Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The protective action of R-(-)-deprenyl against the aglycemia (glucose-free) and the ischemia (glucose-free and O2-free)-induced changes in the synaptic transmission was investigated. The in vitro "glucose-free and O2-free" condition mimics in vivo ischemia where there is a deficiency of O2 and energy substrate, hence the term ischemia was used. The monosynaptic reflex (MSR) and polysynaptic reflex (PSR) potentials were elicited in the ventral root by stimulating the corresponding dorsal root in an isolated spinal cord from the neonatal rat. Aglycemia and ischemia depressed the spinal reflexes in a time-dependent manner and abolished them within 30 min. The 50% depression of the reflexes (T-50) occurred around 25 min for aglycemia and 15 min for ischemia. Creatine phosphate, an energy supplement, attenuated the aglycemia- and ischemia-induced depression of the reflexes. The T-50 values for both the reflexes were around 40 and 25 min for aglycemia and ischemia, respectively. Deprenyl (10 microM) blocked the aglycemia-induced depression completely but failed to block the ischemia-induced depression. The present results indicate that aglycemia and ischemia abolished the synaptic transmission simultaneously and energy supplementation partially attenuated the depression. The protective effects of deprenyl against aglycemia may not be due to its MAO-B action and suggest for the involvement of non-MAO-B mechanisms.
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PMID:Deprenyl blocks the aglycemia-induced depression of the synaptic transmission but not the ischemia-induced depression in neonatal rat spinal cord in vitro. 1294 43

Normal cellular metabolism produces oxidants that are neutralized by the cells' antioxidant enzymes and antioxidants taken from outside. An imbalance between oxidant and antioxidant has been postulated to lead to the neurodegeneration in the ischemic condition. In this study, we have demonstrated the prevention or slowdown of neuronal injury in middle cerebral artery occlusion (MCAO) by sodium selenite. Rats were pretreated with 0.05, 0.1, and 0.2 mg/kg body wt of sodium selenite for 7 d. The rats of group I (sham) and group II (ischemia) were pretreated with physiological saline for 7 d. On d 8, MCAO was induced for 2 h in the right side of brain of group II, III, IV, and V rats. Brains were dissect out after 22 h of reperfusion and washed with chilled physiological saline. The right cerebral hemisphere was used for the preparation of mitochondria. The activity of superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase, and monoamine oxidase (MAO-A and MAO-B) was depleted significantly; conversely, the activity of poly(ADP-ribosyl) polymerase was elevated significantly as compared to the sham, and the pretreatment of the animals with different doses of sodium selenite has protected the activity of these enzymes significantly. The content of glutathione was decreased significantly, whereas the level of lipid peroxidation was increased significantly in the mitochondria of MCAO as compared to the sham group, and pretreatment with different doses of sodium selenite has protected their levels significantly as compared to the MCAO group. It is concluded that selenium, which is an essential part of our diet, might be helpful in protection against neurodegeneration in cerebral ischemia.
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PMID:Selenium protects cerebral ischemia in rat brain mitochondria. 1551 4

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

Rasagiline (N-propargyl-1R-aminoindan) is a novel, highly potent, irreversible monoamine oxidase (MAO)-B inhibitor designed for use as an antiparkinsonian drug. Unlike selegiline, rasagiline is not derived from amphetamine or metabolized to neurotoxic l-methamphetamine derivative, and it does not have sympathomimetic activity. Moreover, at selective MAO-B inhibitory dosage, it does not induce a "cheese reaction." Rasagiline is effective as monotherapy or as an adjunct to L-dopa for patients with early and late Parkinson's disease. Adverse events do not occur with greater frequency in subjects receiving rasagiline than in those on placebo. Its S-isomer, TVP1022, is more than a thousand times less potent as an MAO inhibitor. However, both drugs have neuroprotective activities in neuronal cell cultures in response to various neurotoxins, as well as in vivo (e.g., in response to global ischemia, neurotrauma, head injury, anoxia, etc.), indicating that MAO inhibition is not a prerequisite for neuroprotection. The neuroprotective activity of these drugs has been demonstrated to be associated with the propargylamine moiety, which protects mitochondrial viability and mitochondrial permeability transition pore by activating Bcl-2 and downregulating the Bax family of proteins. Rasagiline processes amyloid precursor protein (APP) into the neuroprotective-neurotrophic soluble APPalpha (sAPPalpha) by protein kinase C- and mitogen-activated protein kinase-dependent activation of alpha-secretase, and increases nerve growth factor, glial cell- derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) expression and proteins. Thus, rasagiline may induce neuroprotection, neuroplasticity and long-term potentiation. Rasagiline has therefore been chosen by the National Institutes of Health (NIH) to study its neuroprotective effects in neurodegenerative diseases. Long-term studies are required to evaluate the drug's disease-modifying prospects in Parkinson's and Alzheimer's diseases.
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PMID:Neuropharmacological, neuroprotective and amyloid precursor processing properties of selective MAO-B inhibitor antiparkinsonian drug, rasagiline. 1611 Mar 45

Ideal treatment in Parkinson's disease (PD) aims at relieving symptoms and slowing disease progression. Of all remedies, levodopa remains the most effective for symptomatic relief, but the medical need for neuroprotectant drugs is still unfulfilled. Safinamide, currently in phase III clinical trials for the treatment of PD, is a unique molecule with multiple mechanisms of action and a very high therapeutic index. It combines potent, selective, and reversible inhibition of MAO-B with blockade of voltage-dependent Na+ and Ca2+ channels and inhibition of glutamate release. Safinamide has neuroprotective and neurorescuing effects in MPTP-treated mice, in the rat kainic acid, and in the gerbil ischemia model. Safinamide potentiates levodopa-mediated increase of DA levels in DA-depleted mice and reverses the waning motor response after prolonged levodopa treatment in 6-OHDA-lesioned rats. Safinamide has excellent bioavailability, linear kinetics, and is suitable for once-a-day administration. Therefore, safinamide may be used in PD to reduce l-dopa dosage and also represents a valuable therapeutic drug to test disease-modifying potential.
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PMID:Safinamide: from molecular targets to a new anti-Parkinson drug. 1703 Jul 36

Selegiline inhibits the activity of monoamine oxidase B, enhances the release of dopamine, blocks the uptake of dopamine, acts as a calmodulin antagonist, and enhances the level of cyclic AMP, which in turn protects dopaminergic neurons. It possesses cognition-enhancing functions, rejuvenates serum insulin-like growth factor I in aged rats, and enhances life expectancy in rodents. Selegiline possesses neurotrophic-like actions, and rescues axotomized motorneurons independent of monoamine oxidase B inhibition. It enhances the synthesis of nerve growth factor, protects dopaminergic neurons from glutamate-mediated neurotoxicity, and protects dopaminergic neurons from toxic factors present in the spinal fluid of parkinsonian patients, and the said effect may be mediated via elaborating brain derived neurotrophic factor. Selegiline increases the striatal superoxide dismutase, protects against peroxynitrite- and nitric oxide-induced apoptosis, and guards dopaminergic neurons from toxicity induced by glutathione depletion. It stimulates the biosynthesis of interleukin 1-beta and interleukin-6, is an immunoenhancing substance, possesses antiapoptotic actions, and is neuroprotectant in nature. Selegiline has been shown to be efficacious in Parkinson's disease, global ischemia, Gille de la Tourette syndrome, and narcolepsy. Its therapeutic efficacy in Alzheimer's disease remains uncertain. In Alzheimer's disease, short term studies of selegiline suggest a beneficial effect; whereas long term studies are less convincing.
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PMID:Therapeutic efficacy of selegiline in neurodegenerative disorders and neurological diseases. 1710 May 91

An increasing number of reports suggest the involvement of oxidative stress in neurodegenerative diseases where the increased formation of reactive oxygen species (ROS) leads to neuronal damage and cell death. Dopamine may contribute to neurodegenerative disorders such as Parkinson's disease and ischemia/reperfusion-induced damage. Monoamine oxidase (MAO) enzyme (particularly MAO-B) is responsible for metabolizing dopamine and plays an important role in oxidative stress through altering the redox state of neuronal and glial cells. MAO participates in the generation of hydroxyl radicals during ischemia/reperfusion. This suggests the possible use of MAO inhibitors as neuroprotective agents for treating ischemic injury. The protective effect of deprenyl (N-methyl-N-(1-methyl-2-phenyl-ethyl)-prop-2-yn-1-amine, CAS 14611-51-9) (2 and 10 mg/kg), a MAO-B inhibitor, and beta-carotene (10 and 20 mg/kg), a natural antioxidant, was examined in a rat model of cerebral ischemia. Ischemia was induced in rats by bilateral carotid artery occlusion for 1 h followed by declamping for another hour. The effect of the drugs on the brain activity of lactate dehydrogenase (LDH) and some of the oxidative stress biomarkers such as brain activity of superoxide dismutase (SOD) and catalase (CAT) enzymes and brain malondialdehyde (MDA) content was determined. In addition, the content of catecholamines such as noradrenaline (NA) and dopamine (DA) was determined. Deprenyl decreased the ischemia-induced elevation of LDH activity and MDA content and normalized the SOD activity. In addition, deprenyl increased the CAT activity back to normal, and increased the noradrenaline and dopamine content in the brain of rats. Beta-carotene administration ameliorated the effect of ischemia followed by reperfusion (I/R) demonstrated as decreasing the LDH activity and MDA content and by increasing the SOD activity. The drug also increased CAT activity in the brain of rats. However, beta-carotene did not alter the NA and DA content. These results indicate that deprenyl protected the rat brains against the ischemia-induced oxidative damage, an effect which might be explained through multiple mechanisms, possibly due to reduction of dopamine catabolism with a subsequent increased activity on dopaminergic D2 receptors and suppressing the action of ROS as well.
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PMID:Effect of MAO-B inhibition against ischemia-induced oxidative stress in the rat brain. Comparison with a rational antioxidant. 1854 Apr 77

The p38 mitogen-activated protein kinase (MAPK) cascade as well as the enzyme monoamine oxidase-A (MAO-A) have both been associated with oxidative stress. We observed that the specific inhibition of the p38(MAPK) protein [using either a chemical inhibitor or a dominant-negative p38(MAPK) clone] selectively induces MAO-A activity and MAO-A-sensitive toxicity in several neuronal cell lines, including primary cortical neurons. Over-expression of a constitutively active p38(MAPK) results in the phosphorylation of the MAO-A protein and inhibition of MAO-A activity. The MAO-A(Ser209Glu) phosphomimic - bearing a targeted substitution within a putative p38(MAPK) consensus motif - is neither active nor neurotoxic. In contrast, the MAO-A(Ser209Ala) variant (mimics dephosphorylation) does not associate with p38(MAPK), and is both very active and very toxic. Substitution of the homologous serine in the MAO-B isoform, i.e. Ser200, with either Glu or Ala does not affect the catalytic activity of the corresponding over-expressed proteins. These combined in vitro data strongly suggest a direct p38(MAPK)-dependent inhibition of MAO-A function. Based on published observations, this endogenous means of selectively regulating MAO-A function could provide for an adaptive response to oxidative stress associated with disorders as diverse as depression, reperfusion/ischemia, and the early stages of Alzheimer's disease.
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PMID:Serine 209 resides within a putative p38(MAPK) consensus motif and regulates monoamine oxidase-A activity. 1965 Aug 72

Zonisamide is an FDA-approved antiepileptic drug that blocks voltage-dependent Na(+) channels and T-type Ca(2+) channels and improves clinical outcome in Parkinson's disease (PD) patients when used as an adjunct to other PD therapies. Zonisamide also modifies dopamine (DA) activity, provides protection in ischemia models and influences antioxidant systems. Thus, we tested it for its ability to protect DA neurons in a mouse model of PD and investigated mechanisms underlying its protection. Concurrent treatment of mice with zonisamide and 1-methyl-4-phenyl-1,2,3,6-tetraydropyridine (MPTP) attenuated the reduction in striatal contents of DA, its metabolite DOPAC and tyrosine hydroxylase (TH). We also discovered that zonisamide inhibited monoamine oxidase B (MAO-B) activity in vitro with an IC(50) of 25 muM, a concentration that is well within the therapeutic range used for treating epilepsy in humans. Moreover, the irreversible binding of systemically administered selegiline to MAO-B in mouse brain was attenuated by zonisamide as measured by ex vivo assays. Zonisamide treatment alone did not produce any lasting effects on ex vivo MAO-B activity, indicating that it is a reversible inhibitor of the enzyme. Consistent with the effects of zonisamide on MAO-B, the striatal content of 1-methyl-4-phenylpyridinium (MPP(+)), which is derived from the administered MPTP via MAO-B actions, was substantially reduced in mice treated with MPTP and zonisamide. The potency and reversibility with which zonisamide blocks MAO-B may contribute to the ability of the drug to improve clinical symptoms in PD patients. The results also suggest that caution in its use may be necessary, especially when administered with other drugs, in the treatment of epilepsy or PD.
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PMID:The antiepileptic drug zonisamide inhibits MAO-B and attenuates MPTP toxicity in mice: clinical relevance. 2045 Sep 11

Aims: Catecholamine metabolism via monoamine oxidase (MAO) contributes to cardiac injury in models of ischemia and diabetes, but the pathogenic mechanisms involved are unclear. MAO deaminates norepinephrine (NE) and dopamine to produce H2O2 and highly reactive "catecholaldehydes," which may be toxic to mitochondria due to the localization of MAO to the outer mitochondrial membrane. We performed a comprehensive analysis of catecholamine metabolism and its impact on mitochondrial energetics in atrial myocardium obtained from patients with and without type 2 diabetes. Results: Content and maximal activity of MAO-A and MAO-B were higher in the myocardium of patients with diabetes and they were associated with body mass index. Metabolomic analysis of atrial tissue from these patients showed decreased catecholamine levels in the myocardium, supporting an increased flux through MAOs. Catecholaldehyde-modified protein adducts were more abundant in myocardial tissue extracts from patients with diabetes and were confirmed to be MAO dependent. NE treatment suppressed mitochondrial ATP production in permeabilized myofibers from patients with diabetes in an MAO-dependent manner. Aldehyde dehydrogenase (ALDH) activity was substantially decreased in atrial myocardium from these patients, and metabolomics confirmed lower levels of ALDH-catalyzed catecholamine metabolites. Proteomic analysis of catechol-modified proteins in isolated cardiac mitochondria from these patients identified >300 mitochondrial proteins to be potential targets of these unique carbonyls. Innovation and Conclusion: These findings illustrate a unique form of carbonyl toxicity driven by MAO-mediated metabolism of catecholamines, and they reveal pathogenic factors underlying cardiometabolic disease. Importantly, they suggest that pharmacotherapies targeting aldehyde stress and catecholamine metabolism in heart may be beneficial in patients with diabetes and cardiac disease.
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PMID:Enhanced Catecholamine Flux and Impaired Carbonyl Metabolism Disrupt Cardiac Mitochondrial Oxidative Phosphorylation in Diabetes Patients. 3306 17


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