Abstract
The partially cyclized μ/ν-carrageenan 1C3, isolated from the red seaweed Gigartina skottsbergii , was previously shown to be a potent inhibitor of the in vitro replication of Herpes simplex virus types 1 (HSV-1) and 2 (HSV-2). Here the protective effect of 1C3 in a murine model of intraperitoneal (i. p. ) HSV-1 infection was evaluated. OF1 mice were i. p. infected with 5 × 105 PFU of HSV-1 KOS strain, and the effects of different treatments with 1C3 were studied. When 30 mg/kg of body weight of 1C3 was administered by the i. p. route immediately after HSV-1 infection, 87.5 % survival of the animals was achieved (p < 0.005), associated with a delay in the mean day of death in 1C3-treated non-surviving mice. Animal survival was not improved when multiple doses of 1C3 were also given in the period 1 - 48 h post-infection, and no protection was afforded when treatment was started after 24 h of infection. When virus and compound were injected by different routes, i. p. and intravenous (i. v. ), respectively, a still significant protection was achieved (40 % survival, p < 0.05). No toxicity of 1C3 for the animals was recorded. The pharmacokinetic properties were analyzed after injection of 1C3 into the tail vein by monitoring of [3
H ]-1C3 in plasma and organs and by a bioassay of the anti-HSV-1 activity remaining in serum after non-radioactive 1C3 inoculation. A very rapid disappearance of the compound from the blood was observed since only 5.9 - 0.9 % of the radioactivity of the initially administered [3
H ]-1C3 appeared in the plasma between 5 - 300 minutes after administration. A transient peak of radioactivity was detected in the kidney 15 minutes after inoculation. The bioassay confirms the presence of the compound circulating in a biologically active form up to 1 hour after injection.
Key words
antiviral agent -
Herpes simplex virus - natural carrageenan - mouse intraperitoneal infection - pharmacokinetics -
Gigartina skottsbergii
- Gigartinaceae - Gigartinales
References
1
Witvrouw M, De Clercq E.
Sulfated polysaccharides extracted from sea algae as potential antiviral drugs.
Gen Pharmacol.
1997;
29
497-511
2
Damonte E B, Matulewicz M C, Cerezo A S.
Sulfated seaweed polysaccharides as antiviral agents.
Curr Med Chem.
2004;
11
2399-419
3
Lüscher-Mattli M.
Polyanions - a lost chance in the fight against HIV and other virus diseases?.
Antiviral Chem Chemother.
2000;
11
249-59
4
Weiler B E, Schroder H C, Stefanovich V, Stewart D, Forrest J MS, Allen L B. et al .
Sulphoevernan, a polyanionic polysaccharide, and the narcissus lectin potently inhibit human immunodeficiency virus infection by binding to viral envelope protein.
J Gen Virol.
1990;
71
1957-63
5
Furusawa E, Furusawa S, Chou S C.
Antileukemic activity of Viva-Natural , a dietary seaweed extract, on Rauscher murine leukemia in comparison with anti-HIV agents, azidothymidine, dextran sulfate and pentosan polysulfate.
Cancer Lett.
1991;
56
197-20
6
Diringer H, Ehlers B.
Chemoprophylaxis of scrapie in mice.
J Gen Virol.
1991;
I 72
457-60
7
Hamasuna R, Eizuru Y, Shishime Y, Minamishima Y.
Protective effect of carrageenan against murine cytomegalovirus infection in mice.
Antiviral Chem Chemother.
1993;
4
353-60
8
Pancheva S N.
Antiherpes effect of dextran sulphate combined with acyclovir in vitro and in vivo
.
Antiviral Chem Chemother.
1993;
4
189-91
9
Mathes L E, Hayes K A, Swenson C L, Polas P J, Weisbrode S E, Kociba G J.
Evaluation of antiviral activity and toxicity of dextran sulfate in feline leukemia virus-infected cats.
Antimicrob Agents Chemother.
1991;
35
2147-50
10
Offensperger W B, Offensperger S, Walter E, Blum H E, Gerok W.
Sulfated polyanions do not inhibit duck hepatitis B virus infection.
Antimicrob Agents Chemother.
1991;
35
2431-3
11
Zacharopoulos V R, Phillips D M.
Vaginal formulations of carrageenan protect mice from Herpes simplex virus infection.
Clin Diagn Lab Immunol.
1997;
4
465-8
12
Bourne K Z, Bourne N, Reising S F, Stanberry L R.
Plant products as topical microbicide candidates: assessment of in vitro and in vivo activity against herpes simplex virus type 2.
Antiviral Res.
1999;
42
219-26
13
Coggins C, Blanchard K, Alvarez B, Brache V, Weisberg E, Kilmarx P H. et al .
Preliminary safety and acceptability of a carrageenan gel for possible use as a vaginal microbicide.
Sex Trans Infect.
2000;
76
480-3
14
Carlucci M J, Scolaro L A, Noseda M D, Cerezo A S, Damonte E B.
Protective effect of a natural carrageenan on genital herpes simplex virus infection in mice.
Antiviral Res.
2004;
64
137-41
15
Carlucci M J, Pujol C A, Ciancia M, Noseda M D, Matulewicz M C, Damonte E B. et al .
Antiherpetic and anticoagulant properties of carrageenans from the red seaweed Gigartina skottsbergii and their cyclized derivatives: correlation between structure and biological activity.
Int J Biol Macromol.
1997;
20
97-105
16
Carlucci M J, Scolaro L A, Damonte E B.
Inhibitory action of natural carrageenans on Herpes simplex virus infection of mouse astrocytes.
Chemotherapy.
1999;
45
429-36
17
Carlucci M J, Ciancia M, Matulewicz M C, Cerezo A S, Damonte E B.
Antiherpetic activity and mode of action of natural carrageenans of diverse structural types.
Antiviral Res.
1999;
43
93-102
18
Tal-Singer R, Peng C, Ponce de León M, Abrams W R, Banfield B W, Tufaro F. et al .
Interaction of Herpes simplex virus glycoprotein gC with mammalian cell surface molecules.
J Virol.
1995;
69
4471-83
19
Matulewicz M C, Ciancia M, Noseda M D, Cerezo A S.
Carrageenan systems from tetrasporic and cystocarpic stages of Gigartina skottsbergii
.
Phytochemistry.
1989;
28
2937-41
20
Ciancia M, Matulewicz M C, Finch P, Cerezo A S.
Determination of the structures of cystocarpic carrageenans from Gigartina skottsbergii by methylation analysis and NMR spectroscopy.
Carbohydr Res.
1993;
238
241-8
21
Couto A S, Gonçalves M F, Colli W, de Lederkremer R M.
The N -linked carbohydrate chain of the 85-kilodalton glycoprotein from Trypanosoma cruzi trypomastigotes contains sialyl, fucosyl and galactosyl(α-1 - 3)galactose units.
Mol Biochem Parasitol.
1990;
39
101-8
22
Hartman N R, Johns D G, Mitsuya H.
Pharmacokinetic analysis of dextran sulfate in rats as pertains to its clinical usefulness for therapy of HIV infection.
AIDS Res Hum Retroviruses.
1990;
6
805-12
23
Hayashi K, Hayashi T, Kojima I.
A natural sulfated polysaccharide, calcium spirulan, isolated from Spirulina platensis : in vitro and ex vivo evaluation of anti-Herpes simplex virus and anti-human immunodeficiency virus activities.
AIDS Res Hum Retroviruses.
1996;
12
1463-71
24
Nakashima H, Yoshida O, Baba M, De Clercq E, Yamamoto N.
Anti-HIV activity of dextran sulphate as determined under different experimental conditions.
Antiviral Res.
1989;
11
233-46
25
Guimaraes M AM, Mourao P AS.
Urinary excretion of sulfated polysaccharides administered to Wistar rats suggest a renal permselectivity to these polymers based on molecular size.
Biochim Biophys Acta.
1997;
1335
161-72
26
Ni L, Boudinot F D, Boudinot S G, Henson G W, Bossard G E, Martellucci S A. et al .
Pharmacokinetics of antiviral polyoxometalates in rats.
Antimicrob Agents Chemother.
1994;
38
504-10
Carlos Alberto Pujol
Laboratorio de Virología
Departamento de Química Biológica
Facultad de Ciencias Exactas y Naturales
Universidad de Buenos Aires
Pabellón 2
Piso 4
Ciudad Universitaria
C1428BGA Buenos Aires
Argentina
Phone: +54-11-4576-3334
Fax: +54-11-4576-3342
Email: capujol@qb.fcen.uba.ar