Differential Modulation of Brainstem Phosphatidylinositol 3-Kinase/Akt and Extracellular Signal-Regulated Kinase 1/2 Signaling Underlies WIN55,212-2 Centrally Mediated Pressor Response in Conscious Rats

Abstract

Our recent study demonstrated that central cannabinoid receptor 1 (CB 1 R) activation caused dose-related pressor response in conscious rats, and reported studies implicated the brainstem phosphatidylinositol 3-kinase (PI3K)/Akt-extracellular signal-regulated kinase 1/2 (ERK1/2) pathway in blood pressure control. Therefore, in this study, we tested the hypothesis that the modulation of brainstem PI3K/Akt-ERK1/2 signaling plays a critical role in the central CB 1 Rmediated pressor response. In conscious freely moving rats, the pressor response elicited by intracisternal (i.c.)-(1-naphthalenyl) methanone mesylate salt (WIN55,212-2) (15 g) was associated with significant increases in ERK1/2 phosphorylation in the rostral ventrolateral medulla (RVLM) and the nucleus tractus solitarius (NTS). In contrast, Akt phosphorylation was significantly reduced in the same neuronal pools. Pretreatment with the selectiveattenuated the neurochemical responses elicited by central CB 1 R activation. Furthermore, pretreatment with the ERK/mitogenactivated protein kinase kinase inhibitor 2Ј-amino-3Ј-methoxyflavone (PD98059) (5 g i.c.) abrogated WIN55,212-2-evoked increases in blood pressure and neuronal ERK1/2 phosphorylation but not the reduction in Akt phosphorylation. On the other hand, prior PI3K inhibition with wortmannin (0.4 g i.c.) exacerbated the WIN55,212-2 (7.5 and 15 g i.c.) dose-related increases in blood pressure and ERK1/2 phosphorylation in the RVLM. The present neurochemical and integrative studies yield new insight into the critical role of two brainstem kinases, PI3K and ERK1/2, in the pressor response elicited by central CB 1 R activation in conscious rats.

A pivotal role for enhanced brainstem Orexin receptor 1 signaling in the central cannabinoid receptor 1-mediated pressor response in conscious rats

“…This time interval coincided with the peak of WIN55,212-2-evoked pressor response as shown in Fig. 4 and in our previous studies (Ibrahim and Abdel-Rahman, 2012a, 2012b). To gain direct evidence that the activation of RVLM CB 1 R increases local orexin-A level, we measured orexin-A in microinjected and contralateral (control) RVLM tissues collected at the end of the second part of Section 2.3 above.…”

“…A total of 17 rats, divided into 4 groups ( n =3–5 each), were used for the measurement of RVLM orexin-A level in treatment and control groups according to the protocol followed in the first part of Section 2.3 above and in our previous studies (Ibrahim and Abdel-Rahman, 2012a, 2012b). Two groups received WIN55,212-2 (15 µg, i.c.)…”

“…In this study we tested the hypothesis that OX 1 R signaling is implicated in the enhancement of RVLM ERK1/2 and nNOS phosphorylation; the latter is an important neurochemical event in the central CB 1 R (WIN55,212-2)-evoked pressor response (Ibrahim and Abdel-Rahman, 2012a, 2012b). RVLM tissues collected at the conclusion of cardiovascular measurements in Section 2.3 were used for the measurement of the levels of phosphorylated ERK1/2 and nNOS (normalized to their respective total protein) in rats treated with WIN55,212-2 in the absence or presence ( n =5 each) of SB-408124 or vehicle ( n =4).…”

“…Our recent studies implicated the activation (phosphorylation) of the neuronal nitric oxide synthase (nNOS) and extracellular signal-regulated kinase1/2 (ERK1/2) in the central cannabinoid receptor 1 (CB 1 R)-evoked pressor response in conscious freely moving rats (Ibrahim and Abdel-Rahman, 2012a, 2012b). However, the exact mechanisms of such response remain unclear.…”

WIN 55,212-2 Inhibits the Epithelial Mesenchymal Transition of Gastric Cancer Cells via COX-2 Signals

“…It has been reported that WIN induces the activation of the PI3K/AKT signaling pathway in cancer cells [21]. We further wished to determine whether the PI3K/AKT signaling When exposed at the invasive front of a carcinoma, epithelial cells often acquire an enhanced migratory phenotype, which is defined as EMT.…”