Share This Article:

Neuroprotective Effect of a Prostacyclin Agonist (ONO-1301) with Thromboxane Synthase Inhibitory Activity in Rats Subjected to Cerebral Ischemia

Abstract Full-Text HTML Download Download as PDF (Size:3403KB) PP. 306-314
DOI: 10.4236/pp.2011.24039    5,166 Downloads   9,158 Views   Citations

ABSTRACT

ONO-1301 has been developed as a novel long-acting prostacyclin agonist with thromboxane synthase inhibitory activity. In the present study, we investigated the cerebroprotective effect of ONO-1301 on post-ischemic injury induced by cerebral ischemia in rats. ONO-1301 (1 and 10 mg/kg) was administrated orally at reperfusion and then twice a day for 42 days. The cell damage induced by cerebral ischemia in the hippocampal CA1 was evaluated using both Nissl staining and proliferating cell nuclear antigen (PCNA) staining on the 42 days after cerebral ischemia. Activated astrocytes were evaluated using immunofluorescence staining with GFAP on the 42 days after cerebral ischemia. Spatial learning was assessed using a Morris water maze (MWM) task on the 56 days (i.e. after a 14 days washout period). ONO-1301- treated rats (1 and 10 mg/kg) significantly improved cell death in the hippocampal CA1, the number of PCNA-positive cells and astrocyte activation. The spatial learning of ONO-1301-treated rats compared with vehicle- treated rats in the MWM task. These results suggest that repeated treatment with oral ONO-1301 could prevent or limit post-ischemic brain damage. In particular, treatment with ONO-1301 within 7 days after ischemia is most effective to improve ischemic damage.

Conflicts of Interest

The authors declare no conflicts of interest.

Cite this paper

M. Hazekawa, Y. Sakai, M. Yoshida, T. Haraguchi and T. Uchida, "Neuroprotective Effect of a Prostacyclin Agonist (ONO-1301) with Thromboxane Synthase Inhibitory Activity in Rats Subjected to Cerebral Ischemia," Pharmacology & Pharmacy, Vol. 2 No. 4, 2011, pp. 306-314. doi: 10.4236/pp.2011.24039.

References

[1] T. Tanouchi, M. Kawamura, I. Ohyama, I. Kajiwara, Y. Iguchi, T. Okada, T. Miyamoto, K. Taniguchi, M. Hayashi, K. lizuka and M. Nakazawa, “Highly selective inhibitors of thromboxane synthetase. 2 Pyridine derivatives,” J Med Chem, Vol. 24, No. 10, 1981, pp. 1149- 1155.
[2] G.A. FitzGerald, L.A. Friedman, I. Miyamori, J. O’Gray and P.J. Lewis, “A double blind placebo controlled crossover study of prostacyclin in man,” Life Sci, Vol. 25, No. 8, 1979, pp. 665-672.
[3] S. Moncada, R. Gryglewski, S. Bunting and J.R. Vane, “An enzyme isolated from arteries transforms prostaglandin endoperoxides to a stable substance that inhibits platelet aggregation,” Nature, Vol. 263, No. 5579, 1976, pp. 663-665.
[4] S. Mncada, E.A. Higgs and J.R. Vane, “Human arterial and venous tissues generate prostacyclin (prostaglandin x), a potent inhibitor of platelet aggregation,” Lancet, Vol. 1, No. 8001, 1977, pp. 18-20.
[5] V. Seifert, D. Stolke, V. Kaever and H. Dietz. “Arachidonic acid metabolism following aneurysm rupture. Evaluation of cerebrospinal fluid and serum concentration of 6-keto-prostaglandin F1 alpha and thromboxane B2 in patients with subarachnoid hemorrhage,” Surg Neurol, Vol. 27, No.3, 1987, pp. 243-252.
[6] D.J. Boullin, S. Bunting, W.P. Blaso, T.M. Hunt and S. Moncada, “Responses of human and baboon arteries to prostaglandin endoperoxides and biologically generated and synthetic prostacyclin: their relevance to cerebral arterial spasm in man,” Br J Clin Pharmacol, Vol. 7, No. 2, 1979, pp. 139-147.
[7] L. Brandt, B. Ljunggren, K.E. Anderson, B. Hindfelt and T. Uski, “Effects of indomethacin and prostacyclin on isolated human pial arteries contracted by CSF from patients with aneurysmal SAH,” J Neurosurg, Vol. 55, No. 6, 1981, pp. 877-883.
[8] L. Brandt, B. Ljunggren, K.E. Andersson, B. Hindfelt and T. Uski, “Prostaglandin metabolism and prostacyclin in cerebral vasospasm,” Gen Pharmacol, Vol. 14, No. 1, 1983, pp. 141-143.
[9] K.S. Paul, E.T. Whalley, C. Forster, R. Lye and J. Dutton, “Prostacyclin and cerebral vessel relaxation,” J Neurosurg, Vol. 57, No. 3, 1982, pp. 334-340.
[10] P.O. Grande, A.D. M?ller, C.H. Nordestr?n and U. Ungerstedt, “Low-dose prostacyclin in treatment of severe brain trauma evaluated with microdialysis and jugular bulb oxygen measurements,” Acta Anaesthesiol Scand, Vol. 44, No. 7, 2000, pp. 886-894.
[11] S. Naredi, M. Olivecrona, C. Lindgren, A.L. Ostlund, P.O. Grande and L.O. Koskinen, “An outcome study of severe traumatic head injury using the ‘Lund therapy’ with low-dose prostacyclin,” Acta Anaethesiol Scand, Vol. 45, No. 4, 2001, pp. 402-426.
[12] N. Hotta, N. Koh, F. Sakakibara, J. Nakamura, Y. Hamada, T. Hara, K. Mori, E. Nakashima, K. Naruse, H. Fukasawa, H. Kakuta and N. Sakamoto, “Effects of beraprost sodium and insulin on the electroretinogram, nerve conduction, and nerve blood flow in rats with streptozotocin-induced diabetes,” Diabetes, Vol. 45, No. 3, 1996, pp. 361-366.
[13] M. Hazekawa, Y. Sakai, M. Yoshida, T. Haraguchi, T. Morisaki and T. Uchida. “Preparation of ONO-1301- loaded PLGA microspheres and their effect on nerve conduction velocity,” J Pharm Pharmacol, Vol. 63, 2011, pp. 362-368.
[14] M. Kataoka, N. Nagaya, T. Satoh, T. Itoh, S. Murakami, T. Iwase, Y. Miyahara, S. Kyotani, Y. Sakai, K. Kangawa and S. Ogawa, “A long-acting prostacyclin agonist with thromboxane inhibitory activity for pulmonary hypertension,” Am J Respir Crit Care Med, Vol. 172, No. 12, 2005, pp. 1575-1580.
[15] H. Obata, Y. Sakai, S. Ohnishi, S. Takeshita, H. Mori, M. Kodama, K. Kangawa, Y. Aizawa and N. Nagaya, “Single injection of a sustained-release prostacyclin analog improves pulmonary hypertension in rats,” Am J Respir Crit Care Med, Vol. 177, No. 2, 2008, pp. 195-201.
[16] S. Murakami, N. Nagaya, T. Itoh, M. Kataoka, T. Iwase, T. Horio, Y. Miyahara, Y. Sakai, K. Kangawa and H. Kikuma, “Prostacyclin agonist with thromboxane synthase inhibitory activity (ONO-1301) attenuates bleomycin-induced pulmonary fibrosis in mice,” Am J Physiol Lung Cell Mol Physiol, Vol. 290, No. 1, 2006, pp. 59-65.
[17] W.A. Pulsinelli and J.B. Brierley, “A new model of bilateral hemispheric ischemia in the unanesthetized rat,” Stroke, Vol. 10, No. 3, 1979, pp. 267-272.
[18] F. Pu, K. Mishima, K. Irie, K. Motohashi, Y. Tanaka, K. Orito, T. Egawa, Y. Kitamura, N. Egashira, K. Iwasaki and M. Fujiwara, “Neuroprotective effects of quercetin and rutin on spatial memory impairment in an 8-arm radial maze task and neuronal death induced by repeated cerebral ischemia in rats.” J Pharmacol Sci, Vol. 104, No. 4, 2007, pp. 329-334.
[19] R.P. Ostrowski, A.R. Colohan and J. H. Zhang, “Mechanisms of hyperbaric oxygen-induced neuroprotection in a rat model of subarachnoid hemorrhage,” J Cerebr Blood Flow Metab, Vol. 25, No. 5, 2005, pp. 554-571.
[20] R. Jin, B.H. Bay, V.T. Chow, P.H. Tan, V.C. Lin, “Metallothionein 1E mRNA is highly expressed in oestrogen receptor-negative human invasive ductal breast cancer,” Br J Cancer, Vol. 83, No. 3, 2000, pp. 319-323.
[21] T.F. Freund, A. Ylienen, R. Miettinen, A. Pitkanen, H. Lahtinen, K.G. Baimbridge and P.J. Riekkinen, “Pattern of neuronal death in the rat hippocampus after status epilepticus. Relationship to calcium binding protein content and ischemic vulnerability,” Brain Res Bull, Vol. 28, No. 1, 1992, pp. 27-38.
[22] R.G.M. Morris, “Spiral localization does not require the presence of local cues,” Learn Motiv, Vol. 12, 1981, pp. 239-260.
[23] H. Takamatsu, M. Tatsumi, S. Nitta, R. Ichise, K. Murakami, M. Iida, S. Nishikawa, K. Umemura, “Time course of progress to the chronic stage of middle cerebral artery occlusion models in rats,” Exp Brain Res, Vol. 146, No. 1, 2002, pp. 95-102.
[24] J.W. Ni, H. Ohta, K. Matsumoto and H. Watanabe, “Progressive cognitive impairment following chronic cerebral hypoperfusion induced by permanent occlusion of bilateral carotid arteries in rats,” Brain Res, Vol. 635, No. 1-2, 1994, pp. 231-236.
[25] H. Nakatomi, T. Kuriu, S. Okabe, S. Yamamoto, O. Hatano, N. Kawahara, A. Tamura, T. Kirino and M. Nakafuku, “Regeneration of hippocampal pyramidal neurons after ischemic brain injury by recruitment of endogenous neuronal progenitors,” Cell, Vol. 110, No. 4, 2002, pp. 429-441.
[26] K. Hayakawa, K. Irie, K. Sano, T. Watanabe, S. Higuchi, M. Enoki, T. Nakano, K. Harada, S. Ishikane, T. Ikeda, M. Fujioka, K. Orito, K. Iwasaki, K. Mishima and M. Fujiwara, “Therapeutic time window of Cannabidiol treatment on delayed ischemic damage via high-mobility group box1-inhibition mechanism,” Biol Pharm Bull, Vol. 32, No. 9, 2009, pp. 1538-1544.
[27] C.P. Tiefenbacher, M. Ebert, F. Niroomand, S. Batkai, H. Tillmanns, R. Zimmermann and W. Kübler, “Inhibition of elastase improves myocardial function after repetitive ischemia and myocardial infarction in the rat heart,” Pflugers Arch, Vol. 433, No. 5, 1997, pp. 563-570.
[28] M. Kawai, N. Harada, H. Takeyama and K. Okajima, “Neutrophil elastase contributes to the development of ischemia/reperfusion-induced liver injury by decreasing the production of insulin-like growth factor-I in rats,” Transl Res, Vol. 155, No. 6, 2010, pp. 294-304.

  
comments powered by Disqus

Copyright © 2019 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.