Cerebroprotective action of telmisartan by inhibition of macrophages/microglia expressing HMGB1 via a peroxisome proliferator-activated receptor γ-dependent mechanism

doi:10.1016/j.neulet.2009.08.043

Neuroscience Letters

Volume 464, Issue 3, 30 October 2009, Pages 151-155

https://doi.org/10.1016/j.neulet.2009.08.043 Get rights and content

Abstract

Telmisartan is known to block angiotensin (Ang) II type-1 receptors (AT₁R), and also activate peroxisome proliferator-activated receptor γ (PPARγ) signaling. Recently, PPARγ has been implicated as a regulator of cellular proliferation and inflammatory responses. In the present study, we investigated the anti-inflammatory effects of telmisartan on middle cerebral artery (MCA) occlusion in mice. Telmisartan was administered orally to mice at 2 h before and 2 h after MCA occlusion. Infarct size was determined at 24 h after MCA occlusion. In addition, cerebral blood flow (CBF) was measured during MCA occlusion. The effect of telmisartan on inflammatory markers, including Iba1 (macrophage/microglia marker) immunoreactivity and plasma high-mobility group box1 (HMGB1), was also investigated at 24 h after MCA. Telmisartan significantly decreased the infarct area in dose-dependent manner without affecting CBF. Furthermore, the cerebroprotective effect of telmisartan was inhibited by GW9662, PPARγ antagonist. Telmisartan significantly decreased the number of Iba1-positive cells expressing HMGB1 and decreased plasma HMGB1 levels. These effects were partially inhibited by GW9662. These data suggest that telmisartan may be a potential treatment for post-ischemic injury by partially inhibiting the inflammatory reaction after cerebral ischemia via a PPARγ-dependent HMGB1 inhibiting mechanism.

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Acknowledgment

We thank Nippon Boehringer Ingelheim and Astellas Pharma Inc. for providing the telmisartan.

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Additionally, telmisartan can cross the blood–brain barrier when administered systematically and exhibits slow clearance from the brain [20]. The anti-inflammatory effects of telmisartan have been reported in lipopolysaccharide (LPS)-stimulated BV2 cells and primary microglia as well as in animal models of brain ischemia, traumatic brain injury, and Parkinson’s disease [11,21–24]. However, the molecular and signaling mechanisms underlying the anti-inflammatory effects of telmisartan have yet to be fully elucidated.
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Telmisartan, an angiotensin type 1 receptor blocker (ARB), is used for hypertension to control blood pressure and has been shown to have a partial agonistic effect on peroxisome proliferator-activated receptor γ (PPARγ). Recently, the ligand of PPARγ has been implicated in cerebroprotection due to its anti-inflammatory effect. In this study, we investigated whether telmisartan has a cerebroprotective effect on memory impairment and neuronal cell death induced by repeated cerebral ischemia. Repeated cerebral ischemia (RI: 10 min × 2) significantly induced impairment of spatial memory and hippocampal apoptosis in rats. Fourteen-day pre- and post-ischemic administration of telmisartan (0.3, 1, 3 mg/kg/day, p.o.) increased the number of correct choices and reduced the number of errors made in the eight-arm radial maze task in a dose-dependent manner in RI treated rats. TUNEL-positive cells in the hippocampus CA1 areas were also reduced following 14-day administration of telmisartan (3 mg/kg/day, p.o.). Seven-day post-ischemic administration of telmisartan improved spatial memory and reduced TUNEL-positive cells while 7-day pre-ischemic administration of telmisartan did not. These effects of telmisartan were inhibited by the PPARγ antagonist, GW9662. On further experiment, 7-day post-ischemic administration of telmisartan reduced the expression of caspase-3 in the hippocampus, and this effect was also inhibited by GW9662. These results suggest that telmisartan improves memory impairment and reduces neuronal apoptosis via a PPARγ-dependent caspase-3 inhibiting mechanism. Telmisartan, which has the unique character of having both ARB and PPARγ agonistic effect, will be useful for preventing memory impairment after cerebrovascular disease.

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Cerebroprotective action of telmisartan by inhibition of macrophages/microglia expressing HMGB1 via a peroxisome proliferator-activated receptor γ-dependent mechanism

Abstract

Section snippets

Acknowledgment

Neuropharmacology

Am. J. Pathol.

Neurosci. Res.

Lancet

J. Biol. Chem.

J. Neuroimmunol.

Atherosclerosis

Beneficial effects of PPAR-gamma ligands in ischemia-reperfusion injury, inflammation and shock

Cardiovasc. Res.

HMG-1 as a mediator of acute lung inflammation

J. Immunol.

Identification of telmisartan as a unique angiotensin II receptor antagonist with selective PPARgamma-modulating activity

Hypertension

Peroxisome proliferator-activated receptors (PPARs): nuclear receptors at the crossroads between lipid metabolism and inflammation

Inflamm. Res.

The nuclear receptor PPAR gamma and immunoregulation: PPAR gamma mediates inhibition of helper T cell responses

J. Immunol.

Characterization of new PPARγ agonists: Analysis of telmisartan's structural components

Chem. Med. Chem.

AT1 receptor antagonist telmisartan administered peripherally inhibits central responses to angiotensin II in conscious rats

J. Pharmacol. Exp. Ther.

AT₁ receptor antagonist telmisartan administered peripherally inhibits central responses to angiotensin II in conscious rats