Aristolactam BII of Saururus chinensis Attenuates Glutamate-Induced Neurotoxicity in Rat Cortical Cultures Probably by Inhibiting Nitric Oxide Production

Abstract

Saurolactam and aristolactam BII, aristolactam-type alkaloids isolated from the aerial part of Saururus chinensis (Lour.) Ball (Saururaceae), showed significant neuroprotective activity against glutamate-induced toxicity in primary cultured rat cortical cells. The action mechanism of aristolactam BII, the more potent neuroprotective compound, was investigated using primary cultures of rat cortical cells as an in vitro system. Aristolactam BII attenuated glutamate-induced neurotoxicity significantly when it was added immediately or up to 9 h after the excitotoxic glutamate challenge. The alkaloid could not protect cultured neuronal cells from neurotoxicity induced by kainic acid or N-methyl-D-aspartate in a pre-treatment paradigm. However, aristolactam BII successfully reduced the overproduction of nitric oxide and the level of cellular peroxide in cultured neurons when it was treated as a post-treatment paradigm. These results may suggest that aristolactam BII exerts its significant neuroprotective effects on glutamate-injured primary cultures of rat cortical cells by directly inhibiting the production of nitric oxide.

Abbreviations

CNQX:6-cyano-7-nitroquinoxaline-2,3-dione

DMEM:Dulbecco's modified Eagle's medium

FBS:fetal bovine serum

GSH-px:glutathione peroxidase

GSSG-R:glutathione reductase

HBSS:Hank's balanced salt solution

KA:kainic acid

MTT:3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium

NMDA:N-methyl-D-aspartate

NO:nitric oxide

NOS:nitric oxide synthase

SOD:superoxide dismutase

Key words

Aristolactam alkaloid - Saururus chinensis - Saururaceae - neuroprotection - glutamate-induced toxicity - nitric oxide production

References

• 1 Albright T D, Jessell T M, Kandel E R, Poster M I. Neural science: a century of progress and the mysteries that remain.  Cell. 2000;  18 (Suppl. 100) 1-55
• 2 Choi D W. Glutamate neurotoxicity and diseases of the nervous system.  Neuron. 1988;  1 623-4
• 3 Miyamoto M, Murphy T H, Schnaar R L, Coyle J T. Antioxidants protect against glutamate-induced cytotoxicity in a neuronal cell line.  J Pharmacol Exp Ther. 1989;  250 1132-40
• 4 Aarts M M, Tymianski M. Novel treatment of excitotoxicity: targeted disruption of intra-cellular signalling from glutamate receptors.  Biochem Pharmacol. 2003;  66 877-86
• 5 Michaelis M L. Drugs targeting Alzheimer’s disease: some things old and some things new.  J Pharmacol Exp Ther. 2003;  304 897-904
• 6 Trist D G. Excitatory amino acid agonists and antagonists: pharmacology and therapeutic applications.  Pharm Acta Helv. 2000;  74 221-9
• 7 Kim Y C, Kim S R, Markelonis G J, Oh T H. Ginsenosides Rb₁ and Rg₃ protect cultured rat cortical cells from glutamate-induced neurodegeneration.  J Neurosci Res. 1998;  53 426-32
• 8 Sung S H, Kim Y C. Hepatoprotective diastereomeric lignans from Saururus chinensis Herbs.  J Nat Prod. 2000;  63 1019-21
• 9 Crohare R, Priestap H A, Farina M, Cedola M, Ruveda E A. Aristolactams of Aristolochia argentina .  Phytochemistry. 1962;  13 1957-60
• 10 Priestap H A. Seven aristolactams from Aristolochia argentina .  Phytochemstry. 1985;  24 849-52
• 11 Jang Y P, Kim S R, Choi Y H, Kim J, Kim S G, Markelonis G J, Oh T H, Kim Y C. Arctigenin protects glutamate-induced neurodegeneration by inhibition of binding to kainate receptor.  J Neurosci Res. 2002;  68 233-40
• 12 Dawson V L, Brahbhatt H P, Mong J A, Dawson T M. Expression of inducible nitric oxide synthase causes delayed neurotoxicity in primary mixed neuronal-glial cortical cultures.  Neuropharmacology. 1994;  33 1425-30
• 13 Grynkiewicz G, Poenie M, Tsien R Y. A new generation of calcium indicators with greatly improved fluorescence properties.  J Biol Chem. 1985;  260 3440-50
• 14 Almeida A, Heales S JR, Bolanos J P, Medina J M. Glutamate neurotoxicity is associated with nitric oxide-mediated mitochondrial dysfunction and glutamate depletion.  Brain Res. 1998;  790 209-16
• 15 Wink M. Interference of alkaloids with neuroreceptors and ion channels. In: Atta-ur-Tahman, editor Studies in Natural Products Chemistry, Vol. 21, Bioactive Natural Products (Part B). Amsterdam; Elselvier 2000: pp 3-122
• 16 (a) Kim SK, Ryu SY, No J, Choi SU, Kim YS. Cytotoxic alkaloids from Houttuynia cordata. Arch Pharm Res 2001; 24 : 518 - 21; (b) Sun NJ, Antoun M, Chang CJ, Cassady JM. New cytotoxic aristolactams for Pararistolochia flos-avis .  J Nat Prod. 1987;  50 843-6
• 17 Prehn J H, Lippert K, Krieglstein J. Are NMDA or AMPA/kainite receptor antagonists more efficacious in the delayed treatment of excitotoxic neuronal injury?.  Eur J Pharmacol. 1995;  292 179-89
• 18 Strijbos P JLM, Leach M J, Garthwaite J. Vicious cycle involving Na⁺ channels, glutamate release, and NMDA receptors mediates delayed neurodegeneration through nitric oxide formation.  J Neurosci. 1996;  16 5004-13
• 19 Klatt P, Schmidt K, Brunner F, Mayer B. Inhibitors of brain nitric oxide synthase.  J Biol Chem. 1994;  269 1674-80
• 20 Dawson V L, Dawson T M. Nitric oxide in neurodegeneration.  Prog Brain Res. 1998;  118 215-29