Does inhibition of angiotensin function cause neuroprotection in diffuse traumatic brain injury?

Document Type : Original Article


1 Endocrinology and Metabolism Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran

2 Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran

3 Physiology Research Center, Institute of Neuropharmacology, Afzalipour Faculty of Medical Sciences, Kerman University of Medical Sciences, Kerman, Iran

4 Pharmaceutics Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran


Objective(s): Neuroprotection is created following the inhibition of angiotensin II type 1 receptor (AT1R). Therefore, the purpose of this research was examining AT1R blockage by candesartan in diffuse traumatic brain injury (TBI).
Materials and Methods: Male rats were assigned into sham, TBI, vehicle, and candesartan groups. Candesartan (0.3 mg/kg) or vehicle was administered IP, 30 min post-TBI. Brain water and Evans blue contents were determined, 24 and 5 hr after TBI, respectively. Intracranial pressure (ICP) and neurologic outcome were evaluated at -1, 1, 4 and 24 hr after TBI. Oxidant index [malondialdehyde (MDA)] was determined 24 hr after TBI.
Results: Brain water and Evans blue contents, and MDA and ICP levels increased in TBI and vehicle groups in comparison with the sham group. Candesartan attenuated the TBI-induced brain water and Evans blue contents, and ICP and MDA enhancement. The neurologic score enhanced following candesartan administration, 24 hr after TBI.
Conclusion: The blockage of AT1R may be neuroprotective by decreasing ICP associated with the reduction of lipid peroxidation, brain edema, and blood-brain barrier (BBB) permeability, which led to the improvement of neurologic outcome.


Main Subjects

1. Teasdale G, Jennett B. Assessment of coma and impaired consciousness: a practical scale. Lancet 1974; 304:81-84.
2. Feickert H-J, Drommer S, Heyer R. Severe head injury in children: impact of risk factors on outcome. J Trauma Acute Care Surg 1999; 47:33-38.
3. Stahel PF, Kariya K, Shohami E, Barnum SR, Eugster H-P, Trentz O, et al. Intracerebral complement C5a receptor (CD88) expression is regulated by TNF and lymphotoxin-α following closed head injury in mice. J Neuroimmunol 2000; 109:164-172.
4. Faul M, Xu L, Wald M, Coronado V. Traumatic brain injury in the United States: emergency department visits, hospitalizations, and deaths. Atlanta: Centers for Disease Control and Prevention. National Center for Injury Prevention and Control 2010.
5. Yakovlev AG, Faden AI. Mechanisms of neural cell death: implications for development of neuroprotective treatment strategies. NeuroRx 2004; 1:5-16.
6. O’Connor WT, Smyth A, Gilchrist MD. Animal models of traumatic brain injury: a critical evaluation. Pharmacol Ther 2011; 130:106-113.
7. Fouda AY, Artham S, El-Remessy AB, Fagan SC. Renin–angiotensin system as a potential therapeutic target in stroke and retinopathy: experimental and clinical evidence. Clin Sci 2016; 130:221-238.
8. Maeda A, Okazaki T, Inoue M, Kitazono T, Yamasaki M, Lemonnier FA, et al. Immunosuppressive effect of angiotensin receptor blocker on stimulation of mice CTLs by angiotensin II. Int Immunopharmacol 2009; 9:1183-1188.
9. Villapol S, Balarezo MG, Affram K, Saavedra JM, Symes AJ. Neurorestoration after traumatic brain injury through angiotensin II receptor blockage. Brain 2015; 138: 3299-3315.
10. Saavedra JM. Brain and pituitary angiotensin. Endocr Rev 1992; 13:329-380.
11. Wright JW, Harding JW. Brain renin-angiotensin—a new look at an old system. Prog Neurobiol 2011; 95:49-67.
12. Paul M, Mehr AP, Kreutz R. Physiology of local renin-angiotensin systems. Physiol Rev 2006; 86:747-803.
13. Timaru-Kast R, Wyschkon S, Luh C, Schaible E-V, Lehmann F, Merk P, et al. Delayed inhibition of angiotensin II receptor type 1 reduces secondary brain damage and improves functional recovery after experimental brain trauma. Critical care medicine 2012; 40:935-944.
14. Thöne-Reineke C, Steckelings UM, Unger T. Angiotensin receptor blockers and cerebral protection in stroke. J Hypertens 2006; 24:S115-S121.
15. Bennai F, Morsing P, Paliege A, Ketteler M, Mayer B, Tapp R, et al. Normalizing the expression of nitric oxide synthase by low-dose AT1 receptor antagonism parallels improved vascular morphology in hypertensive rats. J Am Soc Nephrol 1999; 10:S104-115.
16. Ishrat T, Pillai B, Soliman S, Fouda AY, Kozak A, Johnson MH, et al. Low-dose candesartan enhances molecular mediators of neuroplasticity and subsequent functional recovery after ischemic stroke in rats. Mol Neurobiol 2015; 51:1542-1553.
17. Kozak W, Kozak A, Johnson MH, Elewa HF, Fagan SC. Vascular protection with candesartan after experimental acute stroke in hypertensive rats: a dose-response study. J Pharmacol Exp Ther 2008; 326:773-782.
18. Jung K-H, Chu K, Lee S-T, Kim S-J, Song E-C, Kim E-H, et al. Blockade of AT1 receptor reduces apoptosis, inflammation, and oxidative stress in normotensive rats with intracerebral hemorrhage. J Pharmacol Exp Ther 2007; 322:1051-1058.
19. Villapol S, Yaszemski AK, Logan TT, Sánchez-Lemus E, Saavedra JM, Symes AJ. Candesartan, an angiotensin II AT1-receptor blocker and PPAR-γ agonist, reduces lesion volume and improves motor and memory function after traumatic brain injury in mice. Neuropsychopharmacology 2012; 37:2817-2829.
20. Panahpour H, Bohlooli S, Motavallibashi S. Antioxidant activity-mediated neuroprotective effects of an antagonist of At1 receptors, candesartan, against cerebral ischemia and edema in rats. Neurophysiol 2013; 45:441-447.
21. Soltani Z, Khasksari M, Shahrokhi N, Nakhaei N, Shaibani V. Effect of combined administration of estrogen and progesterone on brain edema and neurological outcome after traumatic brain injury in female rats. IJEM 2009; 10:629-638.
22. Khaksari M, Soltani Z, Shahrokhi N, Moshtaghi G, Asadikaram G. The role of estrogen and progesterone, administered alone and in combination, in modulating cytokine concentration following traumatic brain injury. Can J Physiol Pharmacol 2010; 89:31-40.
23. Soltani Z, Khaksari M, Shahrokhi N, Mohammadi G, Mofid B, Vaziri A, et al. Effect of estrogen and/or progesterone administration on traumatic brain injury-caused brain edema: the changes of aquaporin-4 and interleukin-6. J Physiol Biochem 2016; 72:33-44.
24. Soltani Z, Khaksari M, Jafari E, Iranpour M, Shahrokhi N. Is genistein neuroprotective in traumatic brain injury? Physiol Behav 2015; 152:26-31.
25. Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 1979; 95:351-358.
26. Finnie J. Neuroinflammation: beneficial and detrimental effects after traumatic brain injury. Inflammopharmacology 2013; 21:309-320.
27. Johnson VE, Meaney DF, Cullen DK, Smith DH. Animal models of traumatic brain injury. Handb Clin Neurol 2015; 127:115-128.
28. Benigni A, Cassis P, Remuzzi G. Angiotensin II revisited: new roles in inflammation, immunology and aging. EMBO Mol Med 2010; 2:247-257.
29. Ballabh P, Braun A, Nedergaard M. The blood–brain barrier: an overview: structure, regulation, and clinical implications. Neurobiol Dis 2004; 16:1-13.
30. Sarkaki AR, Khaksari Haddad M, Soltani Z, Shahrokhi N, Mahmoodi M. Time-and dose-dependent neuroprotective effects of sex steroid hormones on inflammatory cytokines after a traumatic brain injury. J Neurotrauma 2013; 30:47-54.
31. Shahrokhi N, Khaksari M, Soltani Z, Mahmoodi M, Nakhaee N. Effect of sex steroid hormones on brain edema, intracranial pressure, and neurologic outcomes after traumatic brain injury. Can J Physiol Pharmacol 2010; 88:414-421.
32. Schuier F, Hossmann K. Experimental brain infarcts in cats. II. Ischemic brain edema. Stroke 1980; 11:593-601.
33. Dirnagl U, Iadecola C, Moskowitz MA. Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci 1999; 22:391-397.
34. Gasche Y, Copin J-C, Sugawara T, Fujimura M, Chan PH. Matrix metalloproteinase inhibition prevents oxidative stress-associated blood–brain barrier disruption after transient focal cerebral ischemia. J Cereb Blood Flow Metab 2001; 21:1393-1400.
35. Soustiel JF, Larisch S. Mitochondrial damage: a target for new therapeutic horizons. Neurotherapeutics 2010; 7:13-21.
36. Pelisch N, Hosomi N, Ueno M, Nakano D, Hitomi H, Mogi M, et al. Blockade of AT1 receptors protects the blood–brain barrier and improves cognition in Dahl salt-sensitive hypertensive rats. Am J Hypertens 2011; 24:362-368.
37. Gohlke P, Kox T, Jürgensen T, von Kügelgen S, Rascher W, Unger T, et al. Peripherally applied candesartan inhibits central responses to angiotensin II in conscious rats. Naunyn Schmiedebergs Arch Pharmacol 2002; 365:477-483.
38. Marmarou A. A review of progress in understanding the pathophysiology and treatment of brain edema. Neurosurg Focus 2007; 22:1-10.
39. Miao X, Wei S, XU Q-p. Aquaporin-4 and traumatic brain edema. Chin J Traumatol 2010; 13:103-110.
40. Kusaka I, Kusaka G, Zhou C, Ishikawa M, Nanda A, Granger DN, et al. Role of AT1 receptors and NAD (P) H oxidase in diabetes-aggravated ischemic brain injury. Am J Physiol Heart Circ Physiol 2004; 286:H2442-H2451.
41. Patel HC, Menon DK, Tebbs S, Hawker R, Hutchinson PJ, Kirkpatrick PJ. Specialist neurocritical care and outcome from head injury. Intensive Care Med 2002; 28:547-553.
42. Khaksari M, Mahmmodi R, Shahrokhi N, Shabani M, Joukar S, Aqapour M. The effects of shilajit on brain edema, intracranial pressure and neurologic outcomes following the traumatic brain injury in rat. Iran J Basic Med Sci 2013; 16:858-864.
43. Culman J, Blume A, Gohlke P, Unger T. The renin-angiotensin system in the brain: possible therapeutic implications for AT1-receptor blockers. J Hum Hypertens 2002; 16:S64-S70.
44. Groth W, Blume A, Gohlke P, Unger T, Culman J. Chronic pretreatment with candesartan improves recovery from focal cerebral ischaemia in rats. J Hypertens 2003; 21:2175-2182.
45. Nishimura Y, Ito T, Saavedra JM. Angiotensin II AT1 blockade normalizes cerebrovascular autoregulation and reduces cerebral ischemia in spontaneously hypertensive rats. Stroke 2000; 31:2478-2486.
46. Blume A, Herdegen T, Unger T. Angiotensin peptides and inducible transcription factors. J Mol Med 1999; 77:339-357.
47. Sugawara T, Kinouchi H, Oda M, Shoji H, Omae T, Mizoi K. Candesartan reduces superoxide production after global cerebral ischemia. Neuroreport 2005; 16:325-328.
48. Baranov D, Armstead WM. Selective blockade of AT1 receptor attenuates impairment of hypotensive autoregulation and improves cerebral blood flow after brain injury in the newborn pig. Anesthesiology 2003; 99:1118-1124.
49. Liu H, Kitazato KT, Uno M, Yagi K, Kanematsu Y, Tamura T, et al. Protective mechanisms of the angiotensin II type 1 receptor blocker candesartan against cerebral ischemia: in-vivo and in-vitro studies. J Hypertens 2008; 26:1435-1445.