Author: Spadaccio, Cristiano ; Avtaar Singh, Sanjeet Singh ; Nenna, Antonio ; Chello, Massimo ; Di Domenico, Fabio ; Sutherland, Fraser W ; Nappi, Francesco

CONTEXTAdvanced Glycation End-Products (AGEs) are signaling proteins associated to several vascular and neurological complications in diabetic and non-diabetic patients. AGEs proved to be a marker of negative outcome in both diabetes management and surgical procedures in these patients. The reported role of AGEs prompted the development of pharmacological inhibitors of their effects, giving rise to a number of both preclinical and clinical studies. Clinical trials with anti-AGEs drugs have been gradually developed and this review aimed to summarize most relevant reports.EVIDENCE ACQUISITIONEvidence acquisition process was performed using PubMed and ClinicalTrials.gov with manually checked articles.RESULTSPharmacological approaches in humans include aminoguanidine, pyridoxamine, benfotiamine, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, statin, ALT-711 (alagebrium) and thiazolidinediones. The most recent promising anti-AGEs agents are statins, alagebrium and thiazolidinediones. The role of AGEs in disease and new compounds interfering with their effects are currently under investigation in preclinical settings and these newer anti-AGEs drugs would undergo clinical evaluation in the next years. Compounds with anti-AGEs activity but still not available for clinical scenarios are ALT-946, OPB-9195, tenilsetam, LR-90, TM2002, sRAGE and PEDF.CONCLUSIONSDespite most studies confirm the efficacy of these pharmacological approaches, other reports produced conflicting evidences; in almost any case, these drugs were well tolerated. At present, AGEs measurement has still not taken a precise role in clinical practice, but its relevance as a marker of disease has been widely shown; therefore, it is important for clinicians to understand the value of new cardiovascular risk factors. Findings from the current and future clinical trials may help in determining the role of AGEs and the benefits of anti-AGEs treatment in cardiovascular disease.

01 Aug 2009·Journal of HypertensionQ2 · MEDICINE

Methylglyoxal contributes to the development of insulin resistance and salt sensitivity in Sprague–Dawley rats

Q2 · MEDICINE

Article

Author: Hosoya, Takuma ; Mori, Takefumi ; Sun, Ying ; Nakayama, Masaaki ; Hu, Chunyan ; Yoneki, Yoshimi ; Ogawa, Susumu ; Jiang, Yue ; Miyata, Toshio ; Ito, Sadayoshi ; Osaki, Yusuke ; Kawamata, Akihiro ; Guo, Qi

OBJECTIVESMethylglyoxal, a metabolite of the glycolysis pathway, may play an important role in the development of diabetes and hypertension, but the exact mechanism has not been fully elucidated. The present study was designed to investigate whether methylglyoxal could directly induce insulin resistance and salt sensitivity in Sprague-Dawley rats.METHODSRats were allocated to four groups: control (normal drinking water), 1% methylglyoxal in drinking water, 1% methylglyoxal plus N-acetyl cysteine (NAC) (800 mg/kg per day), a methylglyoxal scavenger, or TM2002 (100 mg/kg per day), an advanced glycation endproducts (AGEs) inhibitor. After 4-week treatment insulin resistance was evaluated by an euglycemic hyperinsulinemic glucose clamp technique. In another set of rats, either a high-salt diet (4%) alone, standard rat chow with 1% methylglyoxal in drinking water or high-salt diet plus methylglyoxal was given for 4 weeks. Immunohistochemistry was performed to measure nitrotyrosine and methylglyoxal-induced AGEs, N-carboxyethyl-lysine (CEL) in the kidney.RESULTSFour-week treatment with NAC or TM2002 completely improved methylglyoxal-induced insulin resistance. Co-administration of methylglyoxal and high-salt diet significantly increased systolic blood pressure, urinary albumin excretion, urinary thiobarbituric acid-reactive substances excretion and the renal nitrotyrosine expression in the kidney (markers of oxidative stress) compared with methylglyoxal or high-salt diet alone. Renal CEL was significantly increased in methylglyoxal-treated rats compared with nonmethylglyoxal-treated rats.CONCLUSIONThese results indicate that methylglyoxal-induced insulin resistance and salt sensitivity at least in part by increasing oxidative stress and/or AGEs formation in Sprague-Dawley rats. The present study provides further evidence for methylglyoxal as one of the causative factors in the pathogenesis of insulin resistance and salt-sensitive hypertension.

01 Dec 2007·Brain ResearchQ4 · MEDICINE

A novel inhibitor of advanced glycation and endoplasmic reticulum stress reduces infarct volume in rat focal cerebral ischemia

Q4 · MEDICINE

Article

Author: Satoshi Ogawa ; Yuko Morita ; Yasuko Kitao ; Toshio Miyata ; Yuko Izuhara ; Charles van Ypersele de Strihou ; Shunya Takizawa ; Osamu Hori ; Shigeharu Takagi

We have developed a novel, non-toxic inhibitor of advanced glycation and oxidative stress, TM2002, devoid of effect on blood pressure. In transient focal ischemia, TM2002 significantly decreased infarct volume compared with vehicle (79.5+/-18.7 vs. 183.3+/-22.9 mm3, p<0.01). In permanent focal ischemia, TM2002 (2.79, 5.58, and 11.16 mg/kg twice a day) dose-dependently reduced infarct volume (242.1+/-32.3, 201.3+/-15.1, and 171.3+/-15.2 mm3, respectively), and improved neurological deficits. Reduction of infarct volume is demonstrable, provided that TM2002 was administered within 1.5 h after the occlusion. To unravel TM2002's mechanism of action, we examined its in vitro effect on endoplasmic reticulum (ER) stress, using aortic smooth muscle cells isolated from ORP 150(+/-) mice and F9 Herp null mutated cells. Cell death induced by ER stress (tunicamycin or hypoxia) was dose-dependently prevented by TM2002. In vivo immunohistochemical study demonstrated a significant reduction of ORP- and TUNEL-positive apoptotic cells, especially in the penumbra. Inhibition of advanced glycation and oxidative stress was confirmed by a significantly reduced number of cells positive for advanced glycation end products and heme oxygenase-1. TM2002 reduced the levels of protein carbonyl formation in ischemic caudate. The efficacy of TM2002 is equivalent to that of a known neuroprotective agent, NXY-059. In conclusion, TM2002 significantly ameliorates ischemic cerebral damage through reduction of ER stress, advanced glycation, and oxidative stress, independently of blood pressure lowering.

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Indication	Highest Phase	Country/Location	Organization	Date
Cardiovascular Diseases	Discovery	JP	Tokai University	-

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