Telmisartan is an angiotensin receptor blocker with high lipid solubility, also called
metabosartan, which exerts a special protective effect on both acute brain damage
and chronic neurodegeneration. We examined the effects of telmisartan on oxidative
stress by advanced glycation end product (AGE) and 4-hydroxynonenal (4-HNE) assays
and the accumulation of phosphorylated α-synuclein (pSyn) in the brain of stroke-resistant
spontaneously hypertensive rats (SHR-SR). At the age of 12 weeks, SHR-SR received
transient middle cerebral artery occlusion (tMCAO) for 90 minutes and were divided
into the following 3 groups: the vehicle group, the low-dose telmisartan group (.3 mg/kg/day),
and the high-dose telmisartan group (3 mg/kg/day, postoperatively). Immunohistologic
analysis was performed when rats were 6, 12, and 18 months old. AGE, 4-HNE, and pSyn–positive
cells (per square millimeter) increased with age in the cerebral cortex and hippocampus
of the vehicle group, in the low-dose telmisartan group, these parameters decreased
without lowering blood pressure (BP), and in the high-dose telmisartan group, these
parameters increased with lowering BP. The present study suggests that a persistent
hypertension after tMCAO caused a progressive oxidative stress with the abnormal accumulation
of pSyn, and that telmisartan reduced oxidative stress and the accumulation of pSyn
without lowering BP (low dose) or improved these conditions with a reduction in BP
(high dose) via its pleiotropic effects through a potential peroxisome proliferator–activated
receptor gamma stimulation in the brain of SHR-SR.
Key Words
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References
- The inflammatory aspect of the microcirculation in hypertension: oxidative stress, leukocytes/endothelial interaction, apoptosis.Microcirculation. 2002; 9: 259-276
- Enhanced oxidative stress and impaired thioredoxin expression in spontaneously hypertensive rats.Antioxid Redox Signal. 2004; 6: 89-97
- Chronic treatment with a superoxide dismutase mimetic prevents vascular remodeling and progression of hypertension in salt-loaded stroke-prone spontaneously hypertensive rats.Am J Hypertens. 2002; 15: 78-84
- Antioxidant-rich diet relieves hypertension and reduces renal immune infiltration in spontaneously hypertensive rats.Hypertension. 2003; 41: 341-346
- Possible contributions of reactive oxygen species and mitogen-activated protein kinase to renal injury in aldosterone/salt-induced hypertensive rats.Hypertension. 2004; 43: 841-848
- Spironolactone improves angiotensin-induced vascular changes and oxidative stress.Hypertension. 2002; 40: 504-510
- Endothelial function and oxidative stress in renovascular hypertension.N Engl J Med. 2002; 346: 1954-1962
- Strong attenuation of ischemic and postischemic brain edema in rats by a novel free radical scavenger.Stroke. 1988; 19: 480-485
- Role of oxidants in ischemic brain damage.Stroke. 1996; 27: 1124-1129
- Oxidative DNA damage precedes DNA fragmentation after experimental stroke in rat brain.FASEB J. 2000; 14: 955-967
- The basis of free radical pathology.Fed Proc. 1973; 32: 1859-1861
- Parkin ubiquitinates the alpha-synuclein-interacting protein, synphilin-1: implications for Lewy-body formation in Parkinson disease.Nat Med. 2001; 7: 1144-1150
- Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions.Science. 2000; 290: 985-989
- Morbidity and mortality after stroke, eprosartan compared with nitrendipine for secondary prevention: principal results of a prospective randomized controlled study (MOSES).Stroke. 2005; 36: 1218-1226
- Protection against ischemia and improvement of cerebral blood flow in genetically hypertensive rats by chronic pretreatment with an angiotensin II AT1 antagonist.Stroke. 2002; 33: 2297-2303
- Inhibiting angiotensin receptors in the brain: possible therapeutic implications.Curr Med Res Opin. 2003; 19: 449-451
- The angiotensin II type 1-receptor blocker candesartan increases cerebral blood flow, reduces infarct size, and improves neurologic outcome after transient cerebral ischemia in rats.J Cereb Blood Flow Metab. 2004; 24: 467-474
- Angiotensin II type-2 receptor stimulation prevents neural damage by transcriptional activation of methyl methanesulfonate sensitive 2.Hypertension. 2006; 48: 141-148
- AT1 receptor antagonist telmisartan administered peripherally inhibits central responses to angiotensin II in conscious rats.J Pharmacol Exp Ther. 2001; 298: 62-70
- In vitro and in vivo characterization of the activity of telmisartan: an insurmountable angiotensin II receptor antagonist.J Pharmacol Exp Ther. 2002; 302: 1089-1095
- Protective effects of angiotensin II type 1 receptor blocker on cerebral circulation independent of blood pressure.Experimental Neurology. 2008; 210: 441-448
- Effects of telmisartan, hydrochlorothiazide and their combination on blood pressure and renal excretory parameters in spontaneously hypertensive rats.JRAAS. 2001; 2: 123-128
- NeuroScale, the battery of behavioral tests with novel scoring system for phenotyping of transgenic rat model of tauopathy.J Neurosci Methods. 2009; 177: 108-114
- The hippocampus in spontaneously hypertensive rats: an animal model of vascular dementia?.Mech Ageing Dev. 2002; 123: 547-559
- Transgenic expression of CD36 in the spontaneously hypertensive rat is associated with amelioration of metabolic disturbances but has no effect on hypertension.Physiol Res/Acad Sci Bohemoslov. 2003; 52: 681-688
- Effect of AT1 receptor antagonism on vascular and circulating inflammatory mediators in SHR: role of NF-kappaB/IkappaB system.Am J Physiol Heart Circ Physiol. 2005; 288: H111-H115
- Antioxidant nutrients and hypoxia/ischemia brain injury in rodents.Toxicology. 2003; 189: 55-61
- Expression of Keap1-Nrf2 system and antioxidative proteins in mouse brain after transient middle cerebral artery occlusion.Brain Res. 2011; 1370: 246-253
- alpha-Synuclein is phosphorylated in synucleinopathy lesions.Nat Cell Biol. 2002; 4: 160-164
- Accumulation of phosphorylated alpha-synuclein in aging human brain.J Neuropathol Exp Neurol. 2003; 62: 644-654
- Telmisartan ameliorates neurotrophic support and oxidative stress in the retina of streptozotocin-induced diabetic rats.Neurochem Res. 2013; 38: 1572-1579
- Anti-inflammatory and anti-oxidant properties of telmisartan in cultured human umbilical vein endothelial cells.Atherosclerosis. 2008; 198: 22-28
- Administration of telmisartan reduced systolic blood pressure and oxidative stress probably through the activation of PI3K/Akt/eNOS pathway and NO release in spontaneously hypertensive rats.Physiol Res/Acad Sci Bohemoslov. 2013; 62: 351-359
- Neuroprotective effects of angiotensin II type 1 receptor (AT1R) blocker, telmisartan, via modulating AT1R and AT2R signaling in retinal inflammation.Invest Ophthalmol Vis Sci. 2006; 47: 5545-5552
Article info
Publication history
Published online: April 28, 2014
Accepted:
December 25,
2013
Received in revised form:
December 4,
2013
Received:
November 6,
2013
Footnotes
This work was partly supported by a Grant-in-Aid for Scientific Research (B) 21390267 from the Ministry of Education, Science, Culture, and Sports of Japan, and by Grants-in-Aid from the Research Committee of CNS Degenerative Diseases (I. Nakano) and grants (H. Mizusawa, M. Nishizawa, H. Sasaki, G. Sobue) from the Ministry of Health, Labour, and Welfare of Japan.
Identification
DOI: https://doi.org/10.1016/j.jstrokecerebrovasdis.2013.12.051
Copyright
© 2014 Published by Elsevier Inc.
