• 2018-07
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • There may be an interplay of


    There may be an interplay of EP2, EP3, EP4 alone, or in combination, with EP1 for the onset of TCDD-induced neonatal hydronephrosis. EP2 and EP4 have been reported to increase AQP2 phosphorylation and membrane trafficking (Li et al., 2009; Olesen et al., 2011). The EP2 and EP4 mRNA concentrations were shown to drastically increase after birth, peak on PNDs 7 − 14, and decrease by week 3 after birth (Brennan et al., 2008). A similar finding was obtained for EP3: EP3 mRNA BQ-788 sodium salt in rabbits and rats was shown to increase rapidly during the first two to three weeks of life, followed by a drastic decrease by adulthood (Bonilla-Felix and Jiang, 1996; Breyer et al., 1993; Melendez et al., 1989). AVP-mediated AQP2 trafficking is blocked by inhibition of cAMP generation via PGE2/EP3 in immature collecting ducts in rabbits (Bonilla-Felix and Jiang, 1996). In the present study, we could not observe whether AQP2 trafficking was inhibited by impaired AVP-stimulated cAMP generation by EP subtypes. However, the incidence of TCDD-induced hydronephrosis was not reduced in EP2–/–, EP3–/–, or chemically EP4-suppressed mouse models (Figs. 2,3, and 4 and Table 2, Table 3, Table 4). These observations strongly suggested that among the four EP subtypes, EP1 plays a predominant role in the onset of TCDD-induced neonatal hydronephrosis.
    Acknowledgements The authors thank Dr. Wataru Yoshioka and Mr. Akinari Shimada (then, at the Tohyama Lab) for their valuable contribution at the initial stage of this study, and Mr. Toshihiro Sakamoto, for animal care. The authors thank Enago for English language editing.
    Introduction PGE2, a major cyclooxygenase 2 product in the mammalian brain, exerts hormone-like properties that modulate many physiological and pathophysiological functions, among them membrane excitability and synaptic transmission in CA1 pyramidal neurons (Chen and Bazan, 2005). However, the pathways and mechanisms involved remain largely unknown. Kainic acid, an excitatory neurotoxin, when injected into rodents at doses ≥20mg/kg induces seizures that can progress into status epilepticus, which in turn eventually causes development of spontaneous recurrent seizures (epilepsy) in the weeks following (Ben-Ari et al., 1979, Hellier et al., 1998). Kainate receptors (KARs) are ionotropic glutamate receptors composed of GluK1 through GluK5 subunits that are located both presynaptically and postsynaptically throughout the CNS and are involved in synaptic plasticity and transmission (Huettner, 2003, Kamiya, 2002, Lerma, 2003, Pinheiro and Mulle, 2006). Recently we demonstrated expression of the high affinity kainate receptor subunits (GluK4 and GluK5) in the CA3 region of the hippocampus (Rojas et al., 2013), which supported a previous report by Darstein et al. (2003). The expression profile of the high affinity kainate receptor subunits is consistent with the localization of kainic acid binding in the hippocampus. Furthermore, the expression profile of GluK5 (one of the high affinity KA subunits) correlates with the neurodegeneration pattern in the hippocampus following kainic acid injection in rodents. A prominent neuropathology associated with kainic acid induced status epilepticus is hippocampal neurodegeneration. Recent studies have suggested that signaling via the prostaglandin EP1 receptor may affect the fate of neurons following brain injury. For example, EP1 deficient mice show less neuronal injury following transient forebrain ischemia (Shimamura et al., 2013) and cerebral ischemia (Zhen et al., 2012). Pharmacological inhibition of the EP1 receptor with SC51089 reduces neuronal loss and blood–brain barrier disruption following ischemic injury (Fukumoto et al., 2010, Shimamura et al., 2013) suggesting that EP1 activation may promote cell death. Kawano et al. (2006) demonstrated that EP1 gene inactivation reduced brain injury following NMDA induced excitotoxicity, ischemia or oxygen glucose deprivation, suggesting that the presence of EP1 in normal animals contributes to or exacerbates the injury. Each glutamate receptor subtype (NMDA, AMPA and KA) is likely to play a role in the above mentioned brain injury models. Endogenous kainate receptors are regulated by Gαq coupled BQ-788 sodium salt receptors that are known to modulate excitotoxicity following seizures (Benveniste et al., 2010, Rojas et al., 2013). EP1 is a Gαq-coupled receptor for PGE2, thus we hypothesized that kainate receptors are targeted by EP1 pathways to contribute to the neuropathology that follows status epilepticus. Here we ask the questions: Does genetic inactivation of EP1 alter kainate induced status epilepticus? Do EP1 knockout mice display reduced neurodegeneration or brain inflammation following kainate induced status epilepticus? Is there cross-talk between kainate receptors and prostanoid receptors and if so, what is the mechanism? To address these questions we combined an in vivo rodent model of kainate induced status epilepticus and functional in vitro studies of native and co-expressed recombinant kainate receptors and prostanoid receptors.