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)

Oxidative stress is a putative factor in the pathogenesis of many human disorders of the central nervous system. Therefore, antioxidants such as vitamin E have become attractive as therapeutic agents in the treatment of several diseases. In addition, vitamin E seems to play a specific role in the nervous system. As a result, vitamin E has been used in pharmacologic doses in the treatment of disorders such as Parkinson disease, Alzheimer disease, and tardive dyskinesia. One investigation showed that the use of 2000 IU all-rac-alpha-tocopheryl acetate is beneficial in the treatment of Alzheimer disease. Similar doses of vitamin E, however, were not beneficial for delaying the progression of Parkinson disease. In other studies, dosages >/=400 IU vitamin E/d were found to be beneficial in the treatment of tardive dyskinesia, although this finding was not confirmed in a larger cooperative study conducted by the Veterans Administration. Even though the efficacy of vitamin E in the management of cardiovascular disease has been shown, the potential role of vitamin E in the treatment of cerebrovascular disease remains essentially unknown. The experience from 2 large clinical trials involving the oral intake of 2000 IU vitamin E/d suggests that vitamin E is relatively safe at this dosage for periods <2 y. However, the safety and efficacy of supplemental vitamin E over periods of many years in the prevention of neurologic diseases has not been adequately explored.
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PMID:High doses of vitamin E in the treatment of disorders of the central nervous system in the aged. 1087 82

Free radical are highly reactive chemical species with an unpaired electron in an atomic or molecular orbital. In biological systems, the most important free radicals are superoxide anion and hydrogen peroxide; in the presence of transition metals such as iron, copper and manganese both these free radicals produce hydroxyl radicals. Free radicals attack proteins, nuclei acids and membranes containing large quantities of polyunsaturated fatty acids. Because of their toxicity, the organism has developed ways to deactivate them. The superoxide dismutase enzyme (SOD) catalyzes dismutation of the superoxide radical into hydrogen peroxide and oxygen hydrogen peroxide is in turn reduced to water and oxygen by peroxidase glutathione and catalase enzymes. The production of radicals in the brain is due to catecholamine metabolism such as dopamine and norepinephrine and is increased by the presence of transition metals and by a deficiency of antioxidant agents such as vitamin E. Two main groups of dementia exist in older age: the multi-infarctual dementias, caused by cerebrovascular disorders and the primary degenerative disorders such as Alzheimer, where no vascular disease is evident. Free radicals play an important role in Parkinson's disease, in Alzheimer's disease and in stroke. The value of SOD and CAT activity following the above mentioned degenerative diseases differ among the various studies carried out. In Alzheimer's disease, the value of SOD activity probably increases in the neuropathologically involved areas. In stroke, the SOD value does not vary either in the ischemic area or in the peri-infarctual one during the first 24 hrs after lesion, while the CAT value decreases.
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PMID:Free radicals: important cause of pathologies refer to ageing. 1070 16

Degeneration of nigrostriatal dopaminergic neurons is the major pathogenic substrate of Parkinson's disease (PD). Inhibitors of monoamine oxidase B (MAO-B) have been used in the treatment of PD and at least one of them, i.e., deprenyl, also displays antioxidant activity. Dopamine (DA) autoxidation produces reactive oxygen species implicated in the loss of dopaminergic neurons in the nigrostriatal pathway. In this study we compared the effects of melatonin with those of deprenyl and vitamins E and C in preventing the hydroxyl radical (8OH) generation during DA oxidation. The rate of production of 2,3-dihydroxybenzoate (2,3-DHBA) in the presence of salicylate, an *OH scavenger, was used to detect the in vitro generation of *OH during iron-catalyzed oxidation of DA. The results showed a dose-dependent effect of melatonin, deprenyl and vitamin E in counteracting DA autoxidation, whereas vitamin C had no effect. Comparative analyses between the effect of these antioxidants showed that the protective effect of melatonin against DA autoxidation was significantly higher than that of the other compounds tested. Also, when melatonin plus deprenyl were added to the incubation medium, a potentiation of the antioxidant effect was found. These findings suggest that antioxidants may be useful in brain protection against toxicity of reactive oxygen species produced during DA oxidation, and melatonin, alone or in combination with deprenyl, may be an important component of the brain's antioxidant defenses to protect it from dopaminergic neurodegeneration.
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PMID:Comparative effects of melatonin, L-deprenyl, Trolox and ascorbate in the suppression of hydroxyl radical formation during dopamine autoxidation in vitro. 1098 23

There is strong evidence that oxidative stress participates in the etiology of Parkinson's disease (PD). We designed this study to investigate the neuroprotective effect of vitamin E in the early model of PD. For this purpose, unilateral intrastriatal 6-hydroxydopamine (12.5 microg/5 microl) lesioned rats were pretreated intramuscularly with D-alpha-tocopheryl acid succinate (24 I.U./kg, i.m.) 1 h before and three times per week for 1 month post-surgery. Apomorphine- and amphetamine-induced rotational behavior was measured postlesion fortnightly. A parallel tyrosine hydroxylase immunoreactivity and wheat germ agglutinin-horse radish peroxidase (WGA-HRP) tract-tracing study was performed to evaluate the vitamin E pretreatment efficacy. Tyrosine hydroxylase-immunohistochemical analyses showed a reduction of 18% in ipsilateral substantia nigra pars compacta (SNC) cell number of the vitamin E-pretreated lesioned (L+E) group comparing with contralateral side. The cell number dropped to 53% in the lesioned (L+V) group. In addition, retrograde-labeled neurons in ipsilateral SNC were reduced by up to 30% in the L+E group and 65% in the L+V group. Behavioral tests revealed that there are 74% and 68% reductions in contraversive and ipsiversive rotations in the L+E group, respectively, as compared with the L+V group. Therefore repeated intramuscular administration of vitamin E exerts a rapid protective effect on the nigrostriatal dopaminergic neurons in the early unilateral model of PD.
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PMID:Neuroprotective effect of vitamin E on the early model of Parkinson's disease in rat: behavioral and histochemical evidence. 1117 67

Zinc has several crucial functions in brain development and maintenance: it binds to p53, preventing it from binding to supercoiled DNA and ensuring that p53 cause the expression of several paramount genes, such as the one that encodes for the type I receptors to pituitary adenine cylase-activator peptide (PACAP), which directs embryonic development of the brain cortex, adrenal glands, etc.; it is required for the production of CuZnSOD and Zn-thionein, which are essential to prevent oxidative damage; it is required for many proteins, some of them with Zn fingers, many of them essential enzymes for growth and homeostasis. For example, the synthesis of serotonin involves Zn enzymes and since serotonin is necessary for melatonin synthesis, a Zn deficiency may result in low levels of both hormones. Unfortunately, Zn levels tend to be low when there is excess Cu and Cd. Moreover, high estrogen levels tend to cause increased absorption of Cu and Cd, and smoking and eating food contaminated with Cd result in high levels of the latter. Furthermore, ethanol ingestion increases the elimination of Zn and Mg (which acts as a cofactor for CuZnSOD). Increased Cu levels may also be found in people with Wilson's disease, which is a rather rare disease. However, the heterozygote form (only one faulty copy of the chromosome) is not so rare. Therefore, the developing fetus of a pregnant women who is low in Zn and high in Cu may experience major difficulties in the early development of the brain, which may later manifest themselves as schizophrenia, autism or epilepsy. Similarly, a person who gradually accumulates Cu, will tend to experience a gradual depletion of Zn, with a corresponding increase in oxidative damage, eventually leading to Parkinson's disease. Also discussed are the crucial roles of histidine, histamine, vitamin D, essential fatty acids, vitamin E, peroxynitrate, etc. in the possible oxidative damage involved in these mental diseases.
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PMID:Micronutrient accumulation and depletion in schizophrenia, epilepsy, autism and Parkinson's disease? 1138 83

Oxidative stress has been implicated as a major contributor to selective neuronal death in Parkinson's disease (PD). Vitamin E is an antioxidant that may protect the brain from free radical-induced oxidative damage. It is, therefore, reasonable to hypothesize that low levels of vitamin E concentrations may increase the risk of developing PD. To elucidate the possible role of vitamin E in the pathogenesis of PD, we assessed the plasma levels of vitamin E, measured by high-performance liquid chromatography (HPLC), in 54 patients with PD. Vitamin E concentrations were also assessed in 93 age and sex matched normal individuals. The mean plasma levels of vitamin E did not differ significantly between these two groups (22.5+/-8.15 &mgr;mol/l for PD patients and 21.0+/-7.9 &mgr;mol/l for controls). The results of our study suggest that plasma vitamin E concentrations do not play a major role in the pathogenesis of PD.
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PMID:Plasma levels of vitamin E in Parkinson's disease. 1146 17

Free radicals and other so-called 'reactive species' are constantly produced in the brain in vivo. Some arise by 'accidents of chemistry', an example of which may be the leakage of electrons from the mitochondrial electron transport chain to generate superoxide radical (O2*-). Others are generated for useful purposes, such as the role of nitric oxide in neurotransmission and the production of O2*- by activated microglia. Because of its high ATP demand, the brain consumes O2 rapidly, and is thus susceptible to interference with mitochondrial function, which can in turn lead to increased O2*- formation. The brain contains multiple antioxidant defences, of which the mitochondrial manganese-containing superoxide dismutase and reduced glutathione seem especially important. Iron is a powerful promoter of free radical damage, able to catalyse generation of highly reactive hydroxyl, alkoxyl and peroxyl radicals from hydrogen peroxide and lipid peroxides, respectively. Although most iron in the brain is stored in ferritin, 'catalytic' iron is readily mobilised from injured brain tissue. Increased levels of oxidative damage to DNA, lipids and proteins have been detected by a range of assays in post-mortem tissues from patients with Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis, and at least some of these changes may occur early in disease progression. The accumulation and precipitation of proteins that occur in these diseases may be aggravated by oxidative damage, and may in turn cause more oxidative damage by interfering with the function of the proteasome. Indeed, it has been shown that proteasomal inhibition increases levels of oxidative damage not only to proteins but also to other biomolecules. Hence, there are many attempts to develop antioxidants that can cross the blood-brain barrier and decrease oxidative damage. Natural antioxidants such as vitamin E (tocopherol), carotenoids and flavonoids do not readily enter the brain in the adult, and the lazaroid antioxidant tirilazad (U-74006F) appears to localise in the blood-brain barrier. Other antioxidants under development include modified spin traps and low molecular mass scavengers of O2*-. One possible source of lead compounds is the use of traditional remedies claimed to improve brain function. Little is known about the impact of dietary antioxidants upon the development and progression of neurodegenerative diseases, especially Alzheimer's disease. Several agents already in therapeutic use might exert some of their effects by antioxidant action, including selegiline (deprenyl), apomorphine and nitecapone.
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PMID:Role of free radicals in the neurodegenerative diseases: therapeutic implications for antioxidant treatment. 1159 35

6-Hydroxydopamine (6-OHDA) injected unilaterally into the striatum of rats induced contralateral circling, and increased the duration of stereotyped movements after subcutaneous (sc) injection of apomorphine both 3 and 13 weeks after surgery. Ten weeks after surgery, the spontaneous locomotor activity during 24 h of observation was decreased. Twelve weeks after 6-OHDA injection, the animals had difficulties in carrying out a spatial navigation task in the water maze when the submerged escape platform was moved to another position on each of four consecutive days. When learning to find a new platform position required switching behavior-strategies, latency and swim paths were increased because of significantly more perseverative crossings of the previous platform positions. Intraperitoneal (ip) injection of alpha-tocopherol for 8 days increased the ability of naive control animals to find the hidden platform positions in the water maze one week later. In intrastriatal sham-operated rats, 8 daily pre-injections of alpha-tocopherol significantly increased the duration and number of bursts of stereotyped movements during 30 min following a sc injection of apomorphine if measured 13 weeks after surgery. In 6-OHDA-lesioned rats, alpha-tocopherol prevented the increased response to apomorphine, reduced the apomorphine-induced circling at 3 and 13 weeks, and prevented the decrease in spontaneous locomotion at 10 weeks, as well as the perseverative platform crossings which are caused by an impairment in switching behavior-strategies in the navigation task 12 weeks after surgery. Alpha-Tocopherol has, however, no influence on 6-OHDA-induced changes in problem solving strategies. The used model reflects some of the pathological symptoms of Parkinson's disease, and it seems that alpha-tocopherol may be an effective drug in the early initial stages of the disease.
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PMID:Behavioral alterations after unilateral 6-hydroxydopamine lesions of the striatum. Effect of alpha-tocopherol. 1199 61

Deprenyl (selegiline) delays the need for levodopa therapy in patients with early Parkinson's disease, but the long-term benefits of this treatment remain unclear. During 1987 to 1988, 800 patients with early Parkinson's disease were randomized in the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism trial to receive deprenyl, tocopherol, combined treatments, or a placebo and were then placed on active deprenyl (10mg/day). A second, independent randomization was carried out in early 1993 for 368 subjects who by that time had required levodopa and who had consented to continuing the deprenyl treatment (D subjects) or changing to a matching placebo (P subjects) under double-blind conditions. The first development of wearing off, dyskinesias, or on-off motor fluctuations was the prespecified primary outcome measure. During the average 2-year follow-up, there were no differences between the treatment groups with respect to the primary outcome measure (hazard ratio, 0.87; 95% confidence interval, 0.63, 1.19; p = 0.38), withdrawal from the study, death, or adverse events. Although 34% of D subjects developed dyskinesias and only 19% of P subjects did (p = 0.006), only 16% of D subjects developed freezing of gait but 29% of P subjects did (p = 0.0003). Decline in motor performance was less in D subjects than P subjects. Levodopa-treated Parkinson's disease patients who had been treated with deprenyl for up to 7 years, compared with patients who were changed to a placebo after about 5 years, experienced slower motor decline and were more likely to develop dyskinesias but less likely to develop freezing of gait.
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PMID:Impact of sustained deprenyl (selegiline) in levodopa-treated Parkinson's disease: a randomized placebo-controlled extension of the deprenyl and tocopherol antioxidative therapy of parkinsonism trial. 1211 7

Several neurodegenerative disorders are associated with oxidative stress that is manifested by lipid peroxidation, protein oxidation and other markers. Included in these disorders in which oxidative stress is thought to play an important role in their pathogenesis are Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), tardive dyskinesia, Huntington's disease (HD), and multiple sclerosis. This review presents some of the chemistry of vitamin E as an antioxidant and summarizes studies in which vitamin E has been employed in these disorders and models thereof.
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PMID:Vitamin E and neurodegenerative disorders associated with oxidative stress. 1216 85


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