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several earlier studies, and that the AT1 blocker telmisartan inhibits the enhancing effect of AII on DA cell death. On the other hand, the protective effects of tel misartan have been inhibited by co administration on the PPAR g antagonist GW9662, which suggests that PPAR g activation is important for the neuroprotective effects PluriSln 1 of telmisartan to happen. This neuroprotective effect can be anticipated considering the fact that telmisartan has been shown to be a potent AT1 blocker and to penetrate the blood brain barrier to inhibit centrally mediated effects of AII. On the other hand, the mechanism responsible for this neuroprotection has not been clarified. A 1st possibility is the fact that the pharmaco logical PPAR g activating properties of ARBs will be the only mechanism involved within the neuroprotective effect.
Sev eral studies have shown PPAR g PluriSln 1 activating properties of candesartan and losartan, and that among ARBs, telmi sartan is definitely the most potent agonist of PPAR g. The present final results are consistent having a significant part of PPAR g activation because the data show that the protective effect of telmisartan was inhibited by co administration on the PPAR g antagonist GW9662. On the other hand, RGFP966 the present study shows that pharmacologi cal PPAR g activating properties of ARBs are not the only factor responsible for neuroprotection. the outcomes obtained with mice deficient in AT1 show that, indepen dently of any pharmacological effect of ARBs, AT1 inhi bition induces significant neuroprotection of DA neurons against RNA polymerase neurotoxins such as MPTP. In fact, the neuropro tective effect of telmisartan against MPTP did not seem larger than that previously observed with candesartan.
which features a significantly less potent AT1 independent PPAR g agonistic effect. this also suggests that there is absolutely no significant added effect of AT1 blockage and phar macological DBeQ PPAR g activating properties of ARBs. It is actually attainable that the present experimental design was not in a position to reveal any attainable added effect. On the other hand, it might be also connected to the PPAR g activating effect on the AT1 deletion observed within the present study. we observed that administration of GW9662 substantially enhanced the MPTP induced DA neuron death in AT1 deficient mice, which suggests that PPAR g activation plays a significant part within the neuroprotective effects of AT1 inhibition.
The results hence suggest that inhibition PluriSln 1 of AT1 with ARBs, and with telmisartan in distinct, results in activation of PPAR g by a double mechanism that entails a pharmacological AT1 independent PPAR g agonistic effect and also a direct effect on the blockage on the AT1 itself, which also induces PPAR g activation. An essential degree of crosstalk involving RAS and PPAR g has been recommended in several studies carried out in diverse tissues. It has been observed that remedy with AII inhibited PPAR g expression plus the anti inflammatory defense mechan isms within the artery wall. Furthermore, inhibition of ACE led to enhanced expression of PPAR g in adipose tissue and skeletal muscle cells. It has been sug gested that AII inhibits PPAR g activation by way of AT1 and enhances PPAR g activation by way of AT2 receptors. and that AT2 receptors may possibly acquire functional importance in the course of selective AT1 blockage by a redirection on the obtainable AII to the AT2 receptor.
Conversely, quite a few studies have recommended that PPAR g may possibly mod ulate RAS and AII signaling at multiple levels. PPAR g activators DBeQ have already been observed PluriSln 1 to induce down regulation of AT1 expression and ACE activity. and up regulation of AT2 receptors. Moreover, other studies have shown that PPAR g along with other PPARs may possibly inhibit NADPH oxidase activity along with other signaling pathways involved in AII induced oxidative anxiety and inflammation. This may possibly explain not simply the full inhibition on the neuro protective effect of telmisartan by the PPAR g antagonist GW9662, observed within the present study, but also the GW9662 induced inhibition on the neuroprotective effect of AT1 deletion within the AT1a null mice.
It is actually identified that AII, by way of the AT2 receptor, exerts actions directly DBeQ opposed to these mediated by AT1, therefore antag onizing quite a few on the effects on the latter. In AT1a null mice, AII may possibly act by way of AT2 receptors activat ing PPAR g and contribute to inhibition of inflammation and oxidative anxiety, which has been observed to pro mote longevity and inhibit progression of degenerative diseases in AT1 null mice. The present final results, which showed that the protective effects of AT1 inhibi tion have been blocked by the remedy together with the PPAR g antagonist GW9662, are consistent together with the latter findings. Inside the present study, we have also confirmed that the mechanism involved within the observed neuroprotection is equivalent to that observed in earlier studies on neuropro tective properties of ARBs. In earlier studies in animal models of PD, we have shown that inhibition of micro glial activation plays a significant part within the protective effects of ARBs against DA cell death induced by DA neurotox ins. The present final results, which suggest that each AT1 inhibition with telm