Effects of the compounds MV8608 and MV8612 obtained from Mandevilla velutina in the model of hemorrhagic cystitis induced by cyclophosphamide in rats.
Hemorrhagic cystitis (HC) is a common side effect observed in patients under chemotherapy with cyclophosphamide (CYP). The urotoxic side effects of CYP are attributed to the metabolic compound acrolein, and can be partially prevented by the uroprotector agent 2-mercaptoethene sulfate (Mesna). The present study analyzed the anti-inflammatory and the antinociceptive effects of compounds MV8608 and MV8612 obtained from Mandevilla velutina in the rat model of CYP-induced HC. Male Wistar rats were used (six to eight per group, 220-250 g). HC was induced by a single administration of CYP (100 mg/kg, ip). Three behavioral parameters--breathing rate, closing of the eyes, and specific posture--were used as nociception indexes, and scored at different time intervals (15-180 min) after cystitis induction. As inflammatory parameters, hemorrhage presence, edema formation, and bladder weight were determined at 24 h after CYP administration. The neutrophil migration was assessed by means of myeloperoxidase (MPO activity), 4 h after cystitis induction. As expected, Mesna treatment was able to reduce in a significant manner all the inflammatory and the nociceptive parameters induced by CYP. Of note, the administration of MV8608 significantly inhibited the hemorrhage formation and the neutrophil recruitment, while the MV8612 treatment markedly reduced the bladder weight, without interfering with neutrophil influx. Interestingly, the treatment with either MV8608 or MV8612 markedly reduced the nociceptive responses. The present results clearly indicate that MV8608 and MV8612 might represent important alternatives to prevent side effects, especially the nociception, following chemotherapy with CYP.
Santos
André A
AA
Programa de Pós-Graduação em Biologia Celular e Molecular, PUCRS, Porto Alegre, Rio Grande do Sul, Brazil.
Leal
Paulo C
PC
Edelweiss
Maria I A
MI
Lopes
Tiago Giuliani
TG
Calixto
João B
JB
Morrone
Fernanda B
FB
Campos
Maria M
MM
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects*; D029062:Apocynaceae / Q000737:chemistry*; D003520:Cyclophosphamide / Q000009:adverse effects*; D003556:Cystitis / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D006027:Glycosides / Q000494:pharmacology / Q000627:therapeutic use*; D006470:Hemorrhage / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D015080:Mesna / Q000627:therapeutic use; D009929:Organ Size / Q000187:drug effects; D010147:Pain Measurement; D009195:Peroxidase / Q000378:metabolism; D020011:Protective Agents / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D013256:Steroids / Q000494:pharmacology / Q000627:therapeutic use*; D001743:Urinary Bladder / Q000187:drug effects / Q000201:enzymology / Q000473:pathology
D000893:Anti-Inflammatory Agents; D018906:Antineoplastic Agents, Alkylating; D006027:Glycosides; D020011:Protective Agents; D013256:Steroids; C085133:MV 8608; C085132:MV 8612; D003520:Cyclophosphamide; D009195:Peroxidase; D015080:Mesna
J Urol. 1997 May;157(5):1946-50
9112569
J Urol. 1992 Oct;148(4):1326-30
1404668
Exp Biol Med (Maywood). 2007 Apr;232(4):565-70
17392493
Braz J Med Biol Res. 1999 Oct;32(10):1211-5
10510257
Exp Brain Res. 1995;105(2):220-32
7498375
Pediatr Blood Cancer. 2007 Sep;49(3):341-3
16333822
Br J Pharmacol. 1985 Aug;85(4):729-31
4041675
J Urol. 1993 Apr;149(4):719-23
8455230
BJU Int. 2009 Jan;103(2):264-9
18710439
J Urol. 2001 Sep;166(3):1119-23
11490309
Agents Actions. 1992 Jul;36(3-4):222-9
1382376
Urology. 2006 Mar;67(3):636-41
16527596
Cell Biol Toxicol. 2007 Sep;23(5):303-12
17225077
Agents Actions. 1991 Jul;33(3-4):272-8
1719783
J Urol. 1984 Sep;132(3):580-2
6433044
Eur J Pharmacol. 1993 Oct 26;243(3):213-9
8276072
Prostaglandins. 1991 May;41(5):515-26
1907393
J Immunol. 2004 Feb 1;172(3):1839-47
14734768
Regul Pept. 2006 Sep 11;136(1-3):98-104
16764951
Brain Res. 2003 Jan 31;961(2):269-76
12531494
J Urol. 2000 Jul;164(1):203-8
10840460
BJU Int. 2007 Dec;100(6):1402-8
17979934
Gynecol Oncol. 2000 Feb;76(2):223-5
10637075
J Urol. 2007 Apr;177(4):1531-6
17382773
J Urol. 1986 Aug;136(2):497-500
3090278
Br J Urol. 1996 Oct;78(4):530-3
8944508
Urology. 2006 Feb;67(2):435-9
16461118
J Urol. 2005 May;173(5):1793-6
15821589
Arch Toxicol. 2005 Aug;79(8):461-5
15800758
J Urol. 1999 Jun;161(6):1988-93
10332487