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Arch Pharm Res. 2003 Jan;26(1):24-7. Further isolation of antioxidative (+)-1-hydroxypinoresinol-1-O-beta-D-glucoside from the rhizome of Salvia miltiorrhiza that acts on peroxynitrite, total ROS and 1,1-diphenyl-2-picrylhydrazyl radical. Kang HS, Chung HY, Byun DS, Choi JS.

Faculty of Food Science and Biotechnology, Pukyong National University, Pusan 608-737, Korea. Abstract A furanofuranoid lignan glycoside, with radical scavenging on peroxynitrite, total reactive oxygen species (ROS) and 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical, was isolated from the rhizome of Salvia miltiorrhiza and characterized as (+)-1-hydroxypinoresinol-1-O-beta-D-glucoside based on spectroscopic evidence. The compound exhibited peroxynitrite, total ROS and DPPH radical scavenging activities with IC50 values of 3.23 +/- 0.04, 2.26 +/- 0.07 and 32.3 +/- 0.13 microM, respectively. Penicillamine, Trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid) and L-ascorbic acid, acting as positive controls, showed radical scavenging activities with IC50 values of 6.72 +/- 0.25, 1.43 +/- 0.04 and 11.4 +/- 0.07 microM, respectively.

  [PubMed - indexed for MEDLINE]

Carazalol Edaravone Tropicamide Trihexyphenidyl Bromocriptine Cabergoline Procyclidine Biperiden

http://www.jns-journal.com/article/S0022-510X(97)00266-9/abstract bromocriptine glutamate uptake, other ...........

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(R)-(-)-Phenylephrine hydrochloride -- "α1-adrenoceptor agonist; pKi values are 5.86, 4.87 and 4.70 for α1D, α1B and α1A receptors respectively" (pKi values from Tocris Bio http://www.tocris.com

Synapse. 2006 Apr;59(5):290-8. Effects of COX-1 and COX-2 inhibitors on the firing of rat midbrain dopaminergic neurons--possible involvement of endogenous kynurenic acid. Schwieler L, Erhardt S, Nilsson L, Linderholm K, Engberg G.

Department of Physiology and Pharmacology, Karolinska Institutet, 171 77 Stockholm, Sweden. Abstract Kynurenic acid (KYNA) is an endogenous glutamate-receptor antagonist with a preferential action at the glycine-site of the NMDA-receptor. In the present in vivo study, the importance of brain KYNA to modulate the activity of dopamine (DA) neurons in the ventral tegmental area (VTA) was analyzed by utilizing the decrease in brain KYNA formation induced by the cyclooxygenase (COX)-2 inhibitor parecoxib. A reduction in brain KYNA concentration (39-44%) by parecoxib (25 mg/kg, i.v., 1 h or, i.p., 3.5 h) was associated with a decreased firing rate and burst firing activity. In concordance, an increase in brain KYNA concentration (150-300%), induced by the COX-1 inhibitor indomethacin (50 mg/kg, i.v., 1 h or, i.p., 3.5 h), produced opposite effects, that is, increased firing rate and burst firing activity. The decrease and increase in neuronal firing of VTA DA neurons by the COX-inhibitors was reversed by L-701,324 (antagonist at the NMDA-glycine site; 0.06-2 mg/kg, i.v.) and by D-cycloserine (partial agonist at the NMDA-glycine site; 2-32 mg/kg, i.v.), respectively. In addition, the parecoxib-induced decrease in firing rate and burst firing activity was effectively blocked by pretreatment with kynurenine (5 mg/kg, i.p., 30 min), the immediate precursor of KYNA. Present results suggest that the action of COX-inhibitors on the firing of VTA DA neurons are linked to their effects on KYNA formation and that endogenous KYNA is tonically modulating the neuronal activity of VTA DA neurons. Such a modulatory action of KYNA should be of importance for the functioning of mesocorticolimbic DA pathway.

[PubMed - indexed for MEDLINE]

Acetazolamide - helps with altitude sickness..? http://www.ncbi.nlm.nih.gov/pubmed/14624409  Alpha adrenergic 1,  adaptation to hypoxia

Possible neuroprotective effect of ibuprofen

In March 2011, researchers at Harvard Medical School announced in Neurology that ibuprofen had a neuroprotective effect against the risk of developing Parkinson's disease. People regularly consuming ibuprofen were reported to have a 38 percent lower risk of developing Parkinson's disease, but no such effect was found for other pain relievers such as aspirin and acetaminophen. Use of ibuprofen to lower the risk of Parkinson's disease in the general population would not be problem-free, given the possibility of adverse effects on the urinary and digestive systems. In the same week, another study linked regular use of NSAIDs, including ibuprofen, to erectile dysfunction.[42] [edit]

Ibuprofen protects dopaminergic neurons against glutamate toxicity in vitro

a Department of Neurological Surgery, Neurosurgery Lab, Moses Building, 3rd Floor, Montefiore Medical Center, 111 East 210th Street, The Bronx, New York, NY 10467, USA b Department of Neurology, The Albert Einstein College of Medicine, The Bronx, New York, NY, USA c Department of Neurology, The Beth Israel Medical Center, New York NY, USA Received 10 May 2000; revised 20 June 2000; accepted 20 June 2000. Available online 24 August 2000. Abstract Non-steroidal anti-inflammatory drugs (NSAIDs) reduce the risk of Alzheimer's disease, although the underlying mechanisms are unknown. Glutamate excitotoxicity has been implicated in Alzheimer's disease, Parkinson's disease, and others. We examined the effects of aspirin, acetaminophen, and ibuprofen on cultured primary rat embryonic neurons from mesencephalon, the area primarily affected in Parkinson's disease. We evaluated whether these drugs protect dopaminergic neurons against excitotoxicity. All three NSAIDs significantly attenuated the decrease in dopamine uptake caused by glutamate, indicating preservation of neuronal integrity. One hundred micro-moles ibuprofen protected both dopaminergic neurons and neurons overall against glutamate toxicity. In addition, ibuprofen alone increased the relative number of dopaminergic neurons by 47%. Thus, NSAIDs protected neurons against glutamate excitotoxicity in vitro, and deserve further consideration as neuroprotective agents in Parkinson's disease. Author Keywords: Non-steroidal anti-inflammatory drugs; Aspirin; Acetaminophen; Ibuprofen; Neuroprotection; Neurodegeneration; Cell culture; Dopaminergic; Parkinson’s disease

Abstract In order to analyze the putative neuroprotective role of nicotine and cotinine in parkinsonian syndromes, these two compounds were administered in male C57Bl6 mice for 4 weeks. On day 8, four injections of 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine (MPTP) were administered. MPTP intoxication induced a 50% loss of dopaminergic neurons in the substantia nigra and a 45% reduction in dopaminergic fibers in the striatum. Administration of cotinine did not affect MPTP toxicity in the nigrostriatal system but chronic nicotine treatment showed a slight protection (15%) of nigrostriatal dopaminergic neurons against MPTP.

Gangliosides prevent MPTP toxicity in mice - an immunocytochemical study

M. Gupta, a, J. Schwarza, X.L. Chena and F.J. Roisena aDepartment of Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, Louisville, KY 40292 U.S.A. Revised 29 May 1990. Available online 10 March 2003. Abstract The role of gangliosides in preventing neuronal degeneration was examined in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse parkinsonian model. Intraventricular injections of a ganglioside mixture prior to MPTP treatment reduced MPTP's toxicity on tyrosine hydroxylase-positive neurons in the substantia nigra. This raises the interesting possibility that early ganglioside administration may be beneficial in the treatment of neurodegenerative disorders. http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6SYR-483SVXJ-2XY&_user=10&_origUdi=B6SYR-484M7VY-105&_fmt=high&_coverDate=09%2F17%2F1990&_rdoc=1&_orig=article&_origin=article&_zone=related_art&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=e4757d07abafb2285870a9a045d665db

http://www.springerlink.com/content/p73312p26616n286/ An Investigation into the Neuroprotective Properties of Ibuprofen eriatric depression scores on age, nutritional status, and haematologic variables in elderly institutionalized patientsC. H. Alves De Rezende Scroll upScroll down

EXPORT CITATIONABOUT Abstract There is increasing evidence suggesting a protective role for anti-inflammatory medications in neurological disorders such as Alzheimer''s disease (AD). While there has not been any direct evidence for this, a number of clinical studies indicate that those patients who have had a history of nonsteroidal anti-inflammatory use, have a lower incidence of AD. Since there is currently no evidence on the mechanism by which these agents offer possible neuroprotection, we investigated the potential neuroprotective properties of the nonsteroidal anti-inflammatory drug, ibuprofen, by examining whether this agent could reduce lipid peroxidation and superoxide radical generation. Quinolinic acid and cyanide, known neurotoxins, were used to induce lipid peroxidation and superoxide anion formation respectively, in rat brain homogenate. The results show that ibuprofen significantly (p<0.05) reduced="" quinolinic="" acid-induced="" lipid="" peroxidation="" and="" cyanide-induced="" superoxide="" production.="" the="" results="" of="" the="" present="" report="" therefore="" suggest="" a="" possible="" mechanism="" for="" the="" neuroprotective="" effect="" of="">

http://onlinelibrary.wiley.com/doi/10.1046/j.1471-4159.1999.0721117.x/full Antidepressants Noncompetitively Inhibit Nicotinic Acetylcholine Receptor Function

elationship between the increased cell surface alpha7 nicotinic receptor expression and neuroprotection induced by several nicotinic receptor agonists. Jonnala RR, Buccafusco JJ.

Alzheimer's Research Center, Medical College of Georgia, Augusta, Georgia 30912-2300, USA. Abstract Nicotine and other nicotinic acetylcholine receptor agonists have been shown to exert neuroprotective actions in vivo and in vitro by an as yet unknown mechanism. Even the identification of the subtype of nicotinic receptor(s) mediating this action has not been determined. In neural cell lines, the induction of cytoprotection often requires exposure to nicotine for up to 24 hr to produce a full protective effect. One phenomenon associated with chronic exposure of neural cells to nAChR agonists is the increased expression of nAChRs (upregulation), possibly as a response to desensitization. Because nicotinic receptors desensitize rapidly in the continuous presence of agonist, we investigated whether the neuroprotective actions produced by different nicotinic receptor agonists was related to their ability to induce nicotinic receptor upregulation. Differentiated PC12 cells were preincubated for 24 hr with various nAChR ligands, and the cells were subsequently deprived of both NGF and serum to induce cytotoxicity. Under control conditions cell viability was reduced to 66.5 +/- 5.4% of control by trophic factor withdrawal. For those cells pretreated with nicotine (1 nM-100 microM) cell viability increased from 74.2 +/- 1.5 to 97.3 +/- 4%. The neuroprotective action of nicotine was blocked by co-treatment with either 5 microM mecamylamine or 10 nM methyllycaconitine (MLA). The high potency blockade by MLA suggested that neuroprotection was mediated through the alpha7 nicotinic receptor subtype. For the seven agonists examined for neuroprotective activity, only nicotine was capable of evoking a near maximal (near 100% cell viability) neuroprotective action. The next most effective group included epibatidine, 4OHGTS-21, methycarbamylcholine, and 1,1-dimethyl-4-phenyl-piperazinium iodide. These least effective group included cytisine and tetraethylammonium. Incubation of differentiated PC12 cells with 10 microM nicotine increased the number of [(125)I]alpha bungarotoxin ([(125)I]alphaBGTbinding sites by 41% from 82.6 +/- 3.67 to 117 +/- 10.3 fmol/mg protein). Under similar conditions of incubation, the nicotinic receptor agonist cytisine (that was least effective in terms of neuroprotection) failed to increase the number of [(125)I]alphaBGT binding sites. Cells expressing increased levels of cell surface [(125)I]alphaBGT binding sites received added neuroprotective benefit from nicotine. Thus the induced upregulation of the alpha7 subtype of nicotinic receptors during chronic exposure to nicotine may be responsible for the drug's neuroprotective action.

http://www.ncbi.nlm.nih.gov/pubmed/10575026 Peroxynitrite inactivation of tyrosine hydroxylase: mediation by sulfhydryl oxidation, not tyrosine nitration. Kuhn DM, Aretha CW, Geddes TJ.

Department of Psychiatry, Wayne State University School of Medicine, Detroit, Michigan 48201, USA. donald.kuhn@wayne.edu Abstract Tyrosine hydroxylase (TH) is the initial and rate-limiting enzyme in the biosynthesis of dopamine (DA). TH activity is significantly diminished in Parkinson's disease (PD) and by the neurotoxic amphetamines, thereby accentuating the reductions in DA associated with these conditions. Reactive oxygen and nitrogen species have been implicated in the damage to DA neurons seen in PD and in reaction to amphetamine drugs of abuse, so we investigated the hypothesis that peroxynitrite (ONOO(-)) could interfere with TH catalytic function. ONOO(-) caused a concentration-dependent inactivation of TH. The inactivation was associated with tyrosine nitration (maximum of four tyrosine residues nitrated per TH monomer) and extensive sulfhydryl oxidation. Tetranitromethane, which causes sulfhydryl oxidation at pH 6 and 8 but which nitrates tyrosines only at pH 8, inactivated TH equally at either pH. Bicarbonate protected TH from ONOO(-)-induced inactivation and sulfhydryl oxidation but increased significantly tyrosine nitration. PNU-101033 blocked ONOO(-)-induced tyrosine nitration in TH but could not prevent enzyme inactivation or sulfhydryl oxidation. Together, these results indicate that the inactivation of TH by ONOO(-) is mediated by sulfhydryl oxidation. The coincident nitration of tyrosine residues appears to exert little influence over TH catalytic function.

[PubMed - indexed for MEDLINE]Free Article

http://www.ncbi.nlm.nih.gov/pubmed/12771134 Biol Chem. 2003 Aug 1;278(31):28736-42. Epub 2003 May 27. Dopamine prevents nitration of tyrosine hydroxylase by peroxynitrite and nitrogen dioxide: is nitrotyrosine formation an early step in dopamine neuronal damage? Park S, Geddes TJ, Javitch JA, Kuhn DM.

Department of Psychiatry and Behavioral Neurosciences, School of Medicine, Wayne State University, 2125 Scott Hall, 540 E. Canfield, Detroit, MI 48201, USA. Abstract Peroxynitrite and nitrogen dioxide (NO2) are reactive nitrogen species that have been implicated as causal factors in neurodegenerative conditions. Peroxynitrite-induced nitration of tyrosine residues in tyrosine hydroxylase (TH) may even be one of the earliest biochemical events associated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced damage to dopamine neurons. Exposure of TH to peroxynitrite or NO2 results in nitration of tyrosine residues and modification of cysteines in the enzyme as well as inactivation of catalytic activity. Dopamine (DA), its precursor 3,4-dihydroxyphenylalanine, and metabolite 3,4-dihydroxyphenylacetic acid completely block the nitrating effects of peroxynitrite and NO2 on TH but do not relieve the enzyme from inhibition. o-Quinones formed in the reaction of catechols with either peroxynitrite or NO2 react with cysteine residues in TH and inhibit catalytic function. Using direct, real-time evaluation of tyrosine nitration with a green fluorescent protein-TH fusion protein stably expressed in intact cells (also stably expressing the human DA transporter), DA was also found to prevent NO2-induced nitration while leaving TH activity inhibited. These results show that peroxynitrite and NO2 react with DA to form quinones at the expense of tyrosine nitration. Endogenous DA may therefore play an important role in determining how DA neurons are affected by reactive nitrogen species by shifting the balance of their effects away from tyrosine nitration and toward o-quinone formation.

[PubMed - indexed for MEDLINE]Free Article

Tetrahydrobiopterin prevents nitration of tyrosine hydroxylase by peroxynitrite and nitrogen dioxide. Kuhn DM, Geddes TJ.

Wayne State University School of Medicine, 2125 Scott Hall, 540 E. Canfield, Detroit, MI 48201, USA. donald.kuhn@wayne.edu Abstract Tyrosine hydroxylase (TH) is the initial and rate-limiting enzyme in the synthesis of the neurotransmitter dopamine. TH is inhibited and nitrated at tyrosine residues in vitro by the reactive nitrogen species peroxynitrite and nitrogen dioxide (NO2) and in vivo by drugs that damage dopamine neurons. Tetrahydrobiopterin, which is the essential cofactor for TH and is concentrated in dopamine neurons, completely blocks nitration of tyrosine residues in TH caused by peroxynitrite or NO2. Various tetrahydro- and dihydro-analogs of tetrahydrobiopterin, including 6,7-dimethyl-tetrahydropterin, 6-methyl-tetrahydropterin, 6-hydroxymethyl-tetrahydropterin, tetrahydropterin, 7,8-dihydrobiopterin, 7,8-dihydroxanthopterin, and sepiapterin, also prevent nitration of tyrosines caused by the reactive nitrogen species. Biopterin and pterin, the fully oxidized forms of the pterin molecule, fail to block peroxynitrite- or NO2-induced nitration of TH. Reduced pterins prevent neither the inhibition of TH activity nor cysteine modification caused by peroxynitrite or NO2, despite blocking tyrosine nitration. However, dithiothreitol prevents and reverses these effects on TH of tetrahydrobiopterin and reactive nitrogen species. Using an enhanced green fluorescent protein-TH fusion construct as a real-time reporter of intracellular tyrosine nitration, tetrahydrobiopterin was found to prevent NO2-induced tyrosine nitration in intact cells but to leave TH activity inhibited. These results indicate that tetrahydrobiopterin prevents the tyrosine-nitrating properties of peroxynitrite and NO2. Tetrahydrobiopterin-derived radical species formed by reaction with reactive nitrogen species may account for inhibition of TH via mechanisms that do not involve tyrosine nitration.

[PubMed - indexed for MEDLINE]Free Article

http://www.ncbi.nlm.nih.gov/pubmed/14500751

Antioxid Redox Signal. 2005 Jul-Aug;7(7-8):863-9. S-thiolation of tyrosine hydroxylase by reactive nitrogen species in the presence of cysteine or glutathione. Sadidi M, Geddes TJ, Kuhn DM.

Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI 48201, USA. Abstract Tyrosine hydroxylase (TH) is the initial and rate-limiting enzyme in the biosynthesis of the neurotransmitter dopamine. Peroxynitrite (ONOO-) and nitrogen dioxide (NO2) inhibit TH catalytic function and cause nitration of protein tyrosine residues. Exposure of TH to either ONOO- or NO2 in the presence of cysteine (or glutathione) prevents tyrosine nitration and results in S-thiolation instead. TH catalytic activity is suppressed by S-thiolation. Dithiothreitol prevents and reverses the modification of TH by S-thiolation, and returns enzyme activity to control levels. S-Nitrosothiols, which are known to S-thiolate proteins, can be formed in the reaction of cysteine or glutathione with reactive nitrogen species. Therefore, S-nitrosoglutathione (GSNO) was tested for its ability to modify TH. Fresh solutions of GSNO did not modify TH, whereas decomposed GSNO resulted in extensive S-thiolation of the protein. Dimedone, a sulfenic acid trap, prevents S-thiolation of TH when included with GSNO during its decomposition. Taken together, these results show that TH is S-thiolated by ONOO- or NO2 in the presence of cysteine. S-Thiolation occurs at the expense of tyrosine nitration. Glutathione disulfide S-oxide, which forms spontaneously in the decomposition of GSNO and which is found in tissue undergoing oxidative stress, may be the species that S-thiolates TH.

[PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov/pubmed/15998241

Ann N Y Acad Sci. 1999;890:301-11. Neuroprotective properties of nitric oxide. Chiueh CC.

Unit on Neurodegeneration and Neuroprotection, National Institute of Mental Health, NIH Clinical Center, Bethesda, Maryland 20892-1264, USA. chiueh@helix.nih.gov Abstract The discoveries of physiological roles of nitric oxide (.NO) as the mediator of endothelium-derived relaxing factor (EDRF) action and the activator of guanylyl cyclase to increase cyclic guanosine monophosphate (cGMP), which lead to vasorelaxation in the cardiovascular system, have been awarded with the 1998 Nobel Prize of Medicine. The present review discusses putative beneficial effects of .NO in the central nervous system (CNS). In addition to its prominent roles of the regulation of cerebral blood flow and the modulation of cell to cell communication in the brain, recent in vitro and in vivo results indicated that .NO is a potent antioxidative agent. .NO terminates oxidant stress in the brain by (i) suppressing iron-induced generation of hydroxyl radicals (.OH) via the Fenton reaction, (ii) interrupting the chain reaction of lipid peroxidation, (iii) augmenting the antioxidative potency of reduced glutathione (GSH) and (iv) inhibiting cysteine proteases. It is apparent that .NO--a relative long half-life nitrogen-centered weak radical--scavenges those short-lived, highly reactive free radicals such as superoxide anion (O2.-), .OH, peroxyl lipid radicals (LOO.) and thiyl radicals (i.e., GS.), yielding reactive nitrogen species including nitrites, nitrates, S-nitrosoglutathione (GSNO) and peroxynitrite (ONOO-). GSNO is 100-fold more potent than GSH; it completely inhibits the weak peroxidative effect of ONOO-. Moreover, CO2 and .NO neutralize prooxidative effects of ONOO-. CO2 prevents protein oxidation but not 3-nitrotyrosine formation caused by ONOO-. Finally, neuroprotective effects of GSNO and .NO have been demonstrated in brain preparations in vivo. These novel neuroprotective properties of .NO and GSNO may have their physiological significance, since oxidative stress depletes GSH while increasing GS. and .NO formation in astroglial and endothelial cells, resulting in the generation of a more potent antioxidant GSNO and providing additional neuro-protection at microM concentrations. This putative GSNO pathway (GSH-->GS.-->GSNO-->.NO + GSSG-->GSH) may be an important part of endogenous antioxidative defense system, which could protect neurons and other brain cells against oxidative stress caused by oxidants, iron complexes, proteases and cytokines. In conclusion, .NO is a potent antioxidant against oxidative damage caused by reactive oxygen species, which are generated by Fenton reaction or other mechanisms in the brain via redox cycling of iron complexes.

[PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov/pubmed/10668435

FASEB J. 1998 Feb;12(2):165-73. Neuroprotection by S-nitrosoglutathione of brain dopamine neurons from oxidative stress. Rauhala P, Lin AM, Chiueh CC.

Unit on Neurodegeneration and Neuroprotection, Laboratory of Clinical Science, National Institute of Mental Health, Bethesda, Maryland 20892-1264, USA. Abstract The proposed anti- and pro-oxidant effects of nitric oxide (NO) derivatives, such as S-nitrosoglutathione (GSNO) and peroxynitrite, were investigated in the rat nigrostriatal dopaminergic system. Intranigral infusion of freshly prepared GSNO (0-16.8 nmol, i.n.) prevented iron-induced (4.2 nmol, i.n.) oxidative stress and nigral injury, reflected by a decrease in striatal dopamine levels. This neuroprotective effect of GSNO was verified by ex vivo imaging of brain dopamine uptake sites using 125I-labeled RTI-55. In addition, in vitro data indicate that GSNO concentration-dependently inhibited iron-evoked hydroxyl radical generation and brain lipid peroxidation. In this iron-induced oxidant stress model, GSNO was approximately 100-fold more potent than the antioxidant glutathione (GSH). Light-exposed, NO-exhausted GSNO produced neither antioxidative nor neuroprotective effects, which indicates that NO may mediate at least part of GSNO's effects. Moreover, GSNO completely (and GSH only partially) inhibited the weak pro-oxidant effect of peroxynitrite, which produced little injury to nigral neurons in vivo. This study provides relevant in vivo evidence suggesting that nanomol GSNO can protect brain dopamine neurons from iron-induced oxidative stress and degeneration. In conclusion, S-nitrosylation of GSH by NO and oxygen may be part of the antioxidative cellular defense system.

[PubMed - indexed for MEDLINE]Free Article

http://www.ncbi.nlm.nih.gov/pubmed/9681949 Neuroscience. 1998 Aug;85(4):1101-11. Manganese: a transition metal protects nigrostriatal neurons from oxidative stress in the iron-induced animal model of parkinsonism. Sziráki I, Mohanakumar KP, Rauhala P, Kim HG, Yeh KJ, Chiueh CC.

Unit on Neurodegeneration and Neuroprotection, Laboratory of Clinical Science, NIMH, NIH, Bethesda, MD 20892-1264, USA. Abstract It has been suggested that transition metals such as iron and manganese produce oxidative injury to the dopaminergic nigrostriatal system. which may play a critical role in the pathogenesis of Parkinson's disease. Intranigral infusion of ferrous citrate (0 to 8.4 nmol, i.n.) acutely increased lipid peroxidation in the substantia nigra and dopamine turnover in the caudate nucleus. Subsequently, it caused a severe depletion of dopamine levels in the rat caudate nucleus. In contrast to iron's pro-oxidant effect, manganese (up to 30 nmol, i.n.) causes neither lipid peroxidation nor nigral injury/dopamine depletion. Manganese (1.05 to 4.2 nmol, i.n.) dose-dependently protected nigral neurons from iron-induced oxidative injury and dopamine depletion. Manganese also suppressed acute increase in dopamine turnover and contralateral turning behaviour induced by iron. In brain homogenates manganese (0 to 10 microM) concentration-dependently inhibited propagation of lipid peroxidation caused by iron (0 to 5 microM). Without the contribution of manganese-superoxide dismutase manganese was still effective in sodium azide and/or heat-pretreated brain homogenates. Surprisingly, iron but not manganese, catalysed the Fenton reaction or the conversion of hydrogen peroxide to hydroxyl radicals. The results indicate that iron and manganese are two transition metals mediating opposite effects in the nigrostriatal system, as pro-oxidant and antioxidant, respectively. In conclusion, intranigral infusion of iron, but not manganese, provides an animal model for studying the pathophysiological role of oxidant and oxidative stress in nigrostriatal degeneration and Parkinsonism. The present results further suggest that the atypical antioxidative properties of manganese may protect substantia nigra compacta neurons from iron-induced oxidative stress.

http://www.ncbi.nlm.nih.gov/pubmed/9472981

http://en.wikipedia.org/wiki/AP2M1

Abstract

Danshen, the dried root of Salvia miltiorrhiza, is a Chinese medicine used to promote blood flow and treat vascular disease. The present article reviews the pharmacological effects of Danshen on cerebral infarction and possible interactions between Danshen and Western drugs. Danshen may reduce or prolong the development of atherosclerosis and may have anti-hypertensive and anti-platelet aggregation effects, which prevent cerebral infarction. Danshen may enhance endogenous anti-oxidative enzyme activities such as the expression of endothelial nitric oxide synthase and may scavenge oxygen free radicals. Prevention and treatment of cerebral infarction by Danshen involves multiple pathways, including anti-atherosclerosis, anti-hypertension, anti-platelet aggregation, anti-inflammatory and anti-oxidative effects. Review Background

Danshen, the dried root of Salvia miltiorrhiza, is used in Chinese medicine to treat vascular disease. According to Chinese medicine theory, Danshen promotes blood flow and resolves blood stasis. Among stroke patients, 80% suffer from cerebral infarction and 20% cerebral hemorrhage [1]. Cerebral infarction is an ischemic condition of the brain including thrombosis, embolism or systemic hemodynamic hypotension. Cerebral infarction is often caused by atherosclerosis of large and small arteries. The etiology of atherosclerosis and stroke is related to inflammation and genetic factors. Ischemic cerebral infarction may be prevented through anti-inflammation and treatment for vascular diseases, heart diseases and hypertension [2-4]. Anti-thrombosis and thrombolysis are used to treat ischemic cerebral infarction [2]. The most effective method to re-establish cerebral blood flow is thrombolytic therapy; however, this therapy is often at the risk of bleeding [2]. Neuroprotection is also a potential treatment [5].

While Danshen or its ingredients reduce the infarction volume, the action mechanism of Danshen remains obscure [6-8]. Danshen contains the lipid-soluble tanshinone I (Tan I), tanshinone IIA (Tan IIA), cryptotanshinone and dihydrotan-shinone as well as the water-soluble danshensu and salvianolic acid B (Sal B) [9]. Danshen inhibits platelet aggregation and promotes fibrinolysis [10,11].

Covering literature between 1990 and 2009, this article reviews basic and clinical studies on Danshen in the prevention and treatment for cerebral infarction. The key words used for search in the PubMed library were 'Danshen' or 'Salvia miltiorrhiza' combined with 'cerebral infarction', 'ischemic' or 'cerebral ischemia'. Prevention of cerebral infarction Anti-atherosclerosis and anti-inflammatory effects

Atherosclerosis is caused by endothelial damage, which may lead to platelet aggregation and the release of platelet factor, resulting in the proliferation of smooth muscle in the arterial intima. The process of atherosclerosis comprises inflammation and involves both innate and adaptive immunity [12]. The tanshinones components of Danshen (tanshinone I, dihydrotanshinone and cryptotanshinone) inhibit the production of interleukin-12 (IL-12) induced by lipopolysaccharide (LPS)-activated macrophages and the production of interferon-γ induced by keyhole limpet hemocyanin-primed lymph node cells [13]. Tanshinones also inhibit the expression of the IL-12 p40 gene and prevent nuclear factor-κB (NF-κB) from binding to κB site [13]. As IL-12 and NF-κB are closely associated with inflammatory responses, tanshinones may have anti-inflammatory effects [13]. Tumor necrosis factor-α (TNF-α), a pro-inflammatory cytokine, is regulated by NF-κB while vascular adhesion molecule-1 (VCAM-1) regulates the migration of leukocytes into the vessel wall. Pre-treatment with either aqueous ethanolic extract of Danshen or Sal B component of Danshen inhibits TNF-α-induced expression of VCAM-1 and TNF-α-induced activation of NF-κB in human aortic endothelial cells, suggesting that both SME and Sal B posses anti-inflammatory properties and are closely associated with atherogenesis because leukocytes migrate into the vessel wall in the early stage of atherogenesis [14]. Aqueous extract of Danshen suppresses the adhesion rate of neutrophils stimulated by TNF-α, and also inhibits adhesion of neutrophils stimulated by N-formyl-methionyl-leucyl-phenylalanine (fMLP) [15]. Aqueous extract of Danshen inhibits TNF-α-induced up-regulation of E-selectin, intracellular molecule-1 (ICAM-1) and VCAM-1 expression [15]. Danshen treatment lowers plasma viscosity, erythrocyte aggregation and fibrinogen levels in rats with traumatic brain injury [16]. Tan IIA increases estrogen receptor activity in HeLa cells. Tan IIA inhibits iNOS (inducible nitric oxide synthase) protein production and nitric oxide (NO) production and inhibits pro-inflammatory cytokine IL-1β, IL-6 and TNF-α via estrogen receptors in lipopolysaccharide (LPS) activated RAW 264.7 macrophages, suggesting that Tan IIA may serve as an estrogen-receptor-like modulator to produce immune responses [17]. C-reactive protein (CRP), an inflammation marker, induces pro-inflammatory cytokines through NF-κB and contributes to atherosclerosis in endothelial cells [18,19]. Tan IIA inhibits NF-κB-DNA complex, NF-κB binding activity and the phosphorylation of IκBα and inhibit the translocation of NF-κB from cytosol to nuclei, demonstrating that tanshinone possesses anti-inflammatory properties [20]. Tan IIA down-regulates protein expression and activities of matrix metalloproteinase-2 and -9 (MMP-2, MMP-9) and reduces the VCAM-1 and IL-1β levels to suppress the increase in the aorta intimal area in rabbits treated with a high-fat-diet [21]. Triterpenoids-enriched extract of Danshen reduces the aortic atherosclerotic lesion area and inhibits inflammatory serum marker of CRP and monocyte chemotactic protein (MCP-1) [22]. Moreover, triterpenoids-enriched extract of Danshen reduces the serum levels of total cholesterol and triglyceride in low density lipoprotein receptor (LDLR) +mice via the inhibition of the inflammatory markers CRP and MCP-1 [22]. Triterpenoids are anti-atherogenic which may be associated with its anti-inflammatory properties [22]. In summary, the anti-atherosclerosis and anti-inflammatory actions of Danshen play roles in the prevention of cerebral infarction. Anti-hypertensive effects

Hypertension is a risk factor for cerebral infarction. Maintaining blood pressure within the ideal range has recently been recognized as an important principle in the prevention and treatment of ischemic cerebral infarction. Aqueous extract of Danshen alleviates hypertension in the two-kidney/one-clip (2K1C) Goldblatt renovascular hypertensive rats model and reduced the activity of serum angiotensin converting enzyme and the levels of serum aldosterone [23,24]. MTB70 is composed of 70% (70 mg/ml) of Magnesium tanshinoate B (MTB) which is one of the aqueous active components of Danshen. MTB70 (0.7-175 mg/kg) reduces blood pressure more than the aqueous extract of Danshen with same volume in a saline- or phenylephrine (2.5 μg/kg bolus injection and followed by 100 μg/kg at 0.13 ml/hr injection continuously) -induced hypertension model in rats; However this rapid and potent anti-hypertensive effect is short-lived [25]. Tanshinone IIA reduces blood pressure in the 2K1C renovascular hypertension model of hamsters [26]. Overall, the anti-hypertensive effects of Danshen include inhibition of angiotensin converting enzyme and generation of eNOS and/or vasodilatation. Treatment of cerebral infarction Anti-platelet aggregation effects

Anti-platelet aggregation, which involves platelet adhesion, is widely used to treat acute ischemic cerebral infarction [27]. Platelet adhesion increases in mice with middle cerebral artery occlusion (MCAo) [28]. Eight derivatives of Danshen inhibit platelet aggregation induced by adenosine diphosphate (ADP) in vitro in rabbit plasma [29]. Salvianolic acid B (SAB) inhibits platelet deposition to collagen at venous and arterial shear rates, suggesting that SAB inhibits platelet adhesion to collagen via interfering collagen receptor α2β1 [30]. Salvianolic acid inhibits ADP-induced platelet aggregation in platelet-rich plasma and in washed platelets both in vivo and in vitro, probably through changing protein expression [31]. Danshen decreases the malondialdehyde (MDA) levels of platelets and increases the superoxide dismutase (SOD) activity of platelets to inhibit platelet aggregation in pulmonary thromboembolism induced by collagen and adrenaline in mice [32]. The 764-3 (100 μg/ml), purified compound of Danshen extract, inhibits platelet aggregation induced by arachidonic acid or ADP in humans and rabbits [33]. Danshen decreases the concentration of intra-platelet free calcium, which is closely associated with platelet aggregation and release [34]. Overall, Danshen exhibits anti-platelet aggregation effects via multiple pathways, e.g. the inhibition of intra-platelet calcium and anti-oxidant activities. Neuroprotection through anti-inflammatory effects

Inflammatory responses are critically important to a patient after brain ischemia/reperfusion injury. The pro-inflammatory cytokines IL-1β, TNF-α and IL-6 increase after an ischemia attack, which enhances the expression of adhesion molecules including ICAM-1 and P-selectin, leading to brain edema and neuronal death [35,36]. In addition, leukocytes, neurons and activated microglial cells in ischemic damaged region release cytokines, chemokines and oxygen free radicals which lead to secondary brain tissue damage. Matrix metalloproteinases, which cleave protein components of the extracellular matrix, play a role in neurovascular remodeling and neuronal death [35,36]. The microglia may be activated during brain damage including ischemia, inflammation and infection [37]. The increases of activated microglia may represent the severity of neuronal damage in a MCAo rat model [38]. Danshen inhibits superoxide generation by microglia in primary microglia cell cultures from rat brains [39]. Danshen reduces CD18 and CD11b immunoreactive cells in the peri-vascular region and inhibits leukocyte infiltration and neuronal death in the cerebral infarction region in the ischemia-reperfusion MCAo rat model. As leukocytes are mediated via the combination of surface receptors of CD18 and CD11b and intracellular adhesion molecules of endothelium, the neuroprotection capability of Danshen may be associated with the inhibition of leukocyte adherence to the endothelium [40]. A study on the effects of Danshen on inflammatory response in cerebral ischemia and reperfusion injury in the MCAo rat model indicates that pre-treatment with Tanshinone IIA reduces the cerebral infarction area, neurological deficit score and cerebral edema. As pre-treatment with Tanshinone IIA reduces TNF-α, the myeloperoxidase (MPO) marker of leukocytes, E-selectin and ICAM-1 in ischemic brain tissue and serum IL-8, Danshen may inhibit inflammatory responses to reduce brain damage induced by ischemia-reperfusion injury in rats [41]. The Danshen dripping pill (DDP) is composed of Danshen, Panax notoginseng and Dryobalanops camphor. A controlled pilot study (106 patients) found that the recurrent rate in the DDP group was 9.6% compared with 24.1% in the non-DDP group. The serum CRP levels decreased from 2.33 to 1.50 mg/L in the DPP group were greater than those decreased from 2.21 to 1.77 mg/L in the non-DDP group [42]. Overall, Danshen has anti-inflammatory activity and may improve cerebral infarction and provide neuroprotection. Neuroprotection through anti-oxidative effects

Nitrogen and oxygen free radicals involved in the production of reactive oxygen species (ROS) play an important role in brain damage during the reperfusion period following ischemia [43,44]. These ROS, which are involved in brain damage after cerebral ischemia, affect the signal transmission of mitochondria and DNA repair of enzyme and transcription factors, leading to apoptosis [45]. Danshensu and salvianolic acid B are phenolic acids of Danshen, both of which have scavenging activities towards free radicals of hydroxyl, 1,1-diphenyl-2-picryl-hydrazyl (DPPH), 2-azino-bis(3-ehtylbenzthiazoline-6-sulfonic acid) (ABTS) free radicals, hydrogen peroxidase and superoxide anion in human umbilical vein endothelial cells [46]. Our previous studies show that Danshen reduces the cerebral infarction volume and the neurological deficit score and reduces luminal-chemiluminescence counts [8]. As luminal-chemiluminescence counts may represent ROS, these effects of Danshen may be associated with its free radical scavenging activities in ischemia-reperfusion injured rats [8]. Intra-abdominal administration of Tan IIB, a major active component of Danshen, reduces the focal infarct volume, neurological deficit and apoptosis in the MCAo rat model. As apoptosis is a major pathway leading to neuronal death, Tan IIB is neuroprotective [47]. Damage from oxygen free radicals occurs in the ischemic/reperfusion injury under oxidation response to cell membrane lipids, proteins or DNA. Inhibiting oxidation and free radical scavenging are important in the treatment of ischemic cerebral infarction. A study using a 4-vessel occlusion rat model [48,49] found that (1) Danshen reduced an increase of cerebral NO and MDA 30 minutes prior to occlusion and that (2) pre-treatment with Danshen increased a significantly decreased SOD activity. NO mediates glutamate neurotoxicity and the inhibition of NO synthase may prevent the development of brain edema. SOD is a scavenger of superoxide anion and the levels of MDA may reflect the degree of lipid peroxidation. Thus Danshen is neuroprotective in this occlusion and reperfusion rat model [48,49]. Isopropyl-β,-(3,4-dihydroxyphenyl)-α-hydroxypropanoate (ND-309), a metabolite of Danshen in rat brain, reduces cerebral infarction volume, brain edema and neurological deficit in the MCAo rat model. Moreover, ND309 reduces brain tissue MDA and increases the reduction of ATP induced by ischemia-reperfusion injury [50] of mitochondrial ATP, mitochondrial SOD and glutathione peroxidase (GSH-Px) activities induced by ischemia-reperfusion injury. ND-309 is neuroprotective role to reduce brain damage induced by cerebral ischemia [50]. Danshen reduces the neurological deficit score and the levels of MDA and increases SOD activities in the MCAo rat model [51]. Pretreatment with Danshen may reduce brain edema and MDA concentration of cerebral cortex and hippocampus region in an ischemia-reperfusion injured rat model while Danshen may increase levels of catalase, SOD, GSH and ATP of the cerebral cortex and hippocampus region [52]. In summary, Danshen demonstrates neuroprotective effects that are closely associated with anti-oxidative action. Drug interactions with warfarin

Warfarin is an anticoagulant used to prevent atrial fibrillation, valvular heart disease, ischemic stroke and deep venous thrombosis [53]. Danshen inhibits platelet adhesion and aggregation and suppresses the formation of thromboxane A 2 [53]. The interaction between Danshen and warfarin can cause bleeding and prolong prothrombin time or the International Normalized Ratio (INR) [53]. Co-administration of Danshen and warfarin should be avoided or closely monitored [54]. Tanshinones inhibits CYP1A1, CYP2C6 and CYP2C11-mediated warfarin metabolism to increase the concentration of warfarin [55]. Aspirin prevents and alleviates cerebral infarction. Danshen displaces the binding between aspirin and protein, thereby increasing free aspirin concentration in serum [56]. Atrial fibrillation, which may be prevented and treated by digoxin, is closely related to cerebral infarction induced by embolus. Danshen has digoxin-like immunoreactivity leading to a false interference of digoxin concentration [56]. Compared free radical scavenging ability with other herbs

The extracts of Ginkgo biloba L. leaves (Egb 761), with free radical scavenging activity, reduce the size of cerebral infarction and improve neurological behavior in rats with permanent and transient MCAo [57,58]. Egb 761 is widely used to treat ischemic cerebral infarction. The concentration of salvianolic acid B is lower than Egb 761 in scavenging activity of superoxide anion and hydroxyl radicals in rat microsome, and in SH-SY5Y induced by H 2O 2 [59]. Panax notoginseng (Sanqi) is also used to treat vascular disorders. Danshen is stronger than Panax notoginseng in scavenging activity of superoxide anion, hydroxyl and DPPH radicals, yet it is weaker than Panax notoginseng in the scavenging activity of hydrogen peroxide and ferrous ion chelating activity [60]. While Sanqi demonstrates strong ferrous ion chelating activity and strong scavenging activities of hydrogen peroxide and hydroxyl radicals, it is weak in the scavenging activities of superoxide anion and DPPH radicals. Therefore, the scavenging capabilities of Danshen and Sanqi are quite different among the various free radicals [60]. Conclusion

Prevention and treatment of cerebral infarction by Danshen involves multiple pathways, including anti-atherosclerosis, anti-hypertension, anti-platelet aggregation, anti-inflammatory and anti-oxidative effects (Additional file 1).

Additional file 1. Possible pharmacological actions of Danshen for prevention and treatment of cerebral infarction. Supplemental table

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