Sistemas neuromodulatórios: implicações fisiopatológicas / Neuromodulatory systems: patophysiologic implications

AUTOR(ES)
DATA DE PUBLICAÇÃO

2008

RESUMO

Adenosine has been shown to modulate cardiovascular control at the levels of the nucleus tractus solitarii (NTS). This study shows the distribution and density of adenosine A1 receptor within the nucleus tractus solitarii (NTS) of Wistar Kyoto (WKY) and spontaneously hypertensive (SHR) rats from birth to adulthood (1,15,30 and 90 day-old). [3H]DPCPX was used as a ligant for in vitro autoradiography. The NTS shows heterogeneous distribution of adenosine A1 receptor in dorsomedial/dorsolateral, subpostremal and medial/intermediate subnuclei. Adenosine A1 receptor decrease in dorsomedial/dorsolateral according to rostral-caudal levels of 15, 30 and 90 day-old WKY and SHR rats. On the other hand, those receptors increase in subpostremal according to rostral-caudal levels of 30 and 90 days old WKY, and of 15, 30 and 90 day-old SHR. Furthermore, adenosine A1 receptors are increased in SHR as compared with WKY in dorsomedial/dorsolateral of 30 and 90 day-old rats and in subpostremal of 15, 30 and 90 day-old rats. Surprisingly, even in 15 days old SHR rats when hypertension is not yet apparent, [3H]DPCPX values were increased. Finally, adenosine A1 receptors increase from 1 to 30 day-old rats. Medial/intermediate did not show any changes in adenosine A1 receptors according rostral-caudal levels, age or strain. In summary, our result highlights the importance of A1 adenosine system regarding the neural control of blood pressure and the development of hypertension. Adenosine is known to modulate neuronal activity within the nucleus tractus solitarii (NTS). The modulatory effect of adenosine A1 receptors on alpha2-adrenoceptors was evaluated by quantitative radioautography within NTS subnuclei and by neuronal culture using normotensive (WKY) and hypertensive (SHR) rats. Radioautography was used to perform saturation experiment in order to obtain alpha2-adrenoceptors binding parameters (Bmax, KD) in the presence of 3 concentrations of CPA, an adenosine A1 receptor agonist. Neuronal culture was performed to confirm radioautoraphic results. [3H]RX821002, an alpha2-adrenoceptor antagonist, was used as a ligand for both approaches. Dorsomedial/dorsolateral subnucleus of WKY showed an increase in Bmax values (21%) induced by 10nM of CPA. However, subpostremal subnucleus showed a decrease in KD, values (24%) induced by 10nM of CPA. SHR showed the same pattern of changes within the same nuclei as compared with WKY; however the modulatory effect of CPA was induced by 1nM (increased Bmax, 17%; decreased KD, 26%). Cell culture confirmed these results, since 10-[5M and 10[-7M of CPA promoted an increase in [[3[H]RX821002 binding of WKY (53%) and SHR cells (48%), respectively. DPCPX, an adenosine A1 receptor antagonist, was used to block the modulatory effect promoted by CPA on alpha2-adrenoceptors binding. In conclusion, our study show, for the first time, a specific cross talk between adenosine A1 receptors increasing the binding of alpha2-adrenoceptors within the NTS, which might be important to understand the complex autonomic response induced by adenosine within the NTS. In addition, changes in the interaction between receptors might be relevant to understand the development of hypertension. Adenosine acts at many sites to modulate neuronal activity. The nucleus tractus solitarii (NTS) is known as a major brain site in cardiovascular control. Previous studies from our group have shown the adenosine A1 receptors increase the binding of alpha2-adrenoceptors within the NTS, suggesting the important role of adenosine in cardiovascular control. The aim of the present study is to evaluate the intracellular signaling responsible for such process using brainstem cell culture of Wistar (WR) rats by means of binding assay. 8 different concentration of CPA (10[-4 to 10[-11), an A1 adenosine agonist, were used to modulate [[3[H]RX821002 binding, an alpha2-adrenoceptor antagonist. DPCPX, an A1 adenosine antagonist, was used to block the modulatory effect of CPA on [3VH]RX821002 binding. 10-5M of CPA promote an increase in [[3H]RX821002 binding. The intracellular cascade involved in such modulatory process were evaluated using different intracellular signaling molecules inhibitors and two queletors [SQ22536, an adenylyl cyclase (AC) inhibitor, U-73122, an phospholipase C (PLC) inhibitor, Xestospongin C, an IP3 receptor inhibitor, Ro318220, an protein kinase calcium dependent (PKC), BAPTA, an intracellular calcium quelator, EGTA, an extracelular calcium quelator]. U-73122, Xestospongin C, Ro3326 and BAPTA were capable to inhibit the effect promoted by adenosine A1 receptor on [3H]RX821002 binding suggesting a modulation PLC, PKC, IP3 and Ca2+ dependent pathway. In conclusion, our study show, for the first time, that adenosine A1 receptor modulates the alpha2-adrenoceptors through a non-canonical phospholipase C dependent pathway. This result might be important to understand the adenosine role within the NTS in cardiovascular control. Tau inclusions are a prominent feature of many neurodegenerative diseases including Alzheimers disease. Their presence suggests a failure in Tau degradation. The components of a Tau protein triage system consisting of CHIP/Hsc70 and other chaperones and co-chaperones have begun to emerge. However, the site of triage and the master regulatory elements have not yet been described. We have discovered an elegant mechanism of Tau degradation involving the co-chaperone BAG-2. BAG-2 binds to CHIP inhibiting its activity as an ubiquitine ligase preventing Tau ubiquitination. Tau bound to the microtubule and recruits BAG-2 where it clears Tau through an ubiquitin-independent proteossoma 20S dependent pathway. BAG-2 acts on Tau at precisely the site where it undergoes phosphorylation-dependent binding to the microtubule, more importantly, where it becomes vulnerable to misfolding and aggregation. Under conditions of proteasomal 26S blockade, Tau undergoes caspase mediated degradation. BAG-2 represents a critical point in clearing Tau that is prone to assembling into filaments. The suppression of BAG-2 leads to increased phosphorilated tau in neurons and its over-expression decreases phosphorilated tau.

ASSUNTO(S)

adenosina bag-2 alzheimer adenosine hypertension neuromodulation hipertensão alzheimer neuromodulação bag-2

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