Excitotoxic insults induce c-Jun N-terminal kinase (JNK) activation, which leads to neuronal death and contributes to many neurological conditions such as cerebral ischemia and neurodegenerative disorders. The action of JNK can be inhibited by the Dretro-inverso form of JNK inhibitor peptide (D-JNKI1), which totally prevents death induced by N-methyl-D-aspartate (NMDA) in vitro and strongly protects against different in vivo paradigms of excitotoxicity. To obtain optimal neuroprotection, it is imperative to elucidate the prosurvival action of D-JNKI1 and the death pathways that it inhibits. In cortical neuronal cultures, we first investigate the pathways by which NMDA induces JNK activation and show a rapid and selective phosphorylation of mitogen-activated protein kinase kinase 7 (MKK7), whereas the only other known JNK activator, mitogen-activated protein kinase kinase 4 (MKK4) In many nervous system disorders, including cerebral ischemia, traumatic brain injury and neurodegenerative diseases, overactivation of N-methyl-d-aspartate (NMDA) receptors leads to neuronal damage, resulting in neuronal loss and consequent severe neurological impairment. This cascade of neuronal injury, referred to as 'excitotoxicity', is still only partly understood. Dying neurons activate complex signal transduction events to trigger their death program, and the c-Jun N-terminal kinase (JNK) pathway plays an important role in this process. 1 D-retro-inverso form of JNK inhibitor (D-JNKI1) is an extremely potent neuroprotectant against excitotoxicity of cortical neurons and against different in vivo paradigms of neurodegeneration. [2][3][4] The active part of this peptide contains a retro-inverso form of a 20-amino-acid sequence (JBD 20 ) from the JNK-binding domain (JBD) of the scaffold protein JNK-interacting protein-1 (IB1/JIP-1), and it blocks the access of JNK to many of its targets. [5][6][7] Recently, Negri et al. 8,9 performed a detailed re-examination of the JBD-containing proteins and identified 19 different substrates of JNK. They then proved in a cell-free assay that the JBD 20 sequence prevented interactions and phosphorylations by JNK of nine of these targets. Among these nine substrates, we have studied the following four that might participate in regulating the death of cortical neurons: (1) MADD/DENN (MAPK-activating death domain-containing protein/differentially expressed in normal and neoplastic cells); (2-3) mitogen-activated protein kinase kinase 4 (MKK4) and mitogen-activated protein kinase kinase 7 (MKK7), the two direct upstream activators of JNK and (4) the scaffold protein IB1/JIP-1.,In particularly, MADD/DENN was identified as a substrate for JNK3, 10 the isoform most clearly involved in excitotoxicity 11,12 and mostly expressed in the brain. [10][11][12] Increasing evidence supports a strong correlation between low MADD/ DENN expression and neuronal loss. 13,14 MKK4 and MKK7 are the only known JNK activators. In some cell types, MKK4 activates JNK primarily by stress stimuli and MKK7 by inflammatory cytoki...
These results show that the differences in angiotensin II receptor blockade observed with the various AT(1) antagonists are explained mainly by differences in dosing. When 160-mg or 320-mg doses were investigated, the effects of valsartan hardly differed from those obtained with recommended doses of irbesartan and candesartan.
In vitro studies have shown that telmisartan is an insurmountable angiotensin II subtype-1 (AT1) receptor antagonist. Herein, the molecular basis of this insurmountable antagonism has been investigated in vitro, and the effect of telmisartan has been compared in vivo with that of irbesartan and candesartan. Association and dissociation kinetics of telmisartan to AT1 receptors have been characterized in vitro on rat vascular smooth muscle cells (RVSMC) expressing solely the AT1 receptor subtype. In a second set of experiments, the antagonistic efficacy of single intravenous doses (0.1, 0.3, and 1 mg/kg) of telmisartan was compared with that of irbesartan (0.3, 1.0, 3.0, and 10.0 mg/kg) and candesartan (0.3 and 1 mg/kg) in conscious, normotensive, male Wistar rats. The results show that the specific binding of [ 3 H]telmisartan to the surface of living RVSMC is saturable and increases quickly to reach equilibrium within 1 h. Telmisartan dissociates very slowly from the receptor with a dissociation half-life (t 1/2 ) of 75 min, which is comparable with candesartan and almost 5 times slower than angiotensin II (AngII). In vivo, telmisartan blunts the blood pressure response to exogenous AngII dose dependently. The blockade is long lasting and remains significant at 24 h at doses Ͼ0.1 mg/kg. Ex vivo assessment of the AT1 receptor blockade using an in vitro AngII receptor binding assay shows similar results. When administered intravenously in rats, telmisartan is 10-fold more potent than irbesartan and comparable to candesartan. Taken together, our in vitro data show that the insurmountable antagonism of telmisartan is due at least in part to its very slow dissociation from AT1 receptors.
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