Effect of TTC-909 on Cerebral Infarction Following Permanent Occlusion of the Middle Cerebral Artery in Stroke Prone Spontaneously Hypertensive Rats

Abstract

Abstract. We investigated the effect of TTC-909, a drug preparation of the stable prostaglandin I 2 analogue clinprost (isocarbacyclin methylester; methyl 5-{(1S,5S,6R,7R)-7-hydroxy-6-[(E)-(S)-3-hydroxy-1-octenyl] bicyclo[3.3.0]oct-2-en-3-yl} pentanoate) incorporated into lipid microspheres, on cerebral infarction 7 days after permanent occlusion of the middle cerebral artery (MCA) in stroke prone spontaneously hypertensive rats (SHRSP). Under the anesthesia, the MCA was permanently occluded above the rhinal fissure. In schedule 1, vehicle or TTC-909 was injected i.v. once daily over 7 days starting immediately after MCA occlusion. In schedule 2, vehicle or TTC-909 was infused for 3 h starting immediately after MCA occlusion. In schedule 3, vehicle or TTC-909 was infused for 3 h starting immediately after MCA occlusion followed by bolus injection once daily over 6 days. Seven days later, the infarct volume was estimated following hematoxylin and eosin staining. Cerebral infarction produced by permanent occlusion of MCA was limited to the cerebral cortex. While this volume was reduced significantly in case of schedule 3, the infarct volume was not reduced significantly in schedules 1 and 2. Ozagrel, a thromboxane A 2 synthetase inhibitor, had no effect on the infarct volume in schedule 3. These results suggest that cerebral infarction can be developed progressively not only during the first few hours but also after a permanent occlusion of MCA in SHRSP. TTC-909 inhibited cerebral infarction, maybe by improving cerebral blood flow and by protecting against neuronal damage.

Prostacyclin receptor deletion aggravates hippocampal neuronal loss after bilateral common carotid artery occlusion in mouse

“…The data imply a protective role for the IP receptor in delayed pyramidal neuron cell death. Our findings in C57Bl/6 male mice are also consistent with those of other studies showing that relatively selective IP receptor agonists reduce delayed neuronal loss in gerbil and rat (Awad et al, 1983; Dohi, 1987; Karasawa et al, 2002, 2003; Takamatsu et al, 2002). However, affinity and selectivity of pharmacological analogs to the G-protein-coupled receptors are often limiting factors for optimal interpretation of the experimental results (Narumiya et al, 1999).…”

“…However, numerous studies have demonstrated that PGI 2 analogs reduce memory impairment in rodents with cerebral embolism, suggesting a role for the IP receptor in modulation of neurological impairment (Awad et al, 1983; Dohi, 1987; Karasawa et al, 2002, 2003; Takamatsu et al, 2002). Researchers have observed that PGI 2 analogs provide neuronal protection and improve the outcome of learning and memory defects in the cerebral ischemia models of focal as well as global ischemia (Awad et al, 1983; Dohi, 1987; Karasawa et al, 2002, 2003; Takamatsu et al, 2002).…”

Sustained Neurological Recovery After Stroke in Aged Rats Treated With a Novel Prostacyclin Analog

“…PGI 2 IP receptor deficient (IP −/− ) mice displayed exacerbated neuronal death following brain ischemia 2, 3 . In addition, PGI 2 analogs significantly reduced ischemic brain injury 2, 4–6 . However, the use of PGI 2 and known analogs have limited therapeutic value due to chemical instability, rapid metabolism (t½~ 4 min) 1 , as well as lack of selectivity for the IP receptor resulting in unsafe side effects 7 .…”

Elevated prostacyclin biosynthesis in mice impacts memory and anxiety-like behavior

“…For example, 48 hours following fluid percussion brain injury in rats, PGI 2 treatment reversed blood flow reductions in the injured cortex of rats [13], indicating an improvement in cortical perfusion. Additionally, administration of PGI 2 agonists TTC-909 [14] and ONO-1301 [15] both reduce infarct volume after middle cerebral artery occlusion (MCAO) in rats, with ONO-1301 reducing neurological deficits. TTC-909 was also shown to reduce memory impairments in rats with cerebral embolism [16], supporting the notion that PGI 2 may play a role in cognitive functions.…”