PAR-1 antagonist SCH79797 ameliorates apoptosis following surgical brain injury through inhibition of ASK1-JNK in rats

Abstract

Neurosurgical procedures inevitably produce intraoperative hemorrhage. The subsequent entry of blood into the brain parenchyma results in the release of large amounts of thrombin, a known contributor to perihematomal edema formation and apoptosis after brain injury. The present study seeks to test 1) the effect of surgically induced brain injury (SBI) on thrombin activity, expression of thrombin’s receptor PAR-1, and PAR-1 mediated apoptosis; 2) the effect of thrombin inhibition by argatroban and PAR-1 inhibition by SCH79797 on the development of secondary brain injury in the SBI model on rats. A total of 88 Sprague-Dawley male rats were randomly divided into sham, vehicle-, argatroban-, or SCH79797-treated groups. SBI involved partial resection of the right frontal lobe under inhalation isoflurane anesthesia. Sham-operated animals received only craniotomy. Thrombin activity, brain water content, and neurological deficits were measured at 24 hours following SBI. Involvement of the Ask1/JNK pathway in PAR-1-induced post-SBI apoptosis was characterized by using Ask1 or JNK inhibitors. We observed that SBI increased thrombin activity, yet failed to demonstrate any effect on PAR-1 expression. Argatroban and SCH79797 reduced SBI-induced brain edema and neurological deficits in a dose-dependent manner. SBI-induced apoptosis seemed mediated by the PAR-1/Ask1/JNK pathways. Administration of SCH79797 ameliorated the apoptosis following SBI. Our finding indicate that PAR-1 antagonist protects against secondary brain injury after SBI by decreasing both brain edema and apoptosis by inactivating PAR-1/Ask1/JNK pathway. The anti-apoptotic effect of PAR-1 antagonists may provide a promising path for therapy following SBI.

Interference with Protease-activated Receptor 1 Alleviates Neuronal Cell Death Induced by Lipopolysaccharide-Stimulated Microglial Cells through the PI3K/Akt Pathway

“…Signaling through PAR-1 appears to mediate the process of brain damage in adult animal models of subarachnoid hemorrhage (SAH)1617. Previous rodent studies have shown that the interference with this pathway in primary astrocyte cultures1819 as well as in hippocampal slice cultures20 provided a potential target for therapeutic approach in maintaining vascular integrity following brain damage in rats2122.…”

Contribution of protease-activated receptor 1 in status epilepticus-induced epileptogenesis

“…Both short-term and long-term increases in the thrombin level and PAR1 activation have been observed following different brain insults such as ischemia, neuronal brain injury, inflammation, conditions which can compromise the development of chronic epilepsy(Chapman, 2006; Chen et al, 2012; Manaenko et al, 2013; Rohatgi et al, 2004; Striggow et al, 2001; Wang et al, 2012). One common feature of these conditions is a disturbance of BBB integrity, which even without detectable hemorrhage allows large molecule weight proteins such as albumin or globulins to enter the brain.…”

“…SCH79797 was injected at a concentration of 25 μg/kg. This concentration was shown to be optimal for the reduction of myocardial necrosis observed during experimental ischemia and for the decrease of brain water content and amelioration of neurological deficits following surgical brain injury (Manaenko et al, 2013; Strande et al, 2007). …”

“…Thrombin, through the activation of specific protease-activated receptors (PAR) expressed by neurons and glial cells, is implicated in the exacerbation of brain damage, seizures and induction of inflammation and neurogenesis, all processes that frequently occur during epileptogenesis (Tanuja Rohatgi et al, 2004). Finally, deficiency of PAR1, a major thrombin receptor in the brain, protects against neuronal damage and neurologic deficits in different models of experimental brain insults thus indicating a significant role of PAR1 signaling in the development of neurodegenerative disorders (Chen et al, 2012; Junge et al, 2003; Manaenko et al, 2013; Olson et al, 2004; Wang et al, 2012). …”

Correlation between subacute sensorimotor deficits and brain water content after surgical brain injury in rats

“…Variation in these factors may lead to varied amounts of iron and thrombin accumulation in the tissue as well as varied severity of inflammation, which are known to induce brain edema [25]. Controlling the time of surgery and intra-operative hemorrhage will minimize the variability in brain edema between animals subjected to SBI, and should also be documented and reported.…”