, and pain. 1570 31

Different analyses of neuronal activity in primate models of Parkinson's disease (PD) have resulted in two different views on the effects of dopamine depletion. The first is based on the higher firing rate and bursty firing pattern, and assumes that dopamine depletion results in a hyperactivity of basal ganglia (BG) output structures. The second is based on the less-specific responses to passive joint manipulation and the excessive correlations between neuronal discharges, and assumes that dopamine depletion results in a loss of functional segregation in cortico-BG circuits. The aim of the present study was to test out the predictions of these two different views on thalamic neuronal activity. Three male vervet monkeys (Cercopithecus aethiops) were progressively intoxicated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Neuronal activities were characterized using standard analyses (firing rates and patterns, receptive fields, and cross-correlations) and compared between the normal, asymptomatic (before the stabilization of motor symptoms), and parkinsonian (with persistent akinesia and rigidity) stages of MPTP intoxication. The pallidonigral thalamus (receiving projections from the BG) was characterized in both the asymptomatic and parkinsonian states by (1) an unchanged firing rate and pattern and (2) a proliferation of nonspecific neurons and correlated pairs. In contrast, the cerebellar thalamus (receiving projections from the cerebellum), was characterized by no change (asymptomatic state) or minor changes (symptomatic state). Thus the major dysfunction after dopamine depletion appeared to be the loss of functional segregation within cortico-BG circuits, which could also be at the heart of parkinsonian pathophysiology.
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PMID:Thalamic neuronal activity in dopamine-depleted primates: evidence for a loss of functional segregation within basal ganglia circuits. 1570 6

Mutations in DJ-1 (PARK7) were recently identified as the cause for an autosomal recessive early onset form of familial Parkinson's disease, however, the function of the protein in the brain is yet to be elucidated. Here we report on the development, characterisation and epitope mapping, of two novel monoclonal antibodies to DJ-1. One of them (DJ-1 "clone16") has its epitope between amino acids 56-78 of the human DJ-1 protein and has very similar properties to a commercially available DJ-1 antibody clone 3E8. The second antibody recognised both the rat and human DJ-1 (DJ-1 "clone 48") and its epitope is between amino acids 26-56. We have used immunohistochemistry with these two antibodies to compare the distribution of DJ-1 in human and rat brain tissue. Both antibodies gave similar patterns of labelling in human brain with marked astrocytic expression. Neuronal labelling was weak or absent and the antibodies did not label Lewy bodies or Lewy neurites. In the rat brain, DJ-1 was ubiquitously expressed in neurones but exhibited low expression in astrocytes. These antibodies could be exploited as important tools in dissecting out DJ-1 expression in different species and examination of the role of DJ-1 in Parkinson's disease.
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PMID:Development, characterisation and epitope mapping of novel monoclonal antibodies for DJ-1 (PARK7) protein. 1595 16


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