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Effects of Conivaptan Versus Mannitol on Post-Ischemic Brain Injury and Edema

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Effects of Conivaptan Versus Mannitol on Post-Ischemic Brain Injury and Edema Eurasian J Med 2019; 51(1): 42-8 Original Article Effects of Conivaptan versus Mannitol on Post-Ischemic Brain Injury and Edema Betul Can1 , Semih Oz2 , Varol Sahinturk3 , Ahmet Musmul4 , İbrahim Ozkan Alatas1 ABSTRACT Objective: The aim of this study was to compare the effects of conivaptan, an arginine vasopressin antago- nist, and mannitol, a sugar alcohol, on cerebral ischemia-induced brain injury and edema in rats. Materials and Methods: Fifty-eight 8-week-old male Sprague Dawley rats were randomly divided into five groups: control, ischemia–reperfusion (I/R)+saline, I/R+mannitol, I/R+10 mg/ml conivaptan, and I/R+20 mg/ ml conivaptan. Cerebral ischemia was induced by common carotid artery occlusion for 30 minutes. Saline, mannitol, or conivaptan were administered intravenously at the onset of reperfusion. Blood and brain tissue samples were taken at the 6th hour of reperfusion. The electrolytes (Na+–K+–Cl−), osmolality, arginine va- sopressin, albumin, progranulin (PGRN), neuron-specific enolase (NSE), and myeloperoxidase activity were measured in rat serum samples. Brain frontal/hippocampal sections were stained with hematoxylin–eosin and TUNEL techniques to evaluate histopathological changes. Results: Statistical analyses revealed that conivaptan caused significant changes in the electrolyte, NSE, and PGRN levels and osmolality when compared with mannitol. Conivaptan treatment showed positive effects on serum biochemistry and tissue histology. Cite this article as: Can B, Oz S, Sahinturk V, Musmul A, Alatas IO. Effects of Conivaptan versus Conclusion: Our findings revealed that conivaptan shows more diuretic activity than mannitol and triggers Mannitol on Post-Ischemic Brain Injury and Edema. neither any damages nor edema in the brain tissue. This study may provide beneficial information for the Eurasian J Med 2019; 51(1): 42-8. development of treatment strategies for ischemia-related cerebrovascular diseases. ORCID IDs of the authors: Keywords: Brain injury, conivaptan, ischemia–reperfusion, mannitol, neuronal damage B.C. 0000-0001-8430-5298 S.O. 0000-0001-1543-2223 V.S. 0000-0003-2317-3644 A.M. 0000-0003-3669-7017 Introduction I.O.A 0000-0002-1753-8873 The formation of brain edema (BE), a continuous process with an intense intracellular and extra- 1Department of Medical Biochemistry, Eskisehir cellular ion and water exchange [1], is one of the most important acute/subacute complications Osmangazi University School of Medicine, of cerebral injuries. Changes in intra- and extracellular volumes may threaten the regional or Eskisehir, Turkey global cerebral blood flow and cell metabolism; given the fixed volume of the skull, this can lead 2Department of Health Services, Eskisehir Osmangazi University Vocational School of to critical consequences due to the compression of vital brain structures [2]. Health Services, Eskisehir, Turkey 3Department of Histology and Embryology, Eskisehir Osmangazi University School of The osmotherapy applied as a part of the medical treatment algorithms is of great importance in Medicine, Eskisehir, Turkey the management of cerebral edema and increased intracranial pressure (ICP) following brain injury 4Department of Medical Services and [3]. Mannitol, a widely used osmotic diuretic agent for the treatment of BE and high ICP for many Techniques, Eskisehir Osmangazi University Vocational School of Health Services, Eskisehir, years [4], cannot meet the anticipated efficacy because it can cause serious side effects and more Turkey fluid to be drawn into the tissues [5]. Therefore, the need for further research is strongly empha- sized in the literature to detect an ideal anti-edema agent that has a low number of side effects [2]. Received: October 22, 2018 Accepted: December 20, 2018 Arginine vasopressin (AVP), a neurohypophysial antidiuretic hormone, has many functions, such Correspondence to: Betul Can E-mail: [email protected] as the regulation of free-water reabsorption and body fluid homeostasis, and it acts upon its spe- cific G protein-coupled receptors defined as1A V (V1, vascular), V2 (renal), and V1B (V3, pituitary) DOI 10.5152/eurasianjmed.2019.18368 [6]. It has been suggested that the AVP hypersecretion plays a critical role in the BE formation, leading to vasospasm, water retention, dilutional hyponatremia, and low plasma osmolality [7]. AVP receptors might be also preferred as a crucial therapeutic target [8]. Content of this journal is licensed under a Creative Commons Vaptans, a new group of drugs that blocks the AVP receptors, were recommended for the Attribution 4.0 International License. treatment of diseases accompanied by water retention [9]. Conivaptan, one of these V1A/V2 Eurasian J Med 2019; 51(1): 42-8 Can et al. The Effects of Conivaptan on Post-Ischemic Brain Injury and Edema • 43 receptor antagonists, was approved by the Food Anesthesia Preparation and analysis of serum samples and Drugs Administration in 2005 for the treat- Prior to surgical procedures, the animals All blood samples were centrifuged at 1000 x ment of patients with clinical hyponatremia [10]. were deprived of food for approximately g for 5 minutes. Serum electrolytes (Na+, K+, Conivaptan has aquaretic effects, and as such, it 12 hours. On the day of surgery, their body Cl−), albumin, and osmolality measurements has a high affinity for the2 V receptors in renal weight was measured. The anesthesia was were conducted immediately on the same day, collecting ducts, promoting renal free-water performed by intramuscular injection of ket- and the remaining serum samples were main- excretion without having a significant effect on amine HCl (50 mg/kg), which is an anesthet- tained at −80ºC until the other biochemical electrolyte excretion [11]. However, the ben- ic/analgesic agent for painful procedures, and analysis. The electrolyte levels in serum samples efits of AVP receptor antagonists on the brain xylazine HCl (10 mg/kg), which is a muscle were measured using the Auto Analyzer Sys- edema process, when applied at the onset of relaxant. At the end of the reperfusion pro- tem (Roche Cobas ISE modular; ISE-indirect) reperfusion, have not been clarified. cess, the animals were anesthetized intra- and expressed as mmol/L. Serum albumin was peritoneally again with the same agents and measured using the Roche Cobas C modular This study, designed with the purpose of obtain- doses, and blood and brain tissue specimens and was expressed as g/dL. Serum osmolality ing the above-mentioned scientific data, was were taken immediately. was measured using a vapor pressure osmom- aimed to compare the effects of conivaptan and eter (Vapro Model 5600, Wescor Inc., USA) mannitol treatments on the post-ischemic brain Experimental design and expressed as mmol/kg. injury and BE in the acute phase. In the litera- The rats were randomly divided into the fol- ture, to the best of our knowledge, there are no lowing five groups: control (sham; n=10), isch- The serum AVP, neuron-specific enolase (NSE), studies that compare the effects of mannitol and emia–reperfusion (I/R)+saline (I/R; n=12), I/ and progranulin (PGRN) levels were measured conivaptan with this regard. R+mannitol (MAN; n=12), I/R+conivaptan 10 with the help of the commercial ELISA kits, ac- mg/ml (CON10; n=12), and I/R+conivaptan 20 cording to the manufacturer’s instructions, us- Materials and Methods mg/ml (CON20; n=12). One animal in the I/R ing a Plate Reader (VICTOR X3, PerkinElmer All research protocols in this study were ap- group was eliminated from the study due to re- Inc., USA) at an optical density of 450 nm. The proved by the Institutional Ethics Committee spiratory arrest during reperfusion. AVP ELISA kit was based on a competitive inhi- (Protocol Number: 560-1/2018). bition enzyme immunoassay technique for the Our study was based on a two-vessel occlu- quantitative measurement of AVP in rat serum Chemicals and kits sion model with a slight modification [12]. Un- samples. The other two ELISA kits were based The following chemicals were used in the like this model, hypotension procedures were on a quantitative sandwich enzyme immunoas- study: conivaptan hydrochloride (cat. #TRC- not performed in our study because of the say technique. The detection range, minimum C384700) purchased from Toronto Research diuretic/aquaretic characteristics of the admin- detectable dose, and intra- and inter-assay Chemicals (Canada), dimethyl sulfoxide (cat. istered agents and the necessity of minimizing precisions of all the ELISA kits were as follows, #D5879), D-mannitol (cat. #M4125), hydro- the surgical manipulation to avoid the risk of respectively: 12.35-1,000 pg/mL, 4.63 pg/mL, gen peroxide (cat. #18312), and 3,3’,5,5’-etra- infection, which may affect the results. In brief, and CV<10% and CV<12% for the AVP kit; methylbenzidine dihydrochloride hydrate (cat. we induced cerebral ischemia by clamping ca- 0.625-40 ng/mL, 0.237 ng/mL, and CV<8% and #861510) were purchased from Sigma-Aldrich rotid arteries bilaterally using a vascular clamp CV<10% for the NSE kit; and 7.8-500 ng/mL, (USA). Ketamine HCl was purchased from Pfiz- (Vascu Stop Bulldog Clamp, Turkey) for 30 1.95 ng/mL, and CV<10% and CV<12% for the er (USA); xylazine HCl from Egevet (Turkey); minutes after a vertical midline neck incision, PGRN Kit. eosin Y (cat. #109844) and hematoxylin (cat. without any added hypotension procedures. #105174) solutions from Merck (Germany); After 30 minutes, the clamps were removed, As a predictor of leukocyte infiltration and in- rat commercial enzyme-linked immunosorbent and reperfusion was initiated. Saline (0.9% flammation, the serum myeloperoxidase (MPO) assay (ELISA) kits from AVP (cat. #CEB139Ra); NaCl), mannitol (20% wt/vol; dissolved in sa- activity was measured according to the previ- and NSE (cat. #SEA537Ra) from Cloud-Clone line; MW=182.17), and conivaptan (10 or 20 ously reported method [14]. The method is Corp. (USA). The progranulin (cat. #CSB- mg/ml=18.5 or 37 mg kg-1; dissolved in 5% fi- based on the measurement of the oxidation of EL009939RA) ELISA kit was purchased from nal DMSO vol/vol; MW=535.04) were applied a synthetic substrate, 3,3’-5,5’-tetramethylben- Cusabio Biotech Comp.
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