1 This study aims to investigate whether or not long-term statin treatment causes upregulation of D 1 and D 2 receptor gene expression with concomitant increase in endothelial nitric oxide synthase (eNOS) expression in Sprague-Dawley rats. 2 Serum triglyceride levels were dose dependently reduced in the simvastatin-treated rats reaching statistical significance at the highest dose (49% reduction), while pravastatin caused similar effects (52%) at the same dose. Cholesterol levels remained unchanged in both groups at all doses. 3 Simvastatin, 10 or 30 mg kg À1 day À1 , increased D 1 and D 2 receptor expressions in the prefrontal cortex. Similar upregulation was observed neither with simvastatin in the striatum nor with pravastatin in both brain regions. 4 Simvastatin (10 mg kg À1 day À1 ) also increased eNOS expression in the prefrontal cortex but not neuronal NOS or inducible NOS. 5 D 1 receptor activation by chloro-APB (5 mM) increased cAMP levels in synaptosomes prepared from the prefrontal cortex of control and simvastatin-treated rats by 88 and 285%, respectively. This effect was markedly attenuated by the selective D 1 antagonist SCH-23390 (25 mM). 6 D 2 receptor activation by quinpirole (5 mM) had no effect on the basal cAMP levels in synaptosomes prepared from the prefrontal cortex of control and simvastatin-treated rats, while the same concentration of quinpirole completely abolished the D 1 receptor-mediated increase. 7 These results suggest that lipophilic statins can alter dopaminergic functions in the prefrontal cortex possibly via a central mechanism. The possibility of a nitric oxide mechanism involving eNOS requires further investigation.

1 It has been shown that activation of protein tyrosine kinases is the earliest detectable signalling response to FceRI cross-linking on mast cell. Following tyrosine kinase activation, a family of mitogenactivated protein kinases (MAPKs) was found to be activated as well. The present study examined the role of MAPK signalling cascade in in vitro model of allergic asthma using a speci®c MAPK kinase inhibitor PD 098059. 2 Guinea-pigs were passively sensitized with IgG antibody raised against ovalbumin (OA). E ects of PD 098059 on OA-induced anaphylactic contraction of isolated bronchi and release of histamine and peptidoleukotrienes from chopped lung preparations were studied. 3 PD 098059 (10 ± 50 mM) produced only minor reduction of maximal OA-induced bronchial contraction. In contrast, the rate of relaxation of OA-induced bronchial contraction was markedly faster in the presence of PD 098059 than the vehicle control in a concentration-dependent manner. 4 These observations corroborate well with the inability of PD 098059 (5 ± 50 mM) to substantially block the OA-induced release of histamine and with marked inhibition of OA-induced release of peptidoleukotrienes from lung fragments in the presence of PD 098059. Exogenous arachidonic acidinduced release of peptidoleukotrienes from lung fragments was not blocked by PD 098059. 5 In immunoblotting study, we found that p42 MAPK was constitutively expressed in guinea-pig bronchi. However, treatment with OA, histamine or LTD 4 did not cause activation of p42 MAPK . These ®ndings together with the lack of inhibitory e ects of PD 098059 on bronchial contraction induced by histamine or LTD 4 suggest that histamine-and LTD 4 -induced bronchial contractions are not mediated by p42 MAPK activation. 6 Taken together, our ®ndings show that inhibition of MAPK signalling cascade by PD 098059 signi®cantly reduced the OA-triggered release of peptidoleukotrienes leading to rapid relaxation of anaphylactic bronchial contraction. On the other hand, p42 MAPK did not play a role in histamine-or LTD 4 -induced bronchial smooth muscle contraction suggesting that PD 098059 exerts its inhibitory e ects on OA-induced bronchial contraction primarily through inhibition of peptidoleukotrienes release from mast cells.

No abstract