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Research Article 7 Nicotinic Acetylcholine Receptor Stimulation

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Research Article 7 Nicotinic Acetylcholine Receptor Stimulation Hindawi BioMed Research International Volume 2017, Article ID 8134653, 13 pages https://doi.org/10.1155/2017/8134653 Research Article 훼7 Nicotinic Acetylcholine Receptor Stimulation Attenuates Neuroinflammation through JAK2-STAT3 Activation in Murine Models of Intracerebral Hemorrhage Paul R. Krafft,1,2 Devin McBride,1 William B. Rolland,1 Tim Lekic,1 Jerry J. Flores,1 and John H. Zhang1,2 1 Department of Physiology & Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA, USA 2Department of Neurosurgery, Loma Linda University School of Medicine, Loma Linda, CA, USA Correspondence should be addressed to Paul R. Krafft; [email protected] Received 5 February 2017; Accepted 6 April 2017; Published 26 April 2017 Academic Editor: Carl Muroi Copyright © 2017 Paul R. Krafft et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Accounting for high mortality and morbidity rates, intracerebral hemorrhage (ICH) remains one of the most detrimental stroke subtypes lacking a specific therapy. Neuroinflammation contributes to ICH-induced brain injury and is associated with unfavorable outcomes. This study aimed to evaluate whether 7 nicotinic acetylcholine receptor (7nAChR) stimulation ameliorates neuroinflammation after ICH. Male CD-1 mice and Sprague-Dawley were subjected to intracerebral injection of autologous blood or bacterial collagenase. ICH animals received either 7nAChR agonist PHA-543613 alone or combined with 7nAChR antagonist methyllycaconitine (MLA) or Janus kinase 2 (JAK2) antagonist AG490. Neurobehavioral deficits were evaluated at 24 hours, 72 hours, and 10 weeks after ICH induction. Perihematomal expressions of JAK2, signal transducer and activator of transcription 3 (STAT3), tumor necrosis factor- (TNF-), and myeloperoxidase (MPO) were quantified via Western blot. Histologic volumetric analysis of brain tissues was conducted after 10 weeks following ICH induction. PHA-543613 improved short-term neurobehavioral (sensorimotor) deficits and increased activated perihematomal JAK2 and STAT3 expressions while decreasing TNF- and MPO expressions after ICH. MLA reversed these treatment effects. PHA-543613 also improved long-term neurobehavioral (sensorimotor, learning, and memory) deficits and ameliorated brain atrophy after ICH. These treatment effects were reduced by AG490. 7nAChR stimulation reduced neuroinflammation via activation of the JAK2-STAT3 pathway, thereby ameliorating the short- and long-term sequelae after ICH. 1. Introduction Intraparenchymal hematoma formation leads to mass effect and disruption of brain tissue (primary injury); how- Accounting for high mortality and morbidity rates, sponta- ever, it also triggers subsequent deleterious mechanisms neous intracerebral hemorrhage (ICH) remains one of the including inflammatory pathways (secondary injury). Neu- most detrimental stroke subtypes; yet no specific therapy roinflammation after ICH involves microglia activation, pro- has been proven clinically effective [1, 2]. Poor outcomes duction of inflammatory cytokines, and influx of peripheral following ICH are associated with large hematoma volumes, immune cells, all contributing to the pathophysiology of sec- infratentorial origin, and intraventricular extension of the ondary brain injury [4, 5]. While microglia are implicated in bleed as well as with advanced age and compromised neu- hematoma clearance, classically activated M1 microglial cells rological function of patients upon presentation [3]. Since release proinflammatory cytokines, such as tumor necrosis thesefactorsaremostlyinalterable,currentinvestigations factor- (TNF-) and interleukin-6 (IL-6), thereby attracting aim to manipulate cellular and molecular mechanisms of peripheral leukocytes to the already compromised brain hemorrhage-induced brain injury, pursuing to ameliorate the tissue. Infiltrating leukocytes disrupt the blood-brain barrier clinical sequelae following ICH. (BBB) and aggravate neuroinflammation. Hypothetically, 2 BioMed Research International inhibiting excessive neuroinflammation may decrease the glass syringe with a 26-Gauge needle, which was inserted extent of brain injury and result in improved neurological through the burr hole and advanced 3.0 mm below the dura. function after ICH [6]. At this position, a microinjection pump (Harvard Apparatus, Nicotinic acetylcholine receptors are pentameric, ligand- Holliston, MA) was used to deliver 5 L of blood at a rate of gated ion channels expressed in the central and peripheral 2 L/min. The needle was then lowered to a depth of 3.7 mm, nervous systems as well as at the neuromuscular junction, and after a waiting period of 5 minutes, 25 L of blood was implicated in acetylcholine signaling [7, 8]. The 7nico- injected into the right striatum. tinic acetylcholine receptor (7nAChR), specifically, is a For the collagenase model, 3.0 U of bacterial collagenase 2+ homopentameric ion channel, highly permeable to Ca , (Type VII-S, Sigma-Aldrich, St. Louis, MO), dissolved in which is involved in cellular processes such as cell plasticity 0.5 L phosphate buffered saline (PBS), was filled into a glass and survival as well as in higher brain functions such as syringe. The 26-Gauge needle attached to the syringe was then learning and memory, anxiety, and locomotion [8]. Addition- lowered through the burr hole to a depth of 5.6 mm below the ally, 7nAChRs are expressed by macrophages and microglia dura. Collagenase was delivered into the right striatum at a [7, 9]. Acetylcholine-induced 7nAChR stimulation inhib- rate of 0.25 L/min. ited the release of proinflammatory cytokines by peripheral After completed injection of autologous blood or collage- macrophages in wild-type mice, which was not observed in nase, the needle was left in place for 10 minutes to minimize 7 deficient mice [7]. Although it is not entirely understood, backflow along the needle tract. Sham surgery consisted of 7nAChR stimulation has been associated with recruitment needle insertion without injection of blood or collagenase. and activation of Janus kinase 2 (JAK2) and signal transducer Thirty-six CD-1 mice and 30 Sprague-Dawley rats were and activator of transcription 3 (STAT3), which negatively utilized in this study. Twenty-seven mice were subjected to regulates TNF- synthesis [10]. intrastriatal injection of autologous blood. These animals Administration of specific 7nAChR agonists results in received either intraperitoneal injections of normal saline 1 neuroprotection following experimental ICH [11, 12]; how- hour after surgery (Vehicle, =9), injections of 7nAChR ever, possible underlying anti-inflammatory mechanisms of agonist PHA-543613 (PHA; Sigma-Aldrich (St. Louis, MO); this treatment strategy have yet to be explored. For this 12 mg/kg; 0.2 mL; intraperitoneally (Krafft et al., 2012)) 1 reason, we aimed to evaluate whether PHA-543613, a spe- hour after surgery (PHA-12 mg, =9), or injections cific 7nAChR agonist, can attenuate neuroinflammation of 7nAChR antagonist methyllycaconitine (MLA; Sigma- after ICH via JAK2/STAT3 signaling. We hypothesize that Aldrich (St. Louis, MO); 6 mg/kg; 0.2 mL; intraperitoneally PHA-543613 treatment will decrease hemorrhage-induced (Krafft et al., 2012)) 45 minutes after surgery followed by neuroinflammation by activation of JAK2/STAT3, thus PHA-543613 administration 15 minutes thereafter (PHA + achieving lasting neuroprotection following experimental MLA; =9). Nine animals were subjected to Sham ICH. surgery (Sham). All mice underwent neurobehavioral testing 24 hours after surgery followed by brain tissue collection for Western blotting (=6per group) and immunohistochem- 2. Materials and Methods istry (=3per group). Eighteen rats were subjected to intrastriatal injection 2.1. Animal Surgery and Experimental Groups. The Insti- of collagenase. These animals received either normal saline tutional Animal Care and Use Committee at Loma Linda administrations (Vehicle; =6)orinjectionsofPHA- University approved all experiments. This study was carried 543613 (12 mg/kg; intraperitoneally) on days 1, 2, and 3 after outincompliancewiththeNIHguideforthecareanduse ICH (PHA-12 mg; =6). Another group received the of laboratory animals. Male CD-1 mice (weight: 30–40 g; same treatment regimen of PHA-543613 combined with JAK2 Charles River Laboratory, Wilmington, MA) and male antagonist tyrphostin AG490 (AG490; Sigma-Aldrich (St. Sprague-Dawley rats (weight: 280–350 g; Harlan, Livermore, Louis, MO); dissolved in DMSO; 5 mg/kg; intraperitoneally CA) were housed in a temperature-controlled environment [12, 15]), which was administered 15 minutes prior to the with a 12-hour light/dark cycle and were given free access PHA treatments (PHA + AG490; =6). Twelve rats were to food and water. The autologous blood injection model subjected to Sham surgery, 6 of which received injections of was used to create intracerebral bleeds in mice [13]; however, AG490ondays1,2,and3aftersurgery(Sham+AG490). rats were subjected to intracerebral collagenase injections All rats underwent neurobehavioral testing at 24 and 72 as previously described [14]. Briefly, mice and rats were hours, as well as at 10 weeks, after surgery. Brain tissue anesthetized with a mixture of ketamine (100 mg/kg) and was collected at the end of the 10th week for volumetric xylazine (10 mg/kg). The rodents were placed prone and measurements. secured onto a stereotactic head
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